Exploring the Mechanism of Zhishi-Xiebai-Guizhi Decoction for the Treatment of Hypoxic Pulmonary Hypertension based on Network Pharmacology and Experimental Analyses


Cite item

Full Text

Abstract

Background:Hypoxic Pulmonary Hypertension (HPH), a prevalent disease in highland areas, is a crucial factor in various complex highland diseases with high mortality rates. Zhishi-Xiebai-Guizhi Decoction (ZXGD), traditional Chinese medicine with a long history of use in treating heart and lung diseases, lacks a clear understanding of its pharmacological mechanism.

Objective:This study aimed to investigate the pharmacological effects and mechanisms of ZXGD on HPH.

Methods:We conducted a network pharmacological prediction analysis and molecular docking to predict the effects, which were verified through in vivo experiments.

Results:Network pharmacological analysis revealed 51 active compounds of ZXGD and 701 corresponding target genes. Additionally, there are 2,116 targets for HPH, 311 drug-disease co-targets, and 17 core-targets. GO functional annotation analysis revealed that the core targets primarily participate in biological processes such as apoptosis and cellular response to hypoxia. Furthermore, KEGG pathway enrichment analysis demonstrated that the core targets are involved in several pathways, including the phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway and Hypoxia Inducible Factor 1 (HIF1) signaling pathway. In vivo experiments, the continuous administration of ZXGD demonstrated a significant improvement in pulmonary artery pressure, right heart function, pulmonary vascular remodeling, and pulmonary vascular fibrosis in HPH rats. Furthermore, ZXGD was found to inhibit the expression of PI3K, Akt, and HIF1α proteins in rat lung tissue.

Conclusion:In summary, this study confirmed the beneficial effects and mechanism of ZXGD on HPH through a combination of network pharmacology and in vivo experiments. These findings provided a new insight for further research on HPH in the field of traditional Chinese medicine.

