Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation

References

• Zhao D, Liu J, Wang M, et al. Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol. 2019;16:203–212.
   PubMed Web of Science ®Google Scholar
• Kobiyama K, Ley K. Atherosclerosis. Circ Res. 2018;123:1118–1120.
   PubMed Web of Science ®Google Scholar
• Xu S, Ilyas I, Little PJ, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev. 2021;73:924–967.
   PubMed Web of Science ®Google Scholar
• Gimbrone MA Jr., García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016;118:620–636.
   PubMed Web of Science ®Google Scholar
• Paone S, Baxter AA, Hulett MD, et al. Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis. Cell Mol Life Sci. 2019;76:1093–1106.
   PubMed Web of Science ®Google Scholar
• Wang C, Niimi M, Watanabe T, et al. Treatment of atherosclerosis by traditional Chinese medicine: questions and quandaries. Atherosclerosis. 2018;277:136–144.
   PubMed Web of Science ®Google Scholar
• Guo J, Chen W, Bao B, et al. Protective effect of berberine against LPS-induced endothelial cell injury via the JNK signaling pathway and autophagic mechanisms. Bioengineered. 2021;12:1324–1337.
   PubMed Web of Science ®Google Scholar
• Machado Dutra J, Espitia PJP, Andrade Batista R. Formononetin: biological effects and uses - A review. Food Chem. 2021;359:129975.
   PubMed Web of Science ®Google Scholar
• Li Z, Zeng G, Zheng X, et al. Neuroprotective effect of formononetin against TBI in rats via suppressing inflammatory reaction in cortical neurons. Biomed Pharmacother. 2018;106:349–354.
   PubMed Web of Science ®Google Scholar
• Cho IA, Kim TH, Lim H, et al. Formononetin antagonizes the interleukin-1β-induced catabolic effects through suppressing inflammation in primary rat chondrocytes. Inflammation. 2019;42:1426–1440.
   PubMed Web of Science ®Google Scholar
• Aladaileh SH, Hussein OE, Abukhalil MH. Formononetin upregulates Nrf2/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants (Basel). 2019;8:430.
   PubMedGoogle Scholar
• Wu D, Wu K, Zhu Q, et al. Formononetin administration ameliorates dextran sulfate sodium-induced acute colitis by inhibiting NLRP3 inflammasome signaling pathway. Mediators Inflamm. 2018;2018:3048532.
   PubMed Web of Science ®Google Scholar
• Sugimoto M, Ko R, Goshima H, et al. Formononetin attenuates H2O2-induced cell death through decreasing ROS level by PI3K/Akt-Nrf2-activated antioxidant gene expression and suppressing MAPK-regulated apoptosis in neuronal SH-SY5Y cells. Neurotoxicology. 2021;85:186–200.
   PubMed Web of Science ®Google Scholar
• Cheng Y, Xia Z, Han Y, et al. Plant natural product formononetin protects rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and reoxygenation via inhibiting ros formation and promoting GSK-3β phosphorylation. Oxid Med Cell Longev. 2016;2016:2060874.
   PubMed Web of Science ®Google Scholar
• Wang DS, Yan LY, Yang DZ, et al. Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway. Biochem Biophys Res Commun. 2020;525:759–766.
   PubMed Web of Science ®Google Scholar
• Wu J, Kong M, Lou Y, et al. Simultaneous activation of Erk1/2 and Akt signaling is critical for formononetin-induced promotion of endothelial function. Front Pharmacol. 2020;11:608518.
   PubMed Web of Science ®Google Scholar
• Ma C, Xia R, Yang S, et al. Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE(-/-) mice. Theranostics. 2020;10:1090–1106.
   PubMed Web of Science ®Google Scholar
• Liang C, Zhou A, Sui C, et al. The effect of formononetin on the proliferation and migration of human umbilical vein endothelial cells and its mechanism. Biomed Pharmacother. 2019;111:86–90.
   PubMed Web of Science ®Google Scholar
• Boezio B, Audouze K, Ducrot P, et al. Network-based approaches in pharmacology. Mol Inform. 2017;36:1700048.
   Web of Science ®Google Scholar
• Wang X, Wang ZY, Zheng JH, et al. TCM network pharmacology: a new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med. 2021;19:1–11.
   PubMed Web of Science ®Google Scholar
• Yao ZJ, Dong J, Che YJ, et al. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models. J Comput Aided Mol Des. 2016;30:413–424.
   PubMed Web of Science ®Google Scholar
• Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47:W357–W364.
   PubMed Web of Science ®Google Scholar
• Szklarczyk D, Santos A, von Mering C, et al. STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016;44:D380–D384.
   PubMed Web of Science ®Google Scholar
• Wang X, Shen Y, Wang S, et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45(W1):W356–W360.
   PubMed Web of Science ®Google Scholar
• Amberger JS, Bocchini CA, Schiettecatte F, et al. OMIM.org: online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015;43:D789–D98.
   PubMed Web of Science ®Google Scholar
• Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48:D845–D855.
   PubMed Web of Science ®Google Scholar
• Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46:D1074–D1082.
   PubMed Web of Science ®Google Scholar
• Safran M, Dalah I, Alexander J, et al. GeneCards Version 3: the human gene integrator. Database (Oxford). 2010;2010:baq020.
   PubMed Web of Science ®Google Scholar
• Ivanova EA, Myasoedova VA, Melnichenko AA, et al. Peroxisome Proliferator-Activated Receptor (PPAR) gamma agonists as therapeutic agents for cardiovascular disorders: focus on atherosclerosis. Curr Pharm Des. 2017;23:1119–1124.
   PubMed Web of Science ®Google Scholar
• Herrington W, Lacey B, Sherliker P, et al. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res. 2016;118:535–546.
   PubMed Web of Science ®Google Scholar
• Libby P, Buring JE, Badimon L, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5:56.
   PubMed Web of Science ®Google Scholar
• Little PJ, Askew CD, Xu S, et al. Endothelial dysfunction and cardiovascular disease: history and analysis of the clinical utility of the relationship. Biomedicines. 2021;9:699.
   PubMed Web of Science ®Google Scholar
• Li TT, Wang ZB, Li Y, et al. The mechanisms of traditional Chinese medicine underlying the prevention and treatment of atherosclerosis. Chin J Nat Med. 2019;17:401–412.
   PubMed Web of Science ®Google Scholar
• Luo TT, Lu Y, Yan SK, et al. Network pharmacology in Research of Chinese Medicine formula: methodology, application and prospective. Chin J Integr Med. 2020;26:72–80.
   PubMed Web of Science ®Google Scholar
• Liao L, Huang L, Wei X, et al. Bioinformatic and biochemical studies of formononetin against liver injure. Life Sci. 2021;272:119229.
   PubMed Web of Science ®Google Scholar
• Medina-Leyte DJ, Domínguez-Pérez M, Mercado I, et al. Use of human umbilical vein endothelial cells (HUVEC) as a model to study cardiovascular disease: a review. Appl Sci. 2020;10:938.
   Google Scholar
• Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm. 2013;2013:152786.
   PubMed Web of Science ®Google Scholar
• Haybar H, Shahrabi S, Rezaeeyan H, et al. Endothelial cells: from dysfunction mechanism to pharmacological effect in cardiovascular disease. Cardiovasc Toxicol. 2019;19:13–22.
   PubMed Web of Science ®Google Scholar
• Geovanini GR, Libby P. Atherosclerosis and inflammation: overview and updates. Clin Sci (Lond). 2018;132:1243–1252.
   PubMed Web of Science ®Google Scholar
• Kattoor AJ, Pothineni NVK, Palagiri D, et al. Oxidative stress in atherosclerosis. Curr Atheroscler Rep. 2017;19:42.
   PubMed Web of Science ®Google Scholar
• Choy JC, Granville DJ, Hunt DW, et al. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol. 2001;33:1673–1690.
   PubMed Web of Science ®Google Scholar
• Han L, Shen WJ, Bittner S, et al. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Future Cardiol. 2017;13:279–296.
   PubMed Web of Science ®Google Scholar
• Mukohda M, Stump M, Ketsawatsomkron P, et al. Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress. Am J Physiol Heart Circ Physiol. 2016;310:H39–48.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zhang C, Li H, et al. Down-regulation of vascular PPAR-γ contributes to endothelial dysfunction in high-fat diet-induced obese mice exposed to chronic intermittent hypoxia. Biochem Biophys Res Commun. 2017;492:243–248.
   PubMed Web of Science ®Google Scholar
• Jin H, Gebska MA, Blokhin IO, et al. Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol. 2015;35:838–844.
   PubMed Web of Science ®Google Scholar