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Clarifying the mechanism of apigenin against blood–brain barrier disruption in ischemic stroke using systems pharmacology

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Abstract

Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood–brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients’ death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.

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The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

Abbreviations

BBB:

Blood–brain barrier

BP:

Biological process

BDNF:

Brain-derived neurotrophic factor

CC:

Cellular component

COX:

Cyclooxygenase

DEGs:

Differentially expressed genes

GO:

Gene ontology

GDNF:

Glial cell-derived neurotrophic factor

HT:

Hemorrhagic transformation

iNOS:

Inducible nitric oxide synthase

IL-1β:

Interleukin-1β

IS:

Ischemic strokes

KEGG:

Kyoto encyclopedia genes genomes

MMPs:

Matrix metalloproteinases

MCAO:

Middle cerebral artery occlusion

MD:

Molecular dynamics

MF:

Molecular function

nNOS:

Neuronal nitric oxide synthase

NF-κB:

Nuclear factor-κB

OGD/R:

Oxygen–glucose deprivation/reoxygenation

PPI:

Protein–protein interaction

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

rtPA:

Recombinant tissue plasminogen activator

RMSF:

Root mean square fluctuation

RMSD:

Root-mean-square deviation

SOD:

Superoxide dismutase

TLR4:

Toll-like receptor 4

VEGF:

Vascular endothelial growth factor

TNF-α:

Tumor necrosis factor-α

References

  1. Carcel C, Woodward M, Wang X, Bushnell C, Sandset EC (2020) Sex matters in stroke: a review of recent evidence on the differences between women and men. Front Neuroendocrinol. https://doi.org/10.1016/j.yfrne.2020.100870

    Article  PubMed  Google Scholar 

  2. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang ALR, Cheng SS, Delling FN, Djousse L et al (2020) Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation 141:E139–E596. https://doi.org/10.1161/cir.0000000000000757

    Article  PubMed  Google Scholar 

  3. Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, Vivien D (2011) Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 10:471–480. https://doi.org/10.1016/s1474-4422(11)70066-7

    Article  CAS  PubMed  Google Scholar 

  4. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, Investigators E (2008) Thrombolysis with alteplase 3 to 45 hours after acute ischemic stroke. N Engl J Med 359:1317–1329. https://doi.org/10.1056/NEJMoa0804656

    Article  CAS  PubMed  Google Scholar 

  5. Kastrup A, Groschel K, Ringer TM, Redecker C, Cordesmeyer R, Witte OW, Terborg C (2008) Early disruption of the blood-brain barrier after thrombolytic therapy predicts hemorrhage in patients with acute stroke. Stroke 39:2385–2387. https://doi.org/10.1161/strokeaha.107.505420

    Article  CAS  PubMed  Google Scholar 

  6. Abdullahi W, Tripathi D, Ronaldson PT (2018) Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol 315:C343–C356. https://doi.org/10.1152/ajpcell.00095.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Okada T, Suzuki H, Travis ZD, Zhang JH (2020) The stroke-induced blood-brain barrier disruption: current progress of inspection technique mechanism, and therapeutic target. Curr Neuropharmacol 18:1187–1212. https://doi.org/10.2174/1570159x18666200528143301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Spronk E, Sykes G, Falcione S, Munsterman D, Joy T, Kamtchum-Tatuene J, Jickling GC (2021) Hemorrhagic transformation in ischemic stroke and the role of inflammation. Front Neurol. https://doi.org/10.3389/fneur.2021.661955

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sifat AE, Vaidya B, Abbruscato TJ (2017) Blood-brain barrier protection as a therapeutic strategy for acute ischemic stroke. AAPS J 19:957–972. https://doi.org/10.1208/s12248-017-0091-7

    Article  CAS  PubMed  Google Scholar 

  10. Li YC, Zhong W, Jiang Z, Tang XQ (2019) New progress in the approaches for blood-brain barrier protection in acute ischemic stroke. Brain Res Bull 144:46–57. https://doi.org/10.1016/j.brainresbull.2018.11.006