About the authors

Pan Huang

, Qinghai University Medical College

Email: info@benthamscience.net

Yuxiang Wang

, Qinghai University Medical College

Email: info@benthamscience.net

Chuanchuan Liu

Hydatidosis Laboratory, Affiliated Hospital of Qinghai University

Email: info@benthamscience.net

Qingqing Zhang

, Qinghai University Medical College

Email: info@benthamscience.net

Yougang Ma

, Qinghai University Medical College

Email: info@benthamscience.net

Hong Liu

, Qinghai University Medical College

Email: info@benthamscience.net

Xiaobo Wang

, Qinghai University Medical College,

Email: info@benthamscience.net

Yating Wang

, Qinghai University Medical College,

Email: info@benthamscience.net

Minmin Wei

, Qinghai University Medical College

Email: info@benthamscience.net

Lan Ma

, Qinghai University Medical College,

Author for correspondence.
Email: info@benthamscience.net

References

  1. Swenson ER. Chronic mountain sickness evolving over time. Chest 2022; 161(5): 1136-7. doi: 10.1016/j.chest.2022.01.024 PMID: 35526884
  2. Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: A review. JAMA 2022; 327(14): 1379-91. doi: 10.1001/jama.2022.4402 PMID: 35412560
  3. Rosenkranz S, Gibbs JSR, Wachter R, De Marco T, Vonk-Noordegraaf A, Vachiéry JL. Left ventricular heart failure and pulmonary hypertension. Eur Heart J 2016; 37(12): 942-54. doi: 10.1093/eurheartj/ehv512 PMID: 26508169
  4. Pullamsetti SS, Mamazhakypov A, Weissmann N, Seeger W, Savai R. Hypoxia-inducible factor signaling in pulmonary hypertension. J Clin Invest 2020; 130(11): 5638-51. doi: 10.1172/JCI137558 PMID: 32881714
  5. Xu X-Q, Jing Z-C. High-altitude pulmonary hypertension. Eur Respir Rev 2009; 18(111): 13-7. doi: 10.1183/09059180.00011104 PMID: 20956117
  6. Padang R, Chandrashekar N, Indrabhinduwat M, et al. Aetiology and outcomes of severe right ventricular dysfunction. Eur Heart J 2020; 41(12): 1273-82. doi: 10.1093/eurheartj/ehaa037 PMID: 32047900
  7. Johnson S, Sommer N, Cox-Flaherty K, Weissmann N, Ventetuolo CE, Maron BA. Pulmonary hypertension: A contemporary review. Am J Respir Crit Care Med 2023; 208(5): 528-48. doi: 10.1164/rccm.202302-0327SO PMID: 37450768
  8. He M, Tao K, Xiang M, Sun J. Hpgd affects the progression of hypoxic pulmonary hypertension by regulating vascular remodeling. BMC Pulm Med 2023; 23(1): 116. doi: 10.1186/s12890-023-02401-y PMID: 37055764
  9. Benek O, Korabecny J, Soukup O. A perspective on multi-target drugs for Alzheimer’s disease. Trends Pharmacol Sci 2020; 41(7): 434-45. doi: 10.1016/j.tips.2020.04.008 PMID: 32448557
  10. Zhang JR, Ouyang X, Hou C, et al. Natural ingredients from Chinese materia medica for pulmonary hypertension. Chin J Nat Med 2021; 19(11): 801-14. doi: 10.1016/S1875-5364(21)60092-4 PMID: 34844719
  11. Xue Z, Li Y, Zhou M, et al. Traditional herbal medicine discovery for the treatment and prevention of pulmonary arterial hypertension. Front Pharmacol 2021; 12: 720873. doi: 10.3389/fphar.2021.720873 PMID: 34899290
  12. Liu Y, He X, Di Z, Du X. Study on the active constituents and molecular mechanism of Zhishi Xiebai Guizhi decoction in the treatment of CHD based on UPLC-UESI-Q exactive focus, gene expression profiling, network pharmacology, and experimental validation. ACS Omega 2022; 7(5): 3925-39. doi: 10.1021/acsomega.1c04491 PMID: 35155889
  13. Jianmei W, Ranran W, Tianyi Y, et al. Effect and mechanism of Gualou Xiebai decoction in preventing hypoxic pulmonary hypertension. Pharmacol Clin Chin Materia Medica 2023; 39: 8-15.
  14. Zhao L, Zhang H, Li N, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol 2023; 309: 116306. doi: 10.1016/j.jep.2023.116306 PMID: 36858276
  15. Zhang P, Zhang D, Zhou W, et al. Network pharmacology: Towards the artificial intelligence-based precision traditional Chinese medicine. Brief Bioinform 2023; 25(1): bbad518. doi: 10.1093/bib/bbad518 PMID: 38197310
  16. Ru J, Li P, Wang J, et al. 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
  17. Zhang W, Tian W, Wang Y, et al. Explore the mechanism and substance basis of Mahuang FuziXixin decoction for the treatment of lung cancer based on network pharmacology and molecular docking. Comput Biol Med 2022; 151(Pt A): 106293. doi: 10.1016/j.compbiomed.2022.106293
