Objective To explore the molecular mechanism of the therapeutic effect of Tibetan medicine Caragana jubabt Poir on high altitude polycythemia (HAPC) based on network pharmacology and molecular docking.
Methods The active ingredients of Caragana jubabt Poir were identified through literature review. The SwissTargetPrediction database was used to predict its potential targets. The OMIM and GeneCards databases were used to screen for HAPC targets. The drug action targets and disease targets were intersected to construct a protein-protein interaction network. The DAVID database was used for gene function and pathway enrichment analysis, and AutoDock software was used to perform molecular docking on key active ingredients and core targets, in order to screen out potential targets of action and related signaling pathways for the active ingredients of Caragana jubabt Poir.
Results There were 25 effective active ingredients of Caragana jubabt Poir, with 401 corresponding targets. The top 8 components with the higher connectivity were 7, 3', 4'-Trihgdroxy flavone, Geraldone, Quercetin, biochanin A, lsorhamnetin, 7, 4'-Dihydroxyflavone, Formononetin, Afrormosin. 261 HAPC targets were obtained and there was a total of 41 intersection targets between drug components and HAPC, the core targets including VEGFA, AKT1, TNF, HAP90AA1, ESR1, MMP9, ACE, F2, CYP3A4, REN; Biological process (BP), celluar components (CC), molecular function (MF) were mainly related with response to hypoxia, positive regulation of protein phorylation, cell surface, macromolecular complex, steroid binding, enzyme binding. The key signaling pathways mainly involved Pathways in cancer, Chemical carcinogenesis-receptor activation, Fluid shear stress and atherosclerosis, etc. The molecular docking results showed that the 8 main active ingredients had good binding with ACE and CYP3A4, and the binding energies were all less than -8.5 kcal·mol-1.
Conclusion The active ingredients of Caragana jubabt Poir could act on multiple targets through multiple pathways to treat HAPC, which provides a certain scientific basis for its clinical application.
1.帝玛尔·丹增彭措. 晶珠本草[M]. 上海: 上海科学技术出版社, 1986: 73. [Dimar Tenzin Pengcuo. Jing Zhu Materia Medica[M]. Shanghai: Shanghai Scientific and Technical Publishers, 1986: 73.]
2.巴桑德吉, 索朗. 藏药佐木阿汤散制剂的研究进展[J]. 西藏科技, 2018, (6): 53-55. [Pasong Dekyi, Sonam. Progress of research on the preparation of Tibetan medicine Zomuatang San[J]. Tibet's Science & Technology, 2018, (6): 53-55.] DOI: 10.3969/j.issn.1004-3403.2018.06.016.
3.四川少数民族古迹文献整理组及德格藏医院. 米旁临床集萃[M]. 成都: 四川人民出版社, 1977: 543. [Sichuan Minority Monuments Documentation Group and Dege Tibetan Hospital. Mepan Clinical Collections[M]. Chengdu: Sichuan People's Publishing House, 1977: 543.]
4.宋萍, 马欢, 田娅. 藏药鬼箭锦鸡儿化学成分及药理作用的研究进展[J]. 中国药物与临床, 2009, 9(12): 1149-1151. [Song P, Ma H, Tian Y. New research advances on chemical components and pharmarcological acteions of Caragana jubocta(Pall.) Poir[J]. Chinese Remedies & Clinics, 2009, 9(12): 1149-1151.] DOI: 10.3969/j.issn.1671-2560.2009.12.001.
5.贺春荣, 郭丽娜, 张怡, 等. 鬼箭锦鸡儿抗血栓活性部位筛选[J]. 中国中药杂志, 2016, 41(13): 2473-2480. [He CR, Guo LN, Zhang Y, et al. Screening of active fractions with antithrombotic effect from Caragana jubata[J]. China Journal of Chinese Materia Medica, 2016, 41(13): 2473-2480.] DOI: 10.4268/cjcmm20161317.
6.贺春荣. 鬼箭锦鸡儿的抗血栓作用研究[D]. 天津: 天津大学, 2016. [He CR. Study on the antithrombotic effects of Caragana jubata (Pall.) Poir[D]. Tianjin: Tianjin University, 2016.] DOI: 10.7666/d.D01192561.
7.Chen X, Li H, Tian L, et al. Analysis of the physicochemical properties of acaricides based on Lipinski's Rule of Five[J]. J Comput Biol, 2020, 27(9): 1397-1406. DOI: 10.1089/cmb.2019.0323.
8.汪秋林. 藏药藏锦鸡儿的分析方法及质量评价研究[D]. 天津: 天津大学, 2020. [Wang QL. Analytical methods and quality evaluation of Tibetan materia medica, Lignum Caraganae[D]. Tianjin: Tianjin University, 2020.] DOI: 10.27356/d.cnki.gtjdu.2020.002599.
9.宋萍, 田娅, 马欢. 藏药鬼箭锦鸡儿的开发应用研究 [J]. 北京中医药, 2010, 29(2): 128-130. [Song P, Tian Y, Ma H. Exploitation and application research of Tibetan medicine Caragana Jubata[J]. Beijing Journal of Traditional Chinese Medicine, 2010, 29(2): 128-130.] DOI: 10.16025/j.1674-1307.2010.02.001.
10.Wang L, Yang X, Zhang Y, et al. Anti-inflammatory chalcone-isoflavone dimers and chalcone dimers from Caragana jubata[J]. J Nat Prod, 2019, 82(10): 2761-2767. DOI: 10.1021/acs.jnatprod.9b00365.
11.宋萍, 李小娟, 贾岩岩. 鬼箭锦鸡儿化学成分的研究[J]. 中成药, 2011, 33(11): 1934-1936. [Song P, Li XJ, Jia YY. Chemical constituents of Caragana jubata (Pall.) Poir.[J]. Chinese Traditional Patent Medicine, 2011, 33(11): 1934-1936.] DOI: 10.3969/j.issn.1001-1528.2011.11.023.
12.Kakorin PA, Tereshkina OI, Ramenskaya GV. Potential biological activity and chemical composition of Caragana Jubata (Pall.) Poir. (Review)[J]. Pharm Chem J, 2018, 52(6): 531-535. DOI: 10.1007/s11094-018-1854-x.
13.杨新洲, 吕静南, 徐婵, 等. 鬼箭锦鸡儿细胞毒活性成分研究[J]. 云南大学学报(自然科学版), 2015, 37(1): 134-139. [Yang XZ, Lyu JN, Xu C, et al. Cytotoxic chemical constituents from Caragana jubata (pall) Poir[J]. Journal of Yunnan University (Natural Sciences Edition), 2015, 37(1): 134-139.] DOI: 10.7540/j.ynu.20120364.
14.Gong G, Guan YY, Zhang ZL, et al. Isorhamnetin: a review of pharmacological effects[J]. Biomed Pharmacother, 2020, 128: 110301. DOI: 10.1016/j.biopha.2020.110301.
15.Ren X, Han L, Li Y, et al. Isorhamnetin attenuates TNF-α-induced inflammation, proliferation, and migration in human bronchial epithelial cells via MAPK and NF-κB pathways[J]. Anat Rec (Hoboken), 2021, 304(4): 901-913. DOI: 10.1002/ar.24506.
16.Li WQ, Li J, Liu WX, et al. Isorhamnetin: a novel natural product beneficial for cardiovascular disease[J]. Curr Pharm Des, 2022, 28(31): 2569-2582. DOI: 10.2174/1381612828666220829113132.
17.Hosseini A, Razavi BM, Banach M, et al. Quercetin and metabolic syndrome: a review[J] Phytother Res, 2021, 35(10): 5352-5364. DOI: 10.1002/ptr.7144.
18.Popiolek-Kalisz J, Fornal E. The effects of quercetin supplementation on blood pressure- meta-analysis[J]. Curr Probl Cardiol, 2022, 47(11): 101350. DOI: 10.1016/j.cpcardiol.2022.101350.
19.Migkos T, Pourová J, Vopršalová M, et al. Biochanin A, the most potent of 16 isoflavones, induces relaxation of the coronary artery through the calcium channel and cGMP-dependent pathway[J]. Planta Med, 2020, 86(10): 708-716. DOI: 10.1055/a-1158-9422.
20.Machado Dutra J, Espitia PJP, Andrade Batista R. Formononetin: biological effects and uses-a review[J]. Food Chem, 2021, 359: 129975. DOI: 10.1016/j.foodchem.2021.129975.
21.Zhou Z, Zhou H, Zou X, et al. Formononetin regulates endothelial nitric oxide synthase to protect vascular endothelium in deep vein thrombosis rats[J]. Int J Immunopathol Pharmacol, 2022, 36: 3946320221111117. DOI: 10.1177/03946320221111117.
22.Wang X, Cao Y, Chen S, et al. Antioxidant and anti-inflammatory effects of 6, 3', 4'- and 7, 3', 4'-trihydroxyflavone on 2D and 3D RAW264.7 models[J]. Antioxidants (Basel), 2023, 12(1): 204. DOI: 10.3390/antiox12010204.
23.Katsman M, Azriel A, Horev G, et al. N-VEGF, the autoregulatory arm of VEGF-A[J]. Cells, 2022, 11(8): 1289. DOI: 10.3390/cells11081289.
24.Parkman GL, Turapov T, Kircher DA, et al. Genetic silencing of AKT induces melanoma cell death via mTOR suppression[J]. Mol Cancer Ther, 2024, 23(3): 301-315. DOI: 10.1158/1535-7163.MCT-23-0474.
25.Tosta BR, de Almeida IM, da Cruz Pena L, et al. MTOR gene variants are associated with severe COVID-19 outcomes: a multicenter study[J]. Int Immunopharmacol, 2023, 125(Pt B): 111155. DOI: 10.1016/j.intimp.2023. 111155.
26.Suzuki M, Takeshita K, Kitamura Y, et al. In vitro exposure to glucose alters the expression of phosphorylated proteins in platelets[J]. Biomedicines, 2023, 11(2): 543. DOI: 10.3390/biomedicines11020543.
27.Arejano GG, Hoffmann LV, Ferreira Wyse L, et al. Genetic polymorphisms in the angiotensin converting enzyme, actinin 3 and paraoxonase 1 genes in women with diabetes and hypertension[J]. Arch Endocrinol Metab, 2023, 68: e210204. DOI: 10.20945/2359-4292-2021-0204.
28.Reed JR, Guidry JJ, Eyer M, et al. The influence of lipid microdomain heterogeneity on protein-protein interactions: proteomic analysis of co-immunoprecipitated binding partners of P450 1A2 and P450 3A in rat liver microsomes[J]. Drug Metab Dispos, 2023, 51(9): 1196-1206. DOI: 10.1124/dmd.123.001287.
29.Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1)[J]. Mol Pharmacol, 2006, 70(5): 1469-1480. DOI: 10.1124/mol.106.027029.
30.Nair VB, Samuel CS, Separovic F, et al. Human relaxin-2:historical perspectives and role in cancer biology[J]. Amino Acids, 2012, 43(3): 1131-1140. DOI: 10.1007/s00726-012-1375-y.