Optimization of extraction process for total flavonoids of Sophorae Flos for the treatment of hyperlipidemia based on network pharmacology and molecular docking

Abstract

This study aimed to investigate the mechanism of action of Sophora Flos (SF) in the treatment of hyperlipidemia (HLP) using network pharmacology and molecular docking methods, and to optimize the extraction process of the predicted active components. The STRING database was used for protein interaction analysis and PPI network construction via Cytoscape 3.9.1. Pymol was employed for docking and visualization. An extensive review of SF identified 6 active ingredients, 297 related objectives, 84 disease objectives, and 57 total objectives. After protein interaction and topology analysis, 18 core targets were identified. These included 146 gene function entries (P < 0.05). Active compounds, mainly flavonoids, can modulate the expression of various proteins such as TNF, IL-6, IL-1β, PPARG, and TGFB1 to achieve therapeutic effects on HLP. The network pharmacology and molecular docking results suggested that the active flavonoids component in SF may be related to the treatment of hyperlipidemia. Therefore, the orthogonal experiment method was used to optimize the extraction process of total flavonoid from SF using ethanol reflux extraction, based on a single factor experiment. The effects of reflux time, solid-liquid ratio, ethanol concentration, and other factors on the extraction of total flavonoid from SF were investigated. The optimum process conditions were reflux time of 1.25 h, solid-liquid ratio of 1:15 g/mL and ethanol concentration of 60%. Using these conditions, the purity of total flavonoid extracted from SF was 70.33 ± 0.22%.

Keywords

Sophorae Flos / total flavonoid / process optimization / network pharmacology / hyperlipidemia

References

[1] Yao YS, Li TD, Zeng ZH. Mechanisms underlying direct actions of hyperlipidemia on myocardium: An updated review[J]. Lipids Health Dis, 2020, 19 (1): 23.

[2] Chen Y, Chen LM, Tong Y, et al. Pharmacological effect and toxicology of Sophorae Tonkinensis Radix et Rhizoma[J]. China Journal of Chinese Materia Medica, 2017, 42 (13): 2439-2442.

[3] Li R, Wang C, Lei P, et al. Chemical constituents in Flos Sophorae Carbonisatus[J]. China Journal of Chinese Materia Medica, 2010, 35 (5): 607-609.

[4] Zhao L, Zhang H, Li N, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula[J]. J Ethnopharmacol, 2023, 309: 116306.

[5] Li Y, Chen X, Xue J, et al. Flavonoids furom Coreopsis tinctoria adjust lipid metabolism in hyperlipidemia animals by down-regulating adipose differentiation-related protein[J]. Lipids Health Dis, 2014, 13: 193.

[6] Bai YF, Yue ZL, Wang YN, et al. Synergistic effect of polysaccharides and flavonoids on lipid and gut microbiota in hyperlipidemic rats[J]. Food Funct, 2023, 14 (2): 921-933.

[7] Fan S, Yang G, Zhang J, et al. Optimization of ultrasound- assisted extraction using response surface methodology for simultaneous quantitation of six flavonoids in Flos Sophorae Immaturus and antioxidant activity[J]. Molecules, 2020, 25 (8): 1767.

[8] Manzoni AG, Passos DF, Leitemperger JW, et al. Hyperlipidemia-induced lipotoxicity and immune activation in rats are prevented by curcumin and rutin[J]. Int Immunopharmacol, 2020, 81: 106217.

[9] Li Z, Zhu G, Chen G, et al. Distribution of lipid levels and prevalence of hyperlipidemia: Data from the NHANES 2007-2018[J]. Lipids Health Dis, 2022, 21 (1): 111.

[10] Alloubani A, Nimer R, Samara R. Relationship between hyperlipidemia, cardiovascular disease and stroke: A systematic review[J]. Curr Cardiol Rev, 2021, 17 (6): e051121189015.

[11] Xiang Y, Mao L, Zuo ML, et al. The role of microRNAs in hyperlipidemia: From pathogenesis to therapeutical application[J]. Mediators Inflamm, 2022, 2022: 3101900.

[12] Yang ST, Liu CH, Wang PH. The impact of hyperlipidemia and carotid atherosclerosis[J]. J Chin Med Assoc, 2023, 86 (4): 451-452.

[13] Suh JS, Kim SYJ, Lee SH, et al. Hyperlipidemia is necessary for the initiation and progression of atherosclerosis by severe periodontitis in mice[J]. Mol Med Rep, 2022, 26 (2): 273.

[14] Wang C, Du Z, Ye N, et al. Hyperlipidemia and hypertension have synergistic interaction on ischemic stroke: Insights from a general population survey in China[J]. BMC Cardiovasc Disord, 2022, 22 (1): 47.

[15] Lu S, Yuan Y, Chen F, et al. Holothuria leucospilota polysaccharides alleviate hyperlipidemia via alteration of lipid metabolism and inflammation-related gene expression[J]. J Food Biochem, 2022, 46 (12): e14392.

[16] Zhao H, Li Y. Upregulated microRNA-185-3p inhibits the development of hyperlipidemia in rats[J]. Kidney Blood Press Res, 2023, 48 (1): 35-44.

[17] Chen J, Wu J, Mu J, et al. An antioxidative sophora exosome-encapsulated hydrogel promotes spinal cord repair by regulating oxidative stress microenvironment[J]. Nanomedicine, 2023, 47: 102625.

[18] Wang F, Zhao X, Su X, et al. Isorhamnetin, the xanthine oxidase inhibitor from Sophora japonica, ameliorates uric acid levels and renal function in hyperuricemic mice[J]. Food Funct, 2021, 12 (24): 12503-12512.

[19] Liu Y, Huang W, Ji S, et al. Sophora japonica flowers and their main phytochemical, rutin, regulate chemically induced murine colitis in association with targeting the NF-kappaB signaling pathway and gut microbiota[J]. Food Chem, 2022, 393: 133395.

[20] Sun C, Wang L, Sun J, et al. Hypoglycemic and hypolipidemic effects of rutin on hyperglycemic rats[J]. J Tradit Chin Med, 2020, 40 (4): 640-645.

[21] Zhou J, Liu Q, Yang Z, et al. Rutin maintains redox balance to relieve oxidative stress induced by TBHP in nucleus pulposus cells[J]. In Vitro Cell Dev Biol Anim, 2021, 57 (4): 448-456.

[22] Bermejo-Bescos P, Jimenez-Aliaga KL, Benedi J, et al. A diet containing rutin ameliorates brain intracellular redox homeostasis in a mouse model of Alzheimer’s disease[J]. Int J Mol Sci, 2023, 24 (5): 4863.

[23] Liang XH, Han YY, Wang S, et al. Anti-aging effect of rutin in caenorhabditis elegans and D-Gal-induced aging mouse model[J]. Dokl Biochem Biophys, 2023, 513 (1): 350-354.

[24] Shafeghat M, Kazemian S, Aminorroaya A, et al. Toll- like receptor 7 regulates cardiovascular diseases[J]. Int Immunopharmacol, 2022, 113 (Pt A): 109390.

[25] Ain QU, Sarfraz M, Prasesti GK, et al. Confounders in identification and analysis of inflammatory biomarkers in cardiovascular diseases[J]. Biomolecules, 2021, 11 (10): 1464.

[26] Liu X, Bao Y, Lin Z, et al. Platelets inhibit development of atherosclerosis in atherosclerotic mice[J]. Cell Cycle, 2022, 21 (11): 1222-1232.

[27] Nguyen HT, Nguyen HT, Islam MZ, et al. Antagonistic effects of gingko biloba and sophora japonica on cerebral vasoconstriction in response to histamine, 5-hydroxytryptamine, U46619 and bradykinin[J]. Am J Chin Med, 2016, 44 (8): 1607-1625.

[28] Zhao L, Liu ZM, Piao ZZ. Clinical and experimental study on cerebral thrombosis treated with antithrombotic xinmaining[J]. Chinese Journal of Modern Developments in Traditional Medicine, 1991, 11 (6): 327-330+323.

[29] Ridker PM, Tuttle KR, Perkovic V, et al. Inflammation drives residual risk in chronic kidney disease: A CANTOS substudy[J]. Eur Heart J, 2022, 43 (46): 4832-4844.

[30] Jia Q, Cao H, Shen D, et al. Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARgamma, LXRalpha and ABCA1[J]. Int J Mol Med, 2019, 44 (3): 893-902.

[31] Luo D, Yu B, Sun S, et al. Effects of adjuvant berberine therapy on acute ischemic stroke: A meta-analysis[J]. Phytother Res, 2023, 37 (9): 3820-3838.

[32] Mou Q, He J, Yin R, et al. Response surface optimized Infrared-Assisted extraction and UHPLC determination of flavonoid types from Flos Sophorae[J]. Molecules, 2017, 22 (6): 1000.

[33] Xie Z, Sun Y, Lam S, et al. Extraction and isolation of flavonoid glycosides from Flos Sophorae Immaturus using ultrasonic-assisted extraction followed by high-speed countercurrent chromatography[J]. J Sep Sci, 2014, 37 (8): 957-965.

[34] Liu JL, Li LY, He GH. Optimization of microwave- assisted extraction conditions for five major bioactive compounds from Flos Sophorae Immaturus (cultivars of Sophora japonica L.) using response surface methodology[J]. Molecules, 2016, 21 (3): 296.