  18. Kim S. Getting the most out of PubChem for virtual screening. Expert Opin Drug Discov 2016; 11(9): 843-55. doi: 10.1080/17460441.2016.1216967 PMID: 27454129
  19. Tang B, Dong Y. Network pharmacology and bioinformatics analysis on the underlying mechanisms of baicalein against oral squamous cell carcinoma. J Gene Med 2023; 25(6): e3490. doi: 10.1002/jgm.3490 PMID: 36843559
  20. Hamosh A, Scott AF, Amberger J, Bocchini C, Valle D, McKusick VA. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2002; 30(1): 52-5. doi: 10.1093/nar/30.1.52 PMID: 11752252
  21. Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D. GeneCards: A novel functional genomics compendium with automated data mining and query reformulation support. Bioinformatics 1998; 14(8): 656-64. doi: 10.1093/bioinformatics/14.8.656 PMID: 9789091
  22. Zhang Z, Wang X, Wang S, Jia Z, Mao J. Network pharmacology and molecular docking analysis of shufeiya recipe in the treatment of pulmonary hypertension. BioMed Res Int 2022; 2022: 1-12. doi: 10.1155/2022/7864976 PMID: 36756383
  23. Tang D, Chen M, Huang X, et al. SRplot: A free online platform for data visualization and graphing. PLoS One 2023; 18(11): e0294236. doi: 10.1371/journal.pone.0294236 PMID: 37943830
  24. Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: Protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 2023; 51(D1): D638-46. doi: 10.1093/nar/gkac1000 PMID: 36370105
  25. Doncheva NT, Morris JH, Holze H, et al. Cytoscape stringApp 2.0: Analysis and visualization of heterogeneous biological networks. J Proteome Res 2023; 22(2): 637-46. doi: 10.1021/acs.jproteome.2c00651 PMID: 36512705
  26. Zhang L, Shi X, Huang Z, et al. Network pharmacology approach to uncover the mechanism governing the effect of radix achyranthis bidentatae on osteoarthritis. BMC Comple Med Therap 2020; 20(1): 121. doi: 10.1186/s12906-020-02909-4 PMID: 32316966
  27. Sherman BT, Hao M, Qiu J, et al. DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 2022; 50(W1): W216-21. doi: 10.1093/nar/gkac194 PMID: 35325185
  28. Kitchen DB, Decornez H, Furr JR, Bajorath J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat Rev Drug Discov 2004; 3(11): 935-49. doi: 10.1038/nrd1549 PMID: 15520816
  29. Berman HM, Westbrook J, Feng Z, et al. The protein data bank. Nucleic Acids Res 2000; 28(1): 235-42. doi: 10.1093/nar/28.1.235 PMID: 10592235
  30. Arcon JP, Modenutti CP, Avendaño D, et al. AutoDock Bias: Improving binding mode prediction and virtual screening using known protein–ligand interactions. Bioinformatics 2019; 35(19): 3836-8. doi: 10.1093/bioinformatics/btz152 PMID: 30825370
  31. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31(2): 455-61. doi: 10.1002/jcc.21334 PMID: 19499576
  32. Li J, Miao B, Wang S, et al. Hiplot: A comprehensive and easy- to-use web service for boosting publication-ready biomedical data visualization. Brief Bioinform 2022; 23(4): bbac261. doi: 10.1093/bib/bbac261 PMID: 35788820
  33. Yuan S, Chan HCS, Filipek S, Vogel H. PyMOL and inkscape bridge the data and the data visualization. Structure 2016; 24(12): 2041-2. doi: 10.1016/j.str.2016.11.012 PMID: 27926832
  34. Laskowski RA, Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51(10): 2778-86. doi: 10.1021/ci200227u PMID: 21919503
  35. Chen J, Sun S, Zhou Q. Direct and model-free detection of carbohydrate excipients in traditional Chinese medicine formula granules by ATR-FTIR microspectroscopic imaging. Anal Bioanal Chem 2017; 409(11): 2893-904. doi: 10.1007/s00216-017-0234-9 PMID: 28188353
  36. Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res 2018; 79(8): 373-82. doi: 10.1002/ddr.21461 PMID: 30343496
  37. Wu Z, Zhu L, Nie X, Wei L, Qi Y. USP15 promotes pulmonary vascular remodeling in pulmonary hypertension in a YAP1/TAZ-dependent manner. Exp Mol Med 2023; 55(1): 183-95. doi: 10.1038/s12276-022-00920-y PMID: 36635430
  38. Ogden BE, Pang William W, Agui T, Lee BH. Laboratory Animal Laws, Regulations, Guidelines and Standards in China Mainland, Japan, and Korea. ILAR J 2016; 57(3): 301-11. doi: 10.1093/ilar/ilw018 PMID: 29117401
  39. Umar S, Iorga A, Matori H, et al. Estrogen rescues preexisting severe pulmonary hypertension in rats. Am J Respir Crit Care Med 2011; 184(6): 715-23. doi: 10.1164/rccm.201101-0078OC PMID: 21700911
  40. Abdulkareem AO, Tiwari P, Lone ZR, et al. Ormeloxifene, a selective estrogen receptor modulator, protects against pulmonary hypertension. Eur J Pharmacol 2023; 943: 175558. doi: 10.1016/j.ejphar.2023.175558 PMID: 36731722
  41. Liu H, Wang Y, Zhang Q, et al. Macrophage-derived inflammation promotes pulmonary vascular remodeling in hypoxia-induced pulmonary arterial hypertension mice. Immunol Lett 2023; 263: 113-22. doi: 10.1016/j.imlet.2023.10.005 PMID: 37875238
  42. Krompa A, Marino P. Diagnosis and management of pulmonary hypertension related to chronic respiratory disease. Breathe 2022; 18(4): 220205. doi: 10.1183/20734735.0205-2022 PMID: 36865930
  43. Vanderpool RR, Gorelova A, Ma Y, et al. Reversal of right ventricular hypertrophy and dysfunction by prostacyclin in a rat model of severe pulmonary arterial hypertension. Int J Mol Sci 2022; 23(10): 5426. doi: 10.3390/ijms23105426 PMID: 35628236
  44. Mandras SA, Mehta HS, Vaidya A. Pulmonary hypertension: A brief guide for clinicians. Mayo Clin Proc 2020; 95(9): 1978-88. doi: 10.1016/j.mayocp.2020.04.039 PMID: 32861339
  45. Yang L, Tian J, Wang J, et al. The protective role of EP300 in monocrotaline-induced pulmonary hypertension. Front Cardiovasc Med 2023; 10: 1037217. doi: 10.3389/fcvm.2023.1037217 PMID: 36910531
  46. Ferrara F, Zhou X, Gargani L, et al. Echocardiography in pulmonary arterial hypertension. Curr Cardiol Rep 2019; 21(4): 22. doi: 10.1007/s11886-019-1109-9 PMID: 30828743
  47. Labrada L, Vaidy A, Vaidya A. Right ventricular assessment in pulmonary hypertension. Curr Opin Pulm Med 2023; 29(5): 348-54. doi: 10.1097/MCP.0000000000000980 PMID: 37410491
  48. Liu Y, Tang BL, Lu ML, Wang HX. Astragaloside IV improves pulmonary arterial hypertension by increasing the expression of CCN1 and activating the ERK1/2 pathway. J Cell Mol Med 2023; 27(5): 622-33. doi: 10.1111/jcmm.17681 PMID: 36762748
  49. Pei J, Cai L, Wang F, et al. LPA2 contributes to vascular endothelium homeostasis and cardiac remodeling after myocardial infarction. Circ Res 2022; 131(5): 388-403. doi: 10.1161/CIRCRESAHA.122.321036 PMID: 35920162
  50. Zuo W, Liu N, Zeng Y, et al. Luteolin ameliorates experimental pulmonary arterial hypertension via suppressing hippo-YAP/PI3K/AKT signaling pathway. Front Pharmacol 2021; 12: 663551. doi: 10.3389/fphar.2021.663551 PMID: 33935785
  51. Wang J, Zhang P, Zhang J, et al. Atractylenolide-1 targets FLT3 to regulate PI3K/AKT/HIF1-α pathway to inhibit osteogenic differentiation of human valve interstitial cells. Front Pharmacol 2022; 13: 899775. doi: 10.3389/fphar.2022.899775 PMID: 35571096
  52. Naeije R, Richter MJ, Rubin LJ. The physiological basis of pulmonary arterial hypertension. Eur Respir J 2022; 59(6): 2102334. doi: 10.1183/13993003.02334-2021 PMID: 34737219
  53. Deng H, Tian X, Sun H, Liu H, Lu M, Wang H. Calpain-1 mediates vascular remodelling and fibrosis via HIF-1α in hypoxia-induced pulmonary hypertension. J Cell Mol Med 2022; 26(10): 2819-30. doi: 10.1111/jcmm.17295 PMID: 35365973
  54. Tirpe AA, Gulei D, Ciortea SM, Crivii C, Berindan-Neagoe I. Hypoxia: Overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. Int J Mol Sci 2019; 20(24): 6140. doi: 10.3390/ijms20246140 PMID: 31817513
  55. Luks AM, Hackett PH. Medical conditions and high-altitude travel. N Engl J Med 2022; 386(4): 364-73. doi: 10.1056/NEJMra2104829 PMID: 35081281
  56. Pena E, El Alam S, Siques P, Brito J. Oxidative stress and diseases associated with high-altitude exposure. Antioxidants 2022; 11(2): 267. doi: 10.3390/antiox11020267 PMID: 35204150
  57. Gao L, Cao M, Li JQ, Qin XM, Fang J. Traditional Chinese medicine network pharmacology in cardiovascular precision medicine. Curr Pharm Des 2021; 27(26): 2925-33. doi: 10.2174/18734286MTExhNDUh4 PMID: 33183189
  58. Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT. Natural products in drug discovery: Advances and opportunities. Nat Rev Drug Discov 2021; 20(3): 200-16. doi: 10.1038/s41573-020-00114-z PMID: 33510482
  59. Hao P, Jiang F, Cheng J, Ma L, Zhang Y, Zhao Y. Traditional Chinese medicine for cardiovascular disease. J Am Coll Cardiol 2017; 69(24): 2952-66. doi: 10.1016/j.jacc.2017.04.041 PMID: 28619197
  60. Ahmed LA, Obaid AAZ, Zaki HF, Agha AM. Naringenin adds to the protective effect of l-arginine in monocrotaline-induced pulmonary hypertension in rats: Favorable modulation of oxidative stress, inflammation and nitric oxide. Eur J Pharm Sci 2014; 62: 161-70. doi: 10.1016/j.ejps.2014.05.011 PMID: 24878387
  61. Liu Y, Xu XH, Liu Z, et al. Effects of the natural flavone trimethylapigenin on cardiac potassium currents. Biochem Pharmacol 2012; 84(4): 498-506. doi: 10.1016/j.bcp.2012.05.002 PMID: 22583923
  62. Shao D, Liu X, Wu J, et al. Identification of the active compounds and functional mechanisms of Jinshui Huanxian formula in pulmonary fibrosis by integrating serum pharmacochemistry with network pharmacology. Phytomedicine 2022; 102: 154177. doi: 10.1016/j.phymed.2022.154177 PMID: 35636171
  63. Han Jie L, Jantan I, Yusoff SD, Jalil J, Husain K. Sinensetin: An insight on its pharmacological activities, mechanisms of action and toxicity. Front Pharmacol 2021; 11: 553404. doi: 10.3389/fphar.2020.553404 PMID: 33628166
  64. An P, Wan S, Luo Y, et al. Micronutrient supplementation to reduce cardiovascular risk. J Am Coll Cardiol 2022; 80(24): 2269-85. doi: 10.1016/j.jacc.2022.09.048 PMID: 36480969
  65. Zhou DC, Zheng G, Jia LY, et al. Comprehensive evaluation on anti-inflammatory and anti-angiogenic activities in vitro of fourteen flavonoids from Daphne Genkwa based on the combination of efficacy coefficient method and principal component analysis. J Ethnopharmacol 2021; 268: 113683. doi: 10.1016/j.jep.2020.113683 PMID: 33301910
  66. Mitra R, Nersesyan A, Pentland K, Melin MM, Levy RM, Ebong EE. Diosmin and its glycocalyx restorative and anti-inflammatory effects on injured blood vessels. FASEB J 2022; 36(12): e22630. doi: 10.1096/fj.202200053RR PMID: 36315163
  67. Alamri A, Burzangi A, Coats P, Watson D. Untargeted metabolic profiling cell-based approach of pulmonary artery smooth muscle cells in response to high glucose and the effect of the antioxidant vitamins D and E. Metabolites 2018; 8(4): 87. doi: 10.3390/metabo8040087 PMID: 30513640
  68. Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer 2023; 22(1): 138. doi: 10.1186/s12943-023-01827-6 PMID: 37596643
  69. Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 2011; 4: 51. doi: 10.3389/fnmol.2011.00051 PMID: 22144946
  70. Waypa GB, Schumacker PT. Roles of HIF1 and HIF2 in pulmonary hypertension: It all depends on the context. Eur Respir J 2019; 54(6): 1901929. doi: 10.1183/13993003.01929-2019 PMID: 31831673
  71. Lee SH, Golinska M, Griffiths JR. HIF-1-independent mechanisms regulating metabolic adaptation in hypoxic cancer cells. Cells 2021; 10(9): 2371. doi: 10.3390/cells10092371 PMID: 34572020
  72. Ren M, Liu H, Jiang W, et al. Melatonin repairs osteoporotic bone defects in iron-overloaded rats through PI3K/AKT/GSK-3β/P70S6k signaling pathway. Oxid Med Cell Longev 2023; 2023: 1-14. doi: 10.1155/2023/7718155 PMID: 36703914
  73. Mazurakova A, Koklesova L, Csizmár SH, et al. Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells - A potential contribution to the predictive, preventive, and personalized medicine. J Adv Res 2024; 55: 103-18. doi: 10.1016/j.jare.2023.02.015 PMID: 36871616
  74. Kilic-Eren M, Boylu T, Tabor V. Targeting PI3K/Akt represses Hypoxia inducible factor-1α activation and sensitizes Rhabdomyosarcoma and Ewing’s sarcoma cells for apoptosis. Cancer Cell Int 2013; 13(1): 36. doi: 10.1186/1475-2867-13-36 PMID: 23305405
  75. Fu M, Luo F, Wang E, et al. Magnolol attenuates right ventricular hypertrophy and fibrosis in hypoxia-induced pulmonary arterial hypertensive rats through inhibition of the JAK2/STAT3 signaling pathway. Front Pharmacol 2021; 12: 755077. doi: 10.3389/fphar.2021.755077 PMID: 34764873
  76. Song K, Duan Q, Ren J, et al. Targeted metabolomics combined with network pharmacology to reveal the protective role of luteolin in pulmonary arterial hypertension. Food Funct 2022; 13(20): 10695-709. doi: 10.1039/D2FO01424F PMID: 36172851

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers