On the Hypolipidemic Activity of Elicited Soybeans: Evidences Based on Computational Analysis

https://doi.org/10.22146/ijc.75777

Feri Eko Hermanto(1), Warsito Warsito(2), Muhaimin Rifa'i(3), Nashi Widodo(4*)

(1) Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia; Essential Oil Institute, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
(3) Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia; Biosystem Study Center, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
(4) Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia; Biosystem Study Center, Brawijaya University, Jl. Veteran, Malang 65145, East Java, Indonesia
(*) Corresponding Author

Abstract


Dietary intervention plays a significant role in regulating hyperlipidemia. Besides, elicited soybean has greater bioactive contents with numerous health benefits potential. However, there is no evidence of the hypolipidemic activity of elicited soybean. This study will explore the potential mechanism of hypolipidemic activity of bioactive compounds from elicited soybean through computational modeling. The phytocompounds from elicited soybean were identified by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS), then screened for potential toxicity and drug-likeness properties. Compounds with low potential toxicity and excellent drug-likeness properties were screened for hypolipidemic activity against 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) and Peroxisome Proliferator Activator Receptor-gamma (PPAR-γ) through molecular docking coupled with molecular dynamics. The result showed that phytocompounds from the isoflavonoid group have an excellent affinity to bind with the HMGCR and PPAR-γ. Daidzein, Genistein, and Glycitein interacted with the catalytic residues of HMGCR to act as potential inhibitors with great affinity and stability. Genistein and Glycitein showed strong affinity and stability during their interaction with the agonistic sites of PPAR-γ. Further, the protein network described that targeting HMGCR inhibitor and PPAR-γ had the advantage in orchestrating cholesterol metabolism homeostasis. In summary, isoflavonoids from elicited soybean may have hypolipidemic activity through HMGCR inhibition and PPAR-γ activation.

Keywords


elicitation; HMGCR; hyperlipidemia; PPAR-γ; soybeans



References

[1] Pirillo, A., Casula, M., Olmastroni, E., Norata, G.D., and Catapano, A.L., 2021, Global epidemiology of dyslipidaemias, Nat. Rev. Cardiol., 18 (10), 689–700.

[2] Abe, S., Tokoro, F., Matsuoka, R., Arai, M., Noda, T., Watanabe, S., Horibe, H., Fujimaki, T., Oguri, M., Kato, K., Minatoguchi, S., and Yamada, Y., 2015, Association of genetic variants with dyslipidemia, Mol. Med. Rep., 12 (4), 5429–5436.

[3] García-Giustiniani, D., and Stein, R., 2016, Genetics of dyslipidemia, Arq. Bras. Cardiol., 106 (5), 434–438.

[4] Sayols-Baixeras, S., Irvin, M.R., Elosua, R., Arnett, D.K., and Aslibekyan, S.W., 2016, Epigenetics of lipid phenotypes, Curr. Cardiovasc. Risk Rep., 10 (10), 31.

[5] Gomez-Alonso, M.C., Kretschmer, A., Wilson, R., Pfeiffer, L., Karhunen, V., Seppälä, I., Zhang, W., Mittelstraß, K., Wahl, S., Matias-Garcia, P.R., Prokisch, H., Horn, S., Meitinger, T., Serrano-Garcia, L.R., Sebert, S., Raitakari, O., Loh, M., Rathmann, W., Müller-Nurasyid, M., Herder, C., Roden, M., Hurme, M., Jarvelin, M.R., Ala-Korpela, M., Kooner, J.S., Peters, A., Lehtimäki, T., Chambers, J.C., Gieger, C., Kettunen, J., and Waldenberger, M., 2021, DNA methylation and lipid metabolism: An EWAS of 226 metabolic measures, Clin. Epigenet., 13 (1), 7.

[6] Hedayatnia, M., Asadi, Z., Zare-Feyzabadi, R., Yaghooti-Khorasani, M., Ghazizadeh, H., Ghaffarian-Zirak, R., Nosrati-Tirkani, A., Mohammadi-Bajgiran, M., Rohban, M., Sadabadi, F., Rahimi, H.R., Ghalandari, M., Ghaffari, M.S., Yousefi, A., Pouresmaeili, E., Besharatlou, M.R., Moohebati, M., Ferns, G.A., Esmaily, H., and Ghayour-Mobarhan, M., 2020, Dyslipidemia and cardiovascular disease risk among the MASHAD study population, Lipids Health Dis., 19 (1), 42.

[7] Nguyen, V.S., Tran, X.T., Vo, T.D., and Le, Q.T., 2021, Residual Cardiovascular Risk Factors in Dyslipidemia, in Risk Factors for Cardiovascular Disease, Eds. Chahine, J., IntechOpen, Rijeka, 100046.

[8] Grover, A., Rehan, H.S., Gupta, L.K., and Yadav, M., 2017, Correlation of compliance to statin therapy with lipid profile and serum HMGCoA reductase levels in dyslipidemic patients, Indian Heart J., 69 (1), 6–10.

[9] Charan, J., Riyad, P., Ram, H., Purohit, A., Ambwani, S., Kashyap, P., Singh, G., Hashem, A., Abd Allah, E.F., Gupta, V.K., Kumar, A., and Panwar, A., 2022, Ameliorations in dyslipidemia and atherosclerotic plaque by the inhibition of HMG-CoA reductase and antioxidant potential of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd in rabbits, PLoS One, 17 (3), e0264646.

[10] Chandra, M., Miriyala, S., and Panchatcharam, M., 2017, PPARγ and its role in cardiovascular diseases, PPAR Res., 2017, e6404638.

[11] Balakumar, P., Mahadevan, N., and Sambathkumar, R., 2019, A contemporary overview of PPARα/γ dual agonists for the management of diabetic dyslipidemia, Curr. Mol. Pharmacol., 12 (3), 195–201.

[12] Varady, K.A., and Jones, P.J.H., 2005, Combination diet and exercise interventions for the treatment of dyslipidemia: An effective preliminary strategy to lower cholesterol levels?, J. Nutr., 135 (8), 1829–1835.

[13] Bouchenak, M., and Lamri-Senhadji, M., 2013, Nutritional quality of legumes, and their role in cardiometabolic risk prevention: A review, J. Med. Food, 16 (3), 185–198.

[14] Rosa, C.O.B., dos Santos, C.A., Leite, J.I.A., Caldas, A.P.S., and Bressan, J., 2015, Impact of nutrients and food components on dyslipidemias: What is the evidence?, Adv. Nutr., 6 (6), 703–711.

[15] Adel Mehraban, M.S., Tabatabaei-Malazy, O., Rahimi, R., Daniali, M., Khashayar, P., and Larijani, B., 2021, Targeting dyslipidemia by herbal medicines: A systematic review of meta-analyses, J. Ethnopharmacol., 280, 114407.

[16] Li, S.S., Blanco Mejia, S., Lytvyn, L., Stewart, S.E., Viguiliouk, E., Ha, V., de Souza, R.J., Leiter, L.A., Kendall, C.W.C., Jenkins, D.J.A., and Sievenpiper, J.L., 2017, Effect of plant protein on blood lipids: A systematic review and meta‐analysis of randomized controlled trials, J. Am. Heart Assoc., 6 (12), e006659.

[17] Mullen, E., Brown, R.M., Osborne, T.F., and Shay, N.F., 2004, Soy isoflavones affect sterol regulatory element binding proteins (SREBPs) and SREBP-regulated genes in HepG2 cells, J. Nutr., 134 (11), 2942–2947.

[18] Huang, H., Xie, Z., Boue, S.M., Bhatnagar, D., Yokoyama, W., Yu, L., and Wang, T.T.Y., 2013, Cholesterol-lowering activity of soy-derived glyceollins in the golden Syrian hamster model, J. Agric. Food Chem., 61 (24), 5772–5782.

[19] Tanaka, W., Matsuyama, H., Yokoyama, D., Yamashita, Y., Ashida, H., Sakono, M., and Sakakibara, H., 2020, Daily consumption of black soybean (Glycine max L.) seed coat polyphenols attenuates dyslipidemia in apolipoprotein E-deficient mice, J. Funct. Foods, 72, 104054.

[20] Feldman, F., Koudoufio, M., Desjardins, Y., Spahis, S., Delvin, E., and Levy, E., 2021, Efficacy of polyphenols in the management of dyslipidemia: A focus on clinical studies, Nutrients, 13 (2), 672.

[21] Boué, S.M., Carter, C.H., Ehrlich, K.C., and Cleveland, T.E., 2000, Induction of the soybean phytoalexins coumestrol and glyceollin by Aspergillus, J. Agric. Food Chem., 48 (6), 2167–2172.

[22] Halder, M., Sarkar, S., and Jha, S., 2019, Elicitation: A biotechnological tool for enhanced production of secondary metabolites in hairy root cultures, Eng. Life Sci., 19 (12), 880–895.

[23] Hermanto, F.E., Warsito, W., Rifa’i, M., Widodo, N., and Jatmiko, Y.D., 2021, Unveiling microbial community structure in Ragi tape as elicitors to increase secondary metabolites contents in Glycine max and Vigna radiata, Biologia, 76 (12), 3901–3907.

[24] Barańska, A., Błaszczuk, A., Polz-Dacewicz, M., Kanadys, W., Malm, M., Janiszewska, M., and Jędrych, M., 2021, Effects of soy isoflavones on glycemic control and lipid profile in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials, Nutrients, 13 (6), 1886.

[25] Mezei, O., Banz, W.J., Steger, R.W., Peluso, M.R., Winters, T.A., and Shay, N., 2003, Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells, J. Nutr., 133 (5), 1238–1243.

[26] Purwanti, E., Hermanto, F.E., Souhaly, J.W., Prihanta, W., and Permana, T.I., 2021, Exploring public health benefits of Dolichos lablab as a dietary supplement during the COVID-19 outbreak: A computational study, J. Appl. Pharm. Sci., 11 (2), 135–140.

[27] Banerjee, P., Eckert, A.O., Schrey, A.K., and Preissner, R., 2018, ProTox-II: A webserver for the prediction of toxicity of chemicals, Nucleic Acids Res., 46 (W1), W257–W263.

[28] Trott, O., and Olson, A.J., 2010, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, J. Comput. Chem., 31 (2), 455–461.

[29] Dallakyan, S., and Olson, A.J., 2015, Small-molecule library screening by docking with PyRx, Methods Mol. Biol., 1263, 243–250.

[30] Istvan, E.S., Palnitkar, M., Buchanan, S.K., and Deisenhofer, J., 2000, Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis, EMBO J., 19 (5), 819–830.

[31] Al Sharif, M., Tsakovska, I., Alov, P., Vitcheva, V., Diukendjieva, A., and Pajeva, I., 2019, Molecular modeling approach to study the PPARγ-ligand interactions, Methods Mol. Biol., 1966, 261–289.

[32] Maier, J.A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K.E., and Simmerling, C., 2015, ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB, J. Chem. Theory Comput., 11 (8), 3696–3713.

[33] Krieger, E., and Vriend, G., 2015, New ways to boost molecular dynamics simulations, J. Comput. Chem., 36 (13), 996–1007.

[34] Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N., Schwikowski, B., and Ideker, T., 2003, Cytoscape: A software environment for integrated models of biomolecular interaction networks, Genome Res., 13 (11), 2498–2504.

[35] Otasek, D., Morris, J.H., Bouças, J., Pico, A.R., and Demchak, B., 2019, Cytoscape Automation: empowering workflow-based network analysis, Genome Biol., 20 (1), 185.

[36] Szklarczyk, D., Gable, A.L., Nastou, K.C., Lyon, D., Kirsch, R., Pyysalo, S., Doncheva, N.T., Legeay, M., Fang, T., Bork, P., Jensen, L.J., and 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 (D1), D605–D612.

[37] Sherman, B.T., Hao, M., Qiu, J., Jiao, X., Baseler, M.W., Lane, H.C., Imamichi, T., and Chang, W., 2022, DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update), Nucleic Acids Res., 50 (W1), W216–W221.

[38] Pantsar, T., and Poso, A., 2018, Binding affinity via docking: Fact and fiction, Molecules, 23 (8), 1899.

[39] Chui, P.C., Guan, H.P., Lehrke, M., and Lazar, M.A., 2005, PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1, J. Clin. Invest., 115 (8), 2244–2256.

[40] Zhang, T., and Chi, X.X., 2019, The effect of genistein on lipid levels and LDLR, LXRα and ABCG1 expression in postmenopausal women with hyperlipidemia, Diabetol. Metab. Syndr., 11 (1), 111.

[41] Mansouri, A., Vahdati, A., Nematbakhsh, M., and Moshtaghian, J., 2021, Hypercholesterolemia role of vitamin D3 and genistein effect in reducing atherosclerosis in rat, Hormozgan Med. J., 19 (5), 306–314.

[42] Herwana, E., Pusparini, P., and Graciela, A., 2020, High dietary daidzein intake lowers cholesterol levels among post-menopausal women, Universa Med., 39 (1), 47–54.

[43] Lee, S.O., Renouf, M., Ye, Z., Murphy, P.A., and Hendrich, S., 2007, Isoflavone glycitein diminished plasma cholesterol in female Golden Syrian hamsters, J. Agric. Food Chem., 55 (26), 11063–11067.

[44] Goldstein, J.L., Helgeson, J.A., and Brown, M.S., 1979, Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor, J. Biol. Chem., 254 (12), 5403–5409.

[45] Dahabreh, D.F., and Medh, J.D., 2012, Activation of peroxisome proliferator activated receptor-gamma results in an atheroprotective apolipoprotein profile in HepG2 cells, Adv. Biol. Chem., 2 (3), 218–225.

[46] Borradaile, N.M., de Dreu, L.E., Wilcox, L.J., Edwards, J.Y., and Huff, M.W., 2002, Soya phytoestrogens, genistein and daidzein, decrease apolipoprotein B secretion from HepG2 cells through multiple mechanisms, Biochem. J., 366 (2), 531–539.

[47] Walker, A.K., and Näär, A.M., 2012, SREBPs: Regulators of cholesterol/lipids as therapeutic targets in metabolic disorders, cancers and viral diseases, Clin. Lipidol., 7 (1), 27–36.

[48] Xiao, X., and Song, B.L., 2013, SREBP: A novel therapeutic target, Acta Biochim. Biophys. Sin., 45 (1), 2–10.

[49] Hu, N., Chen, C., Wang, J., Huang, J., Yao, D., and Li, C., 2021, Atorvastatin ester regulates lipid metabolism in hyperlipidemia rats via the PPAR-signaling pathway and HMGCR expression in the liver, Int. J. Mol. Sci., 22 (20), 11107.



DOI: https://doi.org/10.22146/ijc.75777

Article Metrics

Abstract views : 2016 | views : 1071 | views : 745


Copyright (c) 2022 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 


Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web
Analytics View The Statistics of Indones. J. Chem.