    Article  CAS  PubMed  Google Scholar 

  11. Chen HS, Qi SH, Shen JG (2017) One-compound-multi-target: combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol 15:134–156. https://doi.org/10.2174/1570159x14666160620102055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang MQ, Firrman J, Liu LS, Yam K (2019) A review on flavonoid apigenin: dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. Biomed Res Int. https://doi.org/10.1155/2019/7010467

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang S, Xu SK, Duan HF, Zhu ZH, Yang ZH, Cao JN, Zhao YX, Huang ZH, Wu QN, Duan J (2019) A novel, highly-water-soluble apigenin derivative provides neuroprotection following ischemia in male rats by regulating the ERK/Nrf2/HO-1 pathway. Eur J Pharmacol 855:208–215. https://doi.org/10.1016/j.ejphar.2019.03.024

    Article  CAS  PubMed  Google Scholar 

  14. Jiang J, Dai JC, Cui H (2018) Vitexin reverses the autophagy dysfunction to attenuate MCAO-induced cerebral ischemic stroke via mTOR/Ulk1 pathway. Biomed Pharmacother 99:583–590. https://doi.org/10.1016/j.biopha.2018.01.067

    Article  CAS  PubMed  Google Scholar 

  15. Wang JW, Wang SQ, Sun SS, Lu YY, Gao K, Guo C, Li RL, Li WW, Zhao X, Tang HF, Wen AD, Cai M, Zhang W (2020) Apigenin-7-O-beta-D-(-6 ’ ’-p-coumaroyl)-glucopyranoside treatment elicits a neuroprotective effect through GSK-3 beta phosphorylation-mediated Nrf2 activation. Aging-Us 12:23872–23888

    Article  CAS  Google Scholar 

  16. Liu C, Tu FX, Chen X (2008) Neuroprotective effect of apigenin on acute focal cerebral ischemia/reperfusion injury in rats. J Chin Med Mater 6:870–873. https://doi.org/10.13863/j.issn1001-4454.2008.06.029. (in chinese).

  17. Wang Y, Bo P, Zhang ZW et al (2014) Neuroprotective effect of apigenin on cerebral ischemia-reperfusion injury. Lishizhen Med Mater Med Res 25(12):3029–3030 ((in chinese))

    CAS  Google Scholar 

  18. Guo HZ, Kong SZ, Chen WM, Dai ZH, Lin TX, Su JY, Li SS, Xie QF, Su ZR, Xu Y, Lai XP (2014) Apigenin mediated protection of OGD-evoked neuron-like injury in differentiated PC12 cells. Neurochem Res 39:2197–2210. https://doi.org/10.1007/s11064-014-1421-0

    Article  CAS  PubMed  Google Scholar 

  19. Lopez-Lopez E, Bajorath J, Medina-Franco JL (2021) Informatics for chemistry, biology, and biomedical sciences. J Chem Inf Model 61:26–35. https://doi.org/10.1021/acs.jcim.0c01301

    Article  CAS  PubMed  Google Scholar 

  20. Wang X, Li J, Liu L, Kan J-M, Niu P, Yu Z-Q, Ma C, Dong F, Han M-X, Li J, Zhao D-X (2022) Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis. BMC Complement Med Therap 22:253. https://doi.org/10.1186/s12906-022-03732-9

    Article  CAS  Google Scholar 

  21. Safran M, Rosen N, Twik M, BarShir R, Stein TI, Dahary D, Fishilevich S, Lancet D (2021). In: Abugessaisa I, Kasukawa T (eds) Practical guide to life science databases. Springer Nature Singapore, Singapore, pp 27–56

    Chapter  Google Scholar 

  22. Thul PJ, Lindskog C (2018) The human protein atlas: a spatial map of the human proteome. Protein Sci 27:233–244. https://doi.org/10.1002/pro.3307

    Article  CAS  PubMed  Google Scholar 

  23. Ali F, Rahul, Naz F, Jyoti S, Siddique YH (2017) Health functionality of apigenin: a review. Int J Food Prop 20:1197–1238. https://doi.org/10.1080/10942912.2016.1207188

    Article  CAS  Google Scholar 

  24. Wang X, Li J, Zhao D et al (2022) Therapeutic and preventive effects of apigenin in cerebral ischemia: a review. Food Funct 13:11425–11437. https://doi.org/10.1039/d2fo02599j

    Article  CAS  PubMed  Google Scholar 

  25. Daina A, Michielin O, Zoete V (2019) Swiss target prediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 47:W357–W364. https://doi.org/10.1093/nar/gkz382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, Shoichet BK (2007) Relating protein pharmacology by ligand chemistry. Nat Biotechnol 25:197–206. https://doi.org/10.1038/nbt1284

    Article  CAS  PubMed  Google Scholar 

  27. Fang SS, Dong L, Liu L, Guo JC, Zhao LH, Zhang JY, Bu DC, Liu XK, Huo PP, Cao WC, Dong QY, Wu JR, Zeng XX, Wu Y, Zhao Y (2021) HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res 49:D1197–D1206. https://doi.org/10.1093/nar/gkaa1063

    Article  CAS  PubMed  Google Scholar 

  28. Wang X, Shen YH, Wang SW, Li SL, Zhang WL, Liu XF, Lai LH, Pei JF, Li HL (2017) PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res 45:W356–W360. https://doi.org/10.1093/nar/gkx374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu HY, Zhang YQ, Liu ZM, Chen T, Lv CY, Tang SH, Zhang XB, Zhang W, Li ZY, Zhou RR, Yang HJ, Wang XJ, Huang LQ (2019) ETCM: an encyclopaedia of traditional Chinese medicine. Nucleic Acids Res 47:D976–D982. https://doi.org/10.1093/nar/gky987

    Article  CAS  PubMed  Google Scholar 

  30. Gallo K, Goede A, Preissner R, Gohlke BO (2022) SuperPred 3.0: drug classification and target prediction-a machine learning approach. Nucleic Acids Res 50:W726–W731. https://doi.org/10.1093/nar/gkac297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, Jensen LJ, von Mering C (2021) The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 49:D605–D612. https://doi.org/10.1093/nar/gkaa1074

    Article  CAS  PubMed  Google Scholar 

  32. Ding SS, Chen QL, Huang YQ, Li XM, Chai YJ, Li CD, Asakawa T (2022) Exploring miRNA-related molecular targets of Erchen decoction against lipid metabolism disorder using a network pharmacologic approach. Comb Chem High Throughput Screening 25:986–997. https://doi.org/10.2174/1386207324666210302093300

    Article  CAS  Google Scholar 

  33. Doncheva NT, Morris JH, Gorodkin J, Jensen LJ (2019) Cytoscape StringApp: network analysis and visualization of proteomics data. J Proteome Res 18:623–632. https://doi.org/10.1021/acs.jproteome.8b00702

    Article  CAS  PubMed  Google Scholar 

  34. Zhou YY, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. https://doi.org/10.1038/s41467-019-09234-6

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zeng P, Su HF, Ye CY, Qiu SW, Tian Q (2021) Therapeutic mechanism and key alkaloids of uncaria rhynchophylla in Alzheimer’s disease from the perspective of pathophysiological processes. Front Pharmacol. https://doi.org/10.3389/fphar.2021.806984

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han LY, He JE, He SQ, Shoemaker BA, Wang JY, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44:D1202–D1213. https://doi.org/10.1093/nar/gkv951

    Article  CAS  PubMed  Google Scholar 

  37. Burley SK, Berman HM, Christie C, Duarte JM, Feng ZK, Westbrook J, Young J, Zardecki C (2018) RCSB Protein Data Bank: sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education. Protein Sci 27:316–330. https://doi.org/10.1002/pro.3331

    Article  CAS  PubMed  Google Scholar 

  38. Eberhardt J, Santos-Martins D, Tillack AF, Forli S (2021) AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings. J Chem Inf Model 61:3891–3898. https://doi.org/10.1021/acs.jcim.1c00203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang X, Zhao D-X, Kan J-M, Wang J, Chen X, Yu Z-Q, Zhao W-S, Han M-X, Li J (2022) Uncovering the mechanism of Chuanhong stroke capsule in the treatment of stroke based on network pharmacology and molecular docking technology. Nat Prod Commun. https://doi.org/10.1177/1934578X221075988

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, Wei S, Buckner J, Jeong JC, Qi YF, Jo S, Pande VS, Case DA, Brooks CL, MacKerell AD, Klauda JB, Im W (2016) CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput 12:405–413. https://doi.org/10.1021/acs.jctc.5b00935

    Article  CAS  PubMed  Google Scholar 

  41. Batista PR, Wilter A, Durham E, Pascutti PG (2006) Molecular dynamics simulations applied to the study of subtypes of HIV-1 protease common to Brazil Africa, and Asia. Cell Biochem Biophys 44:395–404. https://doi.org/10.1385/cbb:44:3:395

    Article  CAS  PubMed  Google Scholar 

  42. Kikugawa G, Nakano T, Ohara T (2015) Hydrodynamic consideration of the finite size effect on the self-diffusion coefficient in a periodic rectangular parallelepiped system. J Chem Phys. https://doi.org/10.1063/1.4926841

    Article  PubMed  Google Scholar 

  43. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935. https://doi.org/10.1063/1.445869

    Article  CAS  Google Scholar 

  44. Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11:3696–3713. https://doi.org/10.1021/acs.jctc.5b00255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) GROMACS: Fast, flexible, and free. J Comput Chem 26:1701–1718. https://doi.org/10.1002/jcc.20291

    Article  CAS  PubMed  Google Scholar 

  46. Lopez-Lopez E, Cerda-Garcia-Rojas CM, Medina-Franco JL (2020) Consensus virtual screening protocol towards the identification of small molecules interacting with the colchicine binding site of the tubulin-microtubule system. Mol Inf. https://doi.org/10.1002/minf.202200166

    Article  Google Scholar 

  47. Fischer A, Smieško M, Sellner M, Lill MJJOMC (2021) Decision making in structure-based drug discovery: visual inspection of docking results. J Med 64:2489–2500. https://doi.org/10.1021/acs.jmedchem.0c02227

    Article  CAS  Google Scholar 

  48. Luo ZH, Huang JW, Li EN, He XQ, Meng QQ, Huang XA, Shen XL, Yan CK (2022) An integrated pharmacology-based strategy to investigate the potential mechanism of xiebai san in treating pediatric pneumonia. Front Pharmacol. https://doi.org/10.3389/fphar.2022.784729

    Article  PubMed  PubMed Central  Google Scholar 

  49. Barr TL, Latour LL, Lee KY, Schaewe TJ, Luby M, Chang GS, El-Zammar Z, Alam S, Hallenbeck JM, Kidwell CS, Warach S (2010) Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 41:E123–E128. https://doi.org/10.1161/strokeaha.109.570515

    Article  CAS  PubMed  Google Scholar 

  50. Zhang S, An QE, Wang TF, Gao SP, Zhou GQ (2018) Autophagy- and MMP-2/9-mediated reduction and redistribution of ZO-1 contribute to hyperglycemia-increased blood-brain barrier permeability during early reperfusion in stroke. Neuroscience 377:126–137. https://doi.org/10.1016/j.neuroscience.2018.02.035

    Article  CAS  PubMed  Google Scholar 

  51. Yang Y, Estrada EY, Thompson JF, Liu WL, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709. https://doi.org/10.1038/sj.jcbfm.9600375

    Article  CAS  PubMed  Google Scholar 

  52. Candelario-Jalil E, Yang Y, Rosenberg GA (2009) Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158:983–994. https://doi.org/10.1016/j.neuroscience.2008.06.025

    Article  CAS  PubMed  Google Scholar 

  53. Lopez-Navarro ER, Gutierrez J (2022) Metalloproteinases and their inhibitors in neurological disease. Naunyn-Schmiedebergs Archiv Pharmacol 395:27–38. https://doi.org/10.1007/s00210-021-02188-x

    Article  CAS  Google Scholar 

  54. Zhao B, Yin QY, Fei YX, Zhu JP, Qiu YY, Fang WR, Li YM (2020) Research progress of mechanisms for tight junction damage on blood-brain barrier inflammation. Archiv Physiol Biochem. https://doi.org/10.1080/13813455.2020.1784952

    Article  Google Scholar 

  55. Lakhan SE, Kirchgessner A, Tepper D, Leonard A (2013) Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. https://doi.org/10.3389/fneur.2013.00032

    Article  PubMed  PubMed Central  Google Scholar 

  56. Banks W (2020) The blood-brain barrier interface in diabetes mellitus: dysfunctions mechanisms and approaches to treatment. Curr Pharm Des 26:1438–1447. https://doi.org/10.2174/1381612826666200325110014

    Article  CAS  PubMed  Google Scholar 

  57. Min JW, Kong WL, Han S, Bsoul N, Liu WH, He XH, Sanchez RM, Peng BW (2017) Vitexin protects against hypoxic-ischemic injury via inhibiting Ca2+/Calmodulin-dependent protein kinase II and apoptosis signaling in the neonatal mouse brain. Oncotarget 8:25513–25524

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chen XM, Chen HS, Xu MJ, Shen JG (2013) Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury. Acta Pharmacol Sin 34:67–77. https://doi.org/10.1038/aps.2012.82

    Article  CAS  PubMed  Google Scholar 

  59. Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho SH, Orio M, Iadecola C (2006) Prostaglandin E-2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12:225–229. https://doi.org/10.1038/nm1362

    Article  CAS  PubMed  Google Scholar 

  60. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424. https://doi.org/10.1152/physrev.00029.2006

    Article  CAS  PubMed  Google Scholar 

  61. Virag L, Szabo E, Gergely P, Szabo C (2003) Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 140:113–124. https://doi.org/10.1016/s0378-4274(02)00508-8

    Article  PubMed  Google Scholar 

  62. Kononets OM, Tkachenko OV, Kamenetska OO (2021) Cerebral hemispheres—cerebellum—kidney interaction in patients with acute cerebral ischemia. Med Perspect 26:90–98

    Google Scholar 

  63. Liu T, Zhou J, Cui HJ, Li PF, Li HG, Wang Y, Tang T (2018) Quantitative proteomic analysis of intracerebral hemorrhage in rats with a focus on brain energy metabolism. Brain Behavior. https://doi.org/10.1002/brb3.1130

    Article  PubMed  PubMed Central  Google Scholar 

  64. Li KN, Xian MH, Chen C, Liang SW, Chen L, Wang SM (2019) Proteomic assessment of iTRAQ-Based NaoMaiTong in the treatment of ischemic stroke in rats. Evid Complement Altern Med. https://doi.org/10.1155/2019/5107198

    Article  Google Scholar 

  65. Chen HS, Chen X, Li WT, Shen JG (2018) Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery. Acta Pharmacol Sin 39:669–682. https://doi.org/10.1038/aps.2018.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Huang QY, Zhong W, Hu ZP, Tang XQ (2018) A review of the role of cav-1 in neuropathology and neural recovery after ischemic stroke. J Neuroinflamm. https://doi.org/10.1186/s12974-018-1387-y

    Article  Google Scholar 

  67. Tu FX, Pang QY, Chen X, Huang TT, Liu MX, Zhai QX (2017) Angiogenic effects of apigenin on endothelial cells after hypoxia-reoxygenation via the caveolin-1 pathway. Int J Mol Med 40:1639–1648. https://doi.org/10.3892/ijmm.2017.3159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ha SK, Lee P, Park JA, Oh HR, Lee SY, Park JH, Lee EH, Ryu JH, Lee KR, Kim SY (2008) Apigenin inhibits the production of NO and PGE(2) in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal ischemia mice model. Neurochem Int 52:878–886. https://doi.org/10.1016/j.neuint.2007.10.005

    Article  CAS  PubMed  Google Scholar 

  69. Zhao SC, Ma LS, Chu ZH, Xu H, Wu WQ, Liu FD (2017) Regulation of microglial activation in stroke. Acta Pharmacol Sin 38:445–458. https://doi.org/10.1038/aps.2016.162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lee Y, Lee SR, Choi SS, Yeo HG, Chang KT, Lee HJ (2014) Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke. Biomed Res Int. https://doi.org/10.1155/2014/297241

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7:378–391. https://doi.org/10.1016/j.nurt.2010.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Stankovic ND, Teodorczyk M, Ploen R, Zipp F, Schmidt MHH (2016) Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol 131:347–363. https://doi.org/10.1007/s00401-015-1524-y

    Article  Google Scholar 

  73. Taylor RA, Sansing LH (2013) Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol. https://doi.org/10.1155/2013/746068

    Article  PubMed  PubMed Central  Google Scholar 

  74. Hu XM, Li PY, Guo YL, Wang HY, Leak RK, Chen SE, Gao YQ, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063-U3474. https://doi.org/10.1161/strokeaha.112.659656

    Article  CAS  PubMed  Google Scholar 

  75. Xue J, Yu Y, Zhang XJ, Zhang C, Zhao YA, Liu BY, Zhang L, Wang LN, Chen R, Gao X, Jiao P, Song GH, Jiang XC, Qin SC (2019) Sphingomyelin synthase 2 inhibition ameliorates cerebral ischemic reperfusion injury through reducing the recruitment of toll-like receptor 4 to lipid rafts. J Am Heart Assoc. https://doi.org/10.1161/jaha.119.012885

    Article  PubMed  PubMed Central  Google Scholar 

  76. Du HL, Wang SS (2020) Omarigliptin mitigates lipopolysaccharide-induced neuroinflammation and dysfunction of the integrity of the blood- brain barrier. ACS Chem Neurosci 11:4262–4269. https://doi.org/10.1021/acschemneuro.0c00537

    Article  CAS  PubMed  Google Scholar 

  77. Qin WW, Li J, Zhu RJ, Gao SH, Fan JF, Xia MR, Zhao RC, Zhang JW (2019) Melatonin protects blood-brain barrier integrity and perm-ability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-kappa B patnway. Aging-Us 11:11391–11415

    Article  CAS  Google Scholar 

  78. Zhang J, Buller BA, Zhang ZG, Zhang Y, Lu M, Rosene DL, Medalla M, Moore TL, Chopp M (2022) Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system. Exper Neurol. https://doi.org/10.1016/j.expneurol.2021.113895

    Article  Google Scholar 

  79. Zhang TT, Su JY, Guo BY, Wang KW, Li XM, Liang GB (2015) Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats. Int Immunopharmacol 28:79–87. https://doi.org/10.1016/j.intimp.2015.05.024

    Article  CAS  PubMed  Google Scholar 

  80. Li Y, Zhu ZY, Lu BW, Huang TT, Zhang YM, Zhou NY, Xuan W, Chen ZA, Wen DX, Yu WF, Li PY (2019) Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke. CNS Neurosci Ther 25:1343–1352. https://doi.org/10.1111/cns.13260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liu GJ, Zhang QR, Gao X, Wang H, Tao T, Gao YY, Zhou Y, Chen XX, Li W, Hang CH (2020) MiR-146a ameliorates hemoglobin-induced microglial inflammatory response via TLR4/IRAK1/TRAF6 associated pathways. Front Neurosci. https://doi.org/10.3389/fnins.2020.00311

    Article  PubMed  PubMed Central  Google Scholar 

  82. Han D, Li FY, Zhang HX, Ji C, Shu Q, Wang C, Ni HY, Zhu Y, Wang SL (2022) Mesencephalic astrocyte-derived neurotrophic factor restores blood-brain barrier integrity of aged mice after ischaemic stroke/reperfusion through anti-inflammation via TLR4/MyD88/NF-kappa B pathway. J Drug Target 30:430–441. https://doi.org/10.1080/1061186x.2021.2003803

    Article  CAS  PubMed  Google Scholar 

  83. Becerra-Calixto A, Cardona-Gomez GP (2017) The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci. https://doi.org/10.3389/fnmol.2017.00088

    Article  PubMed  PubMed Central  Google Scholar 

  84. Liu ZW, Chopp M (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103–120. https://doi.org/10.1016/j.pneurobio.2015.09.008

    Article  CAS  PubMed  Google Scholar 

  85. Han GY, Song LJ, Ding ZB, Wang Q, Yan YQ, Huang JJ, Ma CG (2022) The important double-edged role of astrocytes in neurovascular unit after ischemic stroke. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2022.833431

    Article  PubMed  PubMed Central  Google Scholar 

  86. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156. https://doi.org/10.1038/nrn1326

    Article  CAS  PubMed  Google Scholar 

  87. Tu FX, Pang QY, Huang TT, Zhao Y, Liu MX, Chen X (2017) Apigenin ameliorates post-stroke cognitive deficits in rats through histone acetylation-mediated neurochemical alterations. Med Sci Monit 23:4004–4013

    Article  PubMed  PubMed Central  Google Scholar 

  88. Li JY, Li C, Loreno EG, Miriyala S, Panchatcharam M, Lu XH, Sun H (2021) Chronic low-dose alcohol consumption promotes cerebral angiogenesis in mice. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2021.681627

    Article  PubMed  PubMed Central  Google Scholar 

  89. Li YN, Pan R, Qin XJ, Yang WL, Qi ZF, Liu WL, Liu KJ (2014) Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J Neurochem 129:120–129. https://doi.org/10.1111/jnc.12611

    Article  CAS  PubMed  Google Scholar 

  90. Ghori A, Prinz V, Nieminen-Kehla M, Bayerl SH, Kremenetskaia I, Riecke J, Krechel H, Broggini T, Scherschinski L, Licht T, Keshet E, Vajkoczy P (2022) Vascular endothelial growth factor augments the tolerance towards cerebral stroke by enhancing neurovascular repair mechanism. Transl Stroke Res. https://doi.org/10.1007/s12975-022-00991-z

    Article  PubMed  PubMed Central  Google Scholar 

  91. Park JC, Baik SH, Han SH, Cho HJ, Choi H, Kim HJ, Choi H, Lee W, Kim DK, Mook-Jung I (2017) Annexin A1 restores A beta(1–42)-induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway. Aging Cell 16:149–161. https://doi.org/10.1111/acel.12530

    Article  CAS  PubMed  Google Scholar 

  92. Feng S, Zou L, Wang HJ, He R, Liu K, Zhu HF (2018) RhoA/ROCK-2 pathway inhibition and tight junction protein upregulation by catalpol suppresses lipopolysaccaride-induced disruption of blood-brain barrier permeability. Molecules. https://doi.org/10.3390/molecules23092371

    Article  PubMed  PubMed Central  Google Scholar 

  93. Lu WZ, Chen ZW, Wen JY (2021) RhoA/ROCK signaling pathway and astrocytes in ischemic stroke. Metab Brain Dis 36:1101–1108. https://doi.org/10.1007/s11011-021-00709-4

    Article  CAS  PubMed  Google Scholar 

  94. Wang LX, Fan WY, Cai P, Fan MC, Zhu XM, Dai YQ, Sun CG, Cheng YN, Zheng P, Zhao BQ (2013) Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol 73:189–198. https://doi.org/10.1002/ana.23762

    Article  CAS  PubMed  Google Scholar 

  95. Yang B, Li WL, Satani N, Nghiem DM, Xi XP, Aronowski J, Savitz SI (2018) Protective effects of autologous bone marrow mononuclear cells after administering t-PA in an embolic stroke model. Transl Stroke Res 9:135–145. https://doi.org/10.1007/s12975-017-0563-1

    Article  PubMed  Google Scholar 

  96. Zhang S, Qi Y, Xu YW, Han X, Peng JY, Liu KX, Sun CK (2013) Protective effect of flavonoid-rich extract from Rosa laevigata Michx on cerebral ischemia-reperfusion injury through suppression of apoptosis and inflammation. Neurochem Int 63:522–532. https://doi.org/10.1016/j.neuint.2013.08.008

    Article  CAS  PubMed  Google Scholar 

  97. Li J, Lv H, Che YQ (2020) Upregulated microRNA-31 inhibits oxidative stress-induced neuronal injury through the JAK/STAT3 pathway by binding to PKD1 in mice with ischemic stroke. J Cell Physiol 235:2414–2428. https://doi.org/10.1002/jcp.29146

    Article  CAS  PubMed  Google Scholar 

  98. Wu XY, Liu SQ, Hu ZH, Zhu GS, Zheng GF, Wang GZ (2018) Enriched housing promotes post-stroke neurogenesis through calpain 1-STAT3/HIF-1 alpha/VEGF signaling. Brain Res Bull 139:133–143. https://doi.org/10.1016/j.brainresbull.2018.02.018

    Article  CAS  PubMed  Google Scholar 

  99. Cai M, Ma YL, Zhang W, Wang SQ, Wang Y, Tian L, Peng ZW, Wang HN, Tan QR (2016) Apigenin-7-O-beta-D-(-6’’-p-coumaroyl)-glucopyranoside treatment elicits neuroprotective effect against experimental ischemic stroke. Int J Biol Sci 12:42–52. https://doi.org/10.7150/ijbs.12275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ma GD, Pan ZR, Kong LL, Du GH (2021) Neuroinflammation in hemorrhagic transformation after tissue plasminogen activator thrombolysis: potential mechanisms, targets, therapeutic drugs and biomarkers. Int Immunopharmacol. https://doi.org/10.1016/j.intimp.2020.107216

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kouwenhoven M, Carlstrom C, Ozenci V, Link H (2001) Matrix metalloproteinase and cytokine profiles in monocytes over the course of stroke. J Clin Immunol 21:365–375. https://doi.org/10.1023/a:1012244820709

    Article  CAS  PubMed  Google Scholar 

  102. Lee WT, Tai SH, Lin YW, Wu TS, Lee EJ (2018) YC-1 reduces inflammatory responses by inhibiting nuclear factor-B translocation in mice subjected to transient focal cerebral ischemia. Mol Med Rep 18:2043–2051. https://doi.org/10.3892/mmr.2018.9178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gliem M, Schwaninger M, Jander S (2016) Protective features of peripheral monocytes/macrophages in stroke. BBA-Mol Basis Dis 1862:329–338. https://doi.org/10.1016/j.bbadis.2015.11.004

    Article  CAS  Google Scholar 

  104. Tsygan NV, Trashkov AP IV, Yakovleva LVA, Ryabtsev AV, Vasiliev AG, Churilov LP (2019) Autoimmunity in acute ischemic stroke and the role of blood-brain barrier: the dark side or the light one? Front Med 13(420):426. https://doi.org/10.1007/s11684-019-0688-6

    Article  Google Scholar 

  105. Suidan GL, Dickerson JW, Chen Y, McDole JR, Tripathi P, Pirko I, Seroogy KB, Johnson AJ (2010) CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions. J Immunol 184:1031–1040. https://doi.org/10.4049/jimmunol.0902773

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Jianming Zeng (University of Macau), and all the members of his bioinformatics team, biotrainee, for generously sharing their experience and codes. The Use of the biorstudio high performance computing cluster(https://biorstudio.cloud) at Biotrainee and the shanghai HS Biotech Co., Ltd for conducting the research reported in this paper,Dr. Qipeng Yan (Hunan Normal University) and Jia-Han Cai (Guangdong Pharmaceutical University) for their help in the molecular modeling and docking and analysis of the results.

Funding

This study was supported by the grants from the National Natural Science Foundation of China (Grant Number 82103892), the Science and Technology Development Bureau of Jilin Province (Grant Number 20220505042ZP), Health Commission of Jilin Province (Grant Number 2022GW016), China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention (Grant Number 2021-CKL-02), and Graduate Innovation Fund of Jilin University (Grant Number 101832022CX188).

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  1. Xu Wang, ZiQiao Yu and Fuxiang Dong have contributed equally to this work.

Authors and Affiliations

  1. College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, Jilin, China

    Xu Wang, ZiQiao Yu, Fuxiang Dong, Jinjian Li, Ping Niu, Qiyi Ta, JunMing Kan, Chunyu Ma, Moxuan Han, Junchao Yu & Dexi Zhao

  2. School of Public Health, Jilin University, Changchun, 130021, Jilin, China

    Xu Wang & Jinhua Li

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Contributions

XW participated in the study design, screened all publications, organized data extraction, and wrote the first draft of the paper. ZQY and FXD contributed to article writing and data analysis. XW, ZQY and FXD contributed equally to this study. JJL and QYT contributed to article writing. JCY, MXH and CYM were responsible for the figures and tables. JMK and PN contributed to software and data curation. DXZ and JHL initiated the study and contributed in supervising, writing and revising the paper. All authors contributed to the article and approved the submitted version.

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Correspondence to Dexi Zhao or Jinhua Li.

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Wang, X., Yu, Z., Dong, F. et al. Clarifying the mechanism of apigenin against blood–brain barrier disruption in ischemic stroke using systems pharmacology. Mol Divers 28, 609–630 (2024). https://doi.org/10.1007/s11030-023-10607-9

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