Soybean and Its Products: Nutritional and Health Benefits

Anti- Diabetic Effects

Diabetes Mellitus (DM) is a metabolic disorder investigated as one of the major health issues globally. It has been rising invariably to around 336 million people in the world and is estimated to exist in around 552 million people by 2030 [17, 18].

There are various phytocompounds derived foods available for the treatment of DM. Among these, soybean and soy products have shown significant results towards the prevention of DM [9]. Dietary soy has proved to be essential and led significant impact on the patients with chronic kidney disease. In most cases, diabetes mellitus is related with the renal disorder at its advanced stages. In case of type 1 diabetes, use of soy proteins as replacement of animal proteins reduces Glomerular Filter Rate (GFR) and the proteinuria [19].

It has been reported that soy products enriched in isoflavonoids illustrated the anti-diabetic effect. It has also been shown that soybean extract is helpful in the inhibition of the glucose uptake into brush border membrane vesicles [9,20].

Anti-diabetic activity of stigmasterol from soybean oil has been studied by targeting the Glucose Transporter 4 (GLUT4). The anti-diabetic activity and the potential mechanism of stigmasterol (SMR) was investigated in-vitro and in-vivo. Stigmasterol is a phytosterol derived from the edible soybean oil which showed significant impact on the treatment of type 2 diabetes mellitus [21]. Chungkookjang, a Korean fermented soy product consisting of isoflavonoid aglycones and smaller peptides has also been studied for its improved insulinotropic activity in islets of type 2 diabetic rats [22].

Screening of fermented soy and flaxseed milk (FSFM) was done for their antidiabetic role in alloxan-induced diabetic rats utilizing the oral route. Fermented milk with probiotics enhanced the effectiveness of isoflavones in the cure of diabetic mellitus. The study on flaxseed and soy milk showed that it is potent in reduction of type 1 diabetes with no side effects [23].

Anti-Oxidant Effects

Oxidative stress takes place due to the imbalance between antioxidant mechanism and free radicals [24]. It continues as a major mechanism in a range of diseases including cancer, diabetes, etc. The soybean and its products are very effective in decreasing the oxidative stress and scavenging the free radicals [25]. Many studies have been performed on antioxidant activity of soybean and its products. Dou-chi, a traditional soybean food which was fermented using Aspergillus sp. showed potential to scavenge free radicals. In the study, isolation of various phenols and flavonoids was done and among them, 3’-hydroxydaidzein was found with high 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging effects [9,26,].

Soy milk is an essential soy product which has been found to inhibit oxidative stress in Type 2 Diabetes Mellitus (T2DM) in human trials. The analysis showed that fermented soy milk is beneficial in regulation of the total antioxidant, oxidized glutathione, 8-iso-prostaglandin F2α, glutathione peroxidase, malondialdehyde, and reduced glutathione (GSH) levels and in improvement of oxidative stress in T2DM [27].

Antioxidant peptides isolated from fermented soybean protein meal hydrolysate utilizing Sephadex G-15 gel filtration chromatography, revealed strong antioxidant activity [28].

Development of fermented soy foods with high nutritional constituents and effective biological properties has also been tested. Lee et al reported the alterations in nutritional components (fatty acids, isoflavones, and amino acids) and antioxidant potential of the fermented soybean against ABTS [2,2’-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)], DPPH, and hydroxyl radicals [29]. Furthermore, they also examined the variations of total phenolic contents, β-glucosidase effects, and α glucosidase inhibitory activities.

Anti-Cancer Effects

Cancer is an anomalous cell growth which either inhabits at a specific site or keeps extending within the body. Various dietary materials ample in nutrients have anti-cancer qualities and are effective in the prevention of a variety of cancer. It has been reported that fermented soy milk beverages were effective in suppressing the in-vitro proliferation of the human colon cancer cell lines Caco-2 and HT-29 [30]. Investigations have been performed on the inhibition of generation of reactive oxygen species and the growth of estrogen-receptor positive MCF-7 human breast cancer in mice, utilizing fermented soy milk [31]. The consumption of soybean and its products may have a considerable impact on the regulation of MMP (matrix metallopeptidase) levels and prevention of cancer [32].

Various investigations have been done on fermented soybean with antitumor and anticancer properties; however, there are only a few reports on peptides having potential against cancer. Anticancer properties of peptides in fermented soybean can be due the peptides formed on hydrolysis of soybean protein or the surfactants (containing cyclic peptide) or lipopeptides generated by the starter culture [33,34]. Soy peptides have also been recognized in various experimental systems to have anti-cancer properties [35,36,37]. Kim et al. reported that purified hydrophobic peptide X-MLPSYSPY from defatted soy protein arrested the cell cycle progression at G2/M phase, of murine lymphoma cells (P388D1) [38]. It has been revealed in various studies that most of the soy peptides exhibiting anti-cancerous properties belong to the minor 2S fraction of soybean proteins [11, 35, 39, 40].

Soy isoflavones have gained much attention over the years due to their potential role in prevention of cancer [41]. Soy isoflavones have been described as dietary components with potential role in reducing the occurrence of various cancers like prostate and breast cancers. Genistein, the prevailing isoflavone present in soybean, has been shown to be effective in the inhibition of carcinogenesis in animal models. There are various investigations that demonstrated the inhibitory effect of genistein on human cancer cells through the modulation of genes associated with the regulation of cell cycle and apoptosis. Furthermore, it has been reported that genistein is effective in inhibition of the activation of NF-κB and Akt signalling pathways, which are recognized to manage a homeostatic balance between cell survival and apoptosis [42]. The translocation of NF-κB dimers to the nucleus and their binding to DNA has been reported to be inhibited by the genistein, interrupting the transcription of NF-κB downstream genes [3, 43].

The antiproliferative influence of soy isoflavones has been generally associated to the interaction of estrogen receptor. The control of apoptosis, cell growth and survival, antioxidant properties or inhibition of angiogenesis and metastasis, have been investigated utilizing different isoflavone dosage and various breast cancer cells [44, 45].

Effects on Coronary Heart Disease

There are reports suggesting the significant impact of soy protein products on health. On the basis of total diet and nutritional perspective, various studies have explained the difference in mortality rates from different types of cancer and Cardiovascular Disease (CVD) in various countries. A number of investigations described that animal protein such as casein, is more cholesterolemic and atherogenic as compared to plant derived protein. Carroll showed that soy proteins have significant potential in lowering the cholesterol level of normal and hypercholesterolemic persons [46]. Anderson et al. conducted a meta-analysis and reported that by consumption of soy protein, blood lipid levels (total cholesterol, triglycerides and LDL-cholesterol) decreased significantly in humans [47,48].

It has been reported that the use of soy isoflavones decreases the risk markers of cardiovascular disease in men [49] and during the early menopause, they help in improvement of cardiovascular disease risk markers in women [50].

Blood pressure imbalance occurs as a crucial event in several cardiovascular diseases and it can be taken as a caution for cardiovascular symptoms. Tsai et al. reported the antihypertensive activity of peptides derived from the Lactobacillus fermented soy milk [51]. The results showed that with the increased peptide levels, there is reduction in the systolic blood pressure and thus it can be the explanation for the maintenance of blood pressure under control [9].

Anti- Obesity Effects

Obesity is the major health issue globally and has attained a pandemic proportion. New targets have been set to recognize the molecules that regulate adipose tissue distribution, arrangement, and decomposition which will help in prevention and treatment of obesity. Advances in food sciences and nutrition studies have highlighted the probability of balancing some specific physiological functions and molecular signalling in the human beings through food-sourced components, which focus at regulating and decreasing obesity progression at molecular level [52,53].

Soy foods are good sources of isoflavones, which probably combine with intracellular estrogen receptors and help in reduction of lipids accumulation and adipose tissue distribution. Various studies have shown the anti-obesity influence of soy foods and its components. Soy isoflavones and their derivatives have structural resemblance with 17β- estradiol (E2) and they revealed to exhibit estrogenic effect with binding affinity to estrogen receptors. Estrogen receptors are expressed in different types of cells and organs including adipose tissues, which perform important function in metabolism regulation and lipid or fat distribution [54].

The anti-adipogenic effect of genistein in primary human adipocytes regulated by its ER-dependent pathway has been investigated [55]. Genistein also exhibited lipolytic properties in fully differentiated 3T3-L1 adipocyte by increasing basal and epinephrine-induced lipolysis and elevating cellular cAMP level in fat cells [56,57].

Hwang and co-workers reported that genistein helps in inhibition of adipogenesis in 3T3-L1 cell by activating AMPK signalling pathway [58]. Genistein also inhibits different enzymes activities associated with estrogenic activities and adipogenic regulation, such as DNA to poisomerases I and II, tyrosine kinase, MAPK families, cdc2 kinase activity, and protein histidine kinase activity [59,60].

It is revealed that genistein down regulated the expression of adipogenic proteins (Fatty acid synthase and C/EBPα) by inhibiting phosphorylation signalling of two kinases (p38 and JAK2) at tyrosine residues [61]. Both genistein (100 μM) and daidzein (100 μM) treatment also showed the growth arrest phase in human preadipocyte cells, AML-I [62].

Various investigations have indicated significant influence of soy isoflavones on human body weight and lipid metabolism profile. Studies showed that intake of daidzein reduced gain in body weight and fat content in liver by down regulating stearoyl-CoA desaturase-1, which is a crucial enzyme in obesity, and up regulating uncoupling protein-1 in adipose tissue [63]. Ali et al. reported that soy isoflavone mixture (0.1% of meal, containing daidzein, glycitein and genistein) caused reduction in fat deposition in both lean and obese rats in a two-week treatment [64]. It also lowered total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol in lean rats, while in obese rats, isoflavones reduced only total and LDL cholesterol.

There are two essential characteristics of adipose tissue driving to obesity, hypertrophy (increased adipocyte size) and hyperplasia (increased adipocyte number). Soy isoflavones are shown to be effective in the reduction of both the processes. Genistein has been reported to reduce adipose tissue in-vivo primarily by attributing to decrease in adipose size while daidzein could decrease overall fat mass in-vivo by reducing adipocyte numbers in mice [65]. Various studies demonstrated soy protein as well as peptides to be the active ingredient to reduce LDL cholesterol and triacylglycerol in human body [66].

Other Health Effects

In addition to the major health benefits mentioned above, soy and soy products also exhibit various other health benefits such as prevention of osteoporosis, maintenance of bone health and the normal endothelial function. Nattokinase (natto derived) activates fibrin degradation and acts as a therapeutic substitute in protection from comorbid asthma [67]. It also has essential role in maintenance of good condition of thyroid and impact on the developmental effects and fertility. Soybean products have also been revealed to be effective in immuno-stimulation. Cheonggukjang is a soybean paste in Korea, fermented by Bacillus subtilis. The polysaccharides gained from this soybean paste induced mRNA expression of various metabolic factors and help to stimulate the immune system by regulating the related parameters [68].

Hyperlipidemia and inflammation are always related with several pathological conditions. The existence of hyperlipidemic condition and low-grade inflammation collectively in atherosclerosis provides evidence for the disorder. The high n-3 FAs contents in soy products and bioactive components consisted of isoflavonoids and plant steroids may be effective on various low-grade inflammation-related diseases [69, 70]. Investigations have been performed on the impact of genistein in prevention of lipopolysaccharide (LPS)-induced cognitive dysfunction [71].

Conclusion

In the trend of nutrition and health, and active interest of people, soybean and soy proteins have attracted immense attention as these are highly nutritious, functional, and economical food ingredients. The soybean composition can be altered by conventional breeding programs or genetic engineering to meet consumer or industrial requirement. Soybean and its products can play an essential role in providing the nutritious foods according to the consumers’ demand. Soybean contains large amount of proteins, vitamins, lecithin, isoflavonoids, micro- and macro- elements. The high amounts of biologically active components in soybean enable them to use in various pharmaceutical industries for production of drugs and dietary supplements. Soybean is also a major source of many peptides that have a broad range of biological activities such as anti-diabetic, hypolipidemic, anti-hypertensive, antioxidant, anti-obesity, anti-cancer, anti-inflammatory, neuro-modulatory and immune-stimulatory properties investigated in various models. Although much information has been gathered about the health benefits of soybean, and fermented soy products but a complete investigation of the different molecular level studies and further clinical trials are required to conclude that soy products are advantageous for the human race as a dietary nutrient. More analyses are required for the identification of the quantity of active soybean peptides liberated by various methods (for instance, in-vivo or in-vitro digestions), and the influence of age and gender on the action or generation of bioactive soybean peptides. In addition, the study on synergistic multi-component impacts of soybean on biological functions is advised for further analysis.

Acknowledgements

SS acknowledges the award of Golden Jubilee Fellowship of Devi Ahilya University, Indore. Authors acknowledge the facilities of the Department of Biotechnology, Ministry of Science and Technology, Government of India, New Delhi (DBT) present in the Department under the Bioinformatics Sub Centre as well as M.Sc. Biotechnology program and used in the present work.

Conflict of interest

Authors declare that no conflict of interest exists.

References

1. Singh G, Ratnaparkhe M, Kumar A. Comparative analysis of transposable elements from Glycine max, Cajanus cajan and Phaseolus vulgaris. J. Expl. Biol. Agricul. Sci. 2019;7(2):167-177.
2. Valliyodan B, Qiu D, Patil G, Zeng P, Huang J, Dai L, et al. Landscape of genomic diversity and trait discovery in soybean. Scientific Reports. 2016;6:23598.
3. Li Y, Guan R, Liu Z, Ma Y, Wang L, Li L, et al. Genetic structure and diversity of cultivated soybean (Glycine max (L.) Merr.) Landraces in China. Theoret. Appl. Genet. 2008;117(6):857-871.
4. He FJ, Chen JQ. Consumption of soybean, soy foods, soy isoflavones and breast cancer incidence: Differences between Chinese women and women in Western countries and possible mechanisms. Food Sci. Human Wellness. 2013;2:146–161.
5. Silva FCDS, Sediyama T, Oliveira RDCT, Borém A, Silva FLD, Bezerra ARG, et al. Economic Importance and Evolution of Breeding. Soybean Breeding. Springer, 2017;p.:1-16.
6. Singh G, Kumar A. Synteny analysis of Glycine max and Phaseolus vulgaris revealing conserved regions of NBS-LRR coding genes. Biosci. Biotechnol. Res. Commun. 2019;12(1):124-133.
7. Alexandratos N, Bruinsma J. World agriculture towards 2030/2050: the 2012 revision. 2012.
8. Kamshybayeva G, Atabayeva SD, Kenzhebayeva S, Domakbayeva A, Utesheva S, Nurmahanova A, et al. The importance of soybean (Glycine max) as a source of biologically valuable substances. Intl. J. Biol. Chem. 2017;10(2):23-27.
9. Jayachandran M, Xu B. An insight into the health benefits of fermented soy products. Food Chem. 2019;271:362-371.
10. Omoni AO, Aluko RE. Soybean foods and their benefits: potential mechanisms of action. Nutrition Rev. 2005;63(8):272-283.
11. Wang W, Dia VP, Vasconez M., de Mejia EG, Nelson RL. Analysis of soybean protein-derived peptides and the effect of cultivar, environmental conditions, and processing on lunasin concentration in soybean and soy products.  J. AOAC Intl. 2008;91(4):936-946.
12. Asif M, Acharya M. Phytochemicals and nutritional health benefits of soy plant. Intl. J. Nutr. Pharmac. Neurol. Dis. 2013;3(1):64–69.
13. Tidke SA, Ramakrishna D, Kiran S, Kosturkova G, Ravishankar GA. Nutraceutical potential of soybean. Asian J. Clin. Nutr. 2015;7(2):22-32.
14. Board J. A comprehensive survey of international soybean research – Genetics, physiology, agronomy and nitrogen relationships. 2012.
15. Kahraman A. Nutritional value and foliar fertilization in soybean. J Elementology. 2017;22(1):55-66.
16. El-Shemy H. Soybean and health. 2011.
17. Habtamu A, Gasmalla MAA, Yang RJ, Zhang W. Bioactive Peptides Derived from Seaweed Protein and Their Health Benefits: Antihypertensive, Antioxidant, and Antidiabetic Properties. J. Food Sci. 2018;83(1):6–16.
18. González-Montoya M, Hernández-Ledesma B, Mora-Escobedo R, Martínez-Villaluenga C. Bioactive peptides from germinated soybean with anti-diabetic potential by inhibition of dipeptidyl peptidase-IV, α-amylase, and α-glucosidase enzymes. Intl. J. Mol. Sci. 2018;19(10):2883.
19. Stephenson TJ, Setchell KD, Kendall CW, Jenkins DJ, Anderson JW, Fanti P. Effect of soy protein-rich diet on renal function in young adults with insulin dependent diabetes mellitus. Clin.Nephrol. 2005;64(1):1–11.
20. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestrogens in obesity and diabetes.  Am. J. Clin. Nutr. 2002;76(6):1191–1201.
21. Wang J, Huang M, Yang J, Ma X, Zheng S, Deng S, et al. Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter. Food Nutr. Res. 2017;61(1):1364117.
22. Yang HJ, Kwon DY, Kim MJ, Kang S, Park S. Meju, unsalted soybeans fermented with Bacillus subtilis and Aspergilus oryzae, potentiates insulinotropic actions and improves hepatic insulin sensitivity in diabetic rats. Nutr. Metabol. 2012;9(1):37.
23. Veerichetty V. Antidiabetic potential of the combination of fermented soy milk and flaxseed milk in alloxan-induced diabetic rats. Intl. J. Green Pharmacy. 2018;12(3).
24. Jayachandran M, Chandrasekaran B, Namasivayam N. Geraniol attenuates oxidative stress by Nrf2 activation in diet-induced experimental atherosclerosis. J Basic Clin. Physiol. Pharmacol. 2015;26(4):335–346.
25. Yoon G, Park S. Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr. Res. Practice. 2014;8(6):618–624.
26. Chen YC, Sugiyama Y, Abe N, Kuruto-Niwa R, Nozawa R, Hirota A. DPPH radical-scavenging compounds from dou-chi, a soybean fermented food. Biosci Biotechnol. Biochem. 2005;69(5):999–1006.
27. Miraghajani M, Zaghian N, Mirlohi M, Feizi A, Ghiasv R. The impact of probiotic soy milk consumption on oxidative stress among type 2 diabetic kidney disease patients: A randomized controlled clinical trial. J. Renal Nutr. 2017;27(5):317-324.
28. Amadou I, Gbadamosi OS, Shi YH, Kamara MT, Jin S, Le GW. Identification of Antioxidative peptides from Lactobacillus plantarum Lp6 fermented soybean protein meal. Res. J. Microbiol. 2010;5(5):372-380.
29. Lee JH, Hwang CE, Son KS, Cho KM. Comparisons of nutritional constituents in soybeans during solid state fermentation times and screening for their glucosidase enzymes and antioxidant properties. Food Chem. 2019;272:362-371.
30. Lai LR, Huang SC, Chou HY, Chun C. Effect of lactic fermentation on the total phenolic, saponin and phytic acid contents as well as anti-colon cancer cell proliferation activity of soymilk. J. Biosci. Bioeng. 2013;115(5):552–556.
31. Zhu Y, Wang A, Liu MC, Zwart A, Lee RY, Gallagher A, et al. Estrogen receptor alpha positive breast tumors and breast cancer cell lines share similarities in their transcriptome data structures. Intl. J. Oncology. 2006;29(6):1581-1589.
32. Lima A, Oliveira J, Saude F, Mota J, Ferreira RB. Proteins in soy might have a higher role in cancer prevention than previously expected: Soybean protein fractions are more effective mmp-9 inhibitors than non-protein fractions, even in cooked seeds. Nutrients. 2017;9(3):201.
33. Lee JH, Nam SH, Seo WT, Yun HD, Hong SY, Kim MK, et al. The production of surfactin during the fermentation of cheonggukjang by potential probiotic Bacillus subtilis CSY191 and the resultant growth suppression of MCF-7 human breast cancer cells. Food Chem. 2012;131(4):1347-1354.
34. Sanjukta S, Rai AK. Production of bioactive peptides during soybean fermentation and their potential health benefits. Trends Food Sci.Technol. 2016;50:1-10.
35. Pabona JMP, Dave B, Su Y, Montales MTE, Lumen BOD, Mejia EGD, et al. The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein. Genes & nutrition. 2013;8(1):79-90.
36. Singh BP, Vij S, Hati S. Functional significance of bioactive peptides derived from soybean. Peptides. 2014;54:171-179.
37. Lule VK, Garg S, Pophaly SD, Tomar SK. Potential health benefits of lunasin: a multifaceted soy‐derived bioactive peptide. J. Food Sci. 2015;80(3):R485-R494.
38. Kim SE, Kim HH, Kim JY, Kang YI, Woo HJ, Lee HJ. Anticancer activity of hydrophobic peptides from soy proteins. Biofactors. 2000;12(1-4):151-155.
39. Park JH, Jeong HJ, Lumen BOD. In vitro digestibility of the cancer-preventive soy peptides lunasin and BBI. J. Agr. Food Chem. 20074;55(26):10703-10706.
40. Chatterjee C, Gleddie S, Xiao CW. Soybean bioactive peptides and their functional properties. Nutrients. 2018;10(9):1211.
41. Xiao CW. Health effects of soy protein and isoflavones in humans. J Nutr. 2008;138(6):1244S-1249S.
42. Sarkar FH, Li Y. Soy isoflavones and cancer prevention: clinical science review. Cancer Investigation. 2003;21(5):744-757.
43. Seo HS, Choi HS, Choi HS, Choi YK, Um JY, Choi I, et al. Phytoestrogens induce apoptosis via extrinsic pathway, inhibiting nuclear factor-κB signaling in HER2-overexpressing breast cancer cells. Anticancer Res. 2011;31(10):3301-3313.
44. Li Z, Li J, Mo B, Hu C, Liu H, Qi H, et al. Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicology in