Identification of the Anti-Atherosclerotic Properties of Benzoinum through Integrative Network Pharmacology and Pharmacological Analyses

Li Zhang^{1, 2}, Yuqing Wang¹, Qili Lu¹, Fengying Ye¹, Qing Zhang^{3, 4}, Feifei Wang^{3, 4}, Shuyao Zhang^1, and Feng Wang^{3, 4,}

¹Department of Pharmacy, Guangzhou Red Cross Hospital of Jinan University, Guangzhou Guangdong, China

²Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China;Engineering & Technology Research Center for Chinese Materia Medica Quality of the Universities of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China

³Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China

⁴Engineering & Technology Research Center for Chinese Materia Medica Quality of the Universities of Guangdong Province, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China

Cite this paper:
Li Zhang, Yuqing Wang, Qili Lu, Fengying Ye, Qing Zhang, Feifei Wang, Shuyao Zhang and Feng Wang. Identification of the Anti-Atherosclerotic Properties of Benzoinum through Integrative Network Pharmacology and Pharmacological Analyses. Journal of Food and Nutrition Research. 2022; 10(11):748-761. doi: 10.12691/jfnr-10-11-2

Abstract

Benzoinum is a resin derived from Styrax tonkinensis bark that has long been used in clinical settings as a traditional Chinese medicine with cardioprotective properties. The mechanistic basis for these pharmacological properties, however, remains to be demarcated. We used a network pharmacology approach to characterise the mechanism of action that benzoinum used to treat AS. The PharmMapper database was used to find potential benzoin target proteins, and the TCMSP, CTD, TTD, GAD, drug Bank, and pharmGkb databases were used to identify AS-related target genes. Following assessments of pathway enrichment, the functional roles of these genes were discovered, allowing the creation of compound-target and target-pathway networks. HUVEC cells were then used to validate these predicted benzoinum-related mechanisms of action, revealing that an active derivative of this resin was able to modulate signaling activity in TNF-α-exposed HUVECs by regulating the caspase-9 and NF-κB signaling pathways. Overall, our predictive network pharmacology analyses and supporting data highlighted the potential mechanisms whereby benzoinum may exert cardiovascular activity in the context of AS.

Keywords:
network pharmacology atherosclerosis cell apoptosis inflammatory

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Khan, R., Spagnoli, V., Tardif, J. C. & L’Allier, P. L. Novel anti-inflammatory therapies for the treatment of atherosclerosis. Atherosclerosis 240, 497-509 (2015).
[2]	Zhou, P. et al. Attenuation of TNF-α-induced inflammatory injury in endothelial cells by ginsenoside Rb1 via inhibiting NF-κB, JNK and p38 signaling pathways. Front. Pharmacol. 8, 1-13 (2017).
[3]	Weber, C., Badimon, L., Mach, F. & van Der Vorst, E. P. C. Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future. Thromb. Haemost. 117, 1258-1264 (2017).
[4]	Zhang, F. et al. Biemamides A-E, Inhibitors of the TGF-β Pathway That Block the Epithelial to Mesenchymal Transition. Org. Lett. 20, 5529-5532 (2018).
[5]	Ren, H. et al. Selenium inhibits homocysteine-induced endothelial dysfunction and apoptosis via activation of AKT. Cell. Physiol. Biochem. 38, 871-882 (2016).
[6]	Bruikman, C. S., Stoekenbroek, R. M., Hovingh, G. K. & Kastelein, J. P. New Drugs for Atherosclerosis. Can. J. Cardiol. 33, 350-357 (2017).
[7]	Choi, E. S. et al. Ligustilide attenuates vascular inflammation and activates Nrf2/HO-1 induction and, NO synthesis in HUVECs. Phytomedicine 38, 12-23 (2018).
[8]	Fei-, W. Chemical Constituents of Benzoinum and Its Anti- tumor Activities in Vitro. 1-7 (2020).
[9]	Zhang, L. et al. Anti-inflammatory and anti-apoptotic effects of stybenpropol a on human umbilical vein endothelial cells. Int. J. Mol. Sci. 20, (2019).
[10]	Paralleloneurum, S. Trzy lignany / neolignany z żywicy benzoinowej. 2, 1000-1004 (2020).
[11]	Guo, W. et al. Integrating network pharmacology and pharmacological evaluation for deciphering the action mechanism of herbal formula Zuojin Pill in suppressing hepatocellular carcinoma. Front. Pharmacol. 10, 1-21 (2019).
[12]	Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44-57 (2009).
[13]	Smoot, M. E., Ono, K., Ruscheinski, J., Wang, P. & Ideker, T. Cytoscape 2. 8 : new features for data integration and network visualization. 27, 431-432 (2011).
[14]	Zhou, Y. qiang et al. Hyperoside Suppresses Lipopolysaccharide-induced Inflammation and Apoptosis in Human Umbilical Vein Endothelial Cells. Curr. Med. Sci. 38, 222-228 (2018).
[15]	Mason, R. P., Dawoud, H., Jacob, R. F., Sherratt, S. C. R. & Malinski, T. Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin. Biomed. Pharmacother. 103, 1231-1237 (2018).
[16]	Wu, S. et al. Potent anti-inflammatory effect of dioscin mediated by suppression of TNF-α-induced VCAM-1, ICAM-1 and EL expression via the NF-κB pathway. Biochimie 110, 62-72 (2015).
[17]	Guo, S. et al. Role of A20 in cIAP-2 protection against tumor necrosis factor α (TNF-α)-mediated apoptosis in endothelial cells. Int. J. Mol. Sci. 15, 3816-3833 (2014).
[18]	Galkina, E. & Ley, K. Vascular adhesion molecules in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27, 2292-2301 (2007).
[19]	Xu, T. et al. Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach. 2018, (2018).
[20]	Sun, L., Chen, S., Gao, H., Ren, L. & Song, G. Visfatin induces the apoptosis of endothelial progenitor cells via the induction of pro-inflammatory mediators through the NF-κB pathway. Int. J. Mol. Med. 40, 637-646 (2017).
[21]	Gwon, W. G. et al. Sargaquinoic Acid Inhibits TNF-α-Induced NF-κB Signaling, Thereby Contributing to Decreased Monocyte Adhesion to Human Umbilical Vein Endothelial Cells (HUVECs). J. Agric. Food Chem. 63, 9053-9061 (2015).
[22]	Wang, M., Wang, Q., Du, Y. & Zhang, X. Network Pharmacology-Based Strategy to Investigate Pharmacological Mechanisms of Qiaoshao Formula for Treatment of Premature Ejaculation. Evidence-based Complement. Altern. Med. 2020, 1-12 (2020).
[23]	González, D. et al. Caspase-3 and -9 are activated in human myeloid HL-60 cells by calcium signal. Mol. Cell. Biochem. 333, 151-157 (2010).
[24]	Chen, T. L. et al. Protective effects of isorhamnetin on apoptosis and inflammation in TNF-α-induced HUVECs injury. Int. J. Clin. Exp. Pathol. 8, 2311-2320 (2015).
[25]	Förstermann, U., Xia, N. & Li, H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res. 120, 713-735 (2017).
[26]	Förstermann, U. & Sessa, W. C. Nitric oxide synthases: Regulation and function. Eur. Heart J. 33, 829-837 (2012).
[27]	Wang F. et al. Neolignan and phenylpropanoid compounds fromthe resin of Styrax tonkinensis.J. Asian. Nat. Prod. Res.23, 1-8 (2021).
[28]	Xie Q. et al. Advances in studies on chemical constituents and pharmacological effects of benzoin. Chin. Med. Mat. 43, 243-248 (2020).
[29]	Wang Y. et al. Research progress of pharmacological action of benzoin.Asia-Pacific Traditional Medicine. 11, 3 (2015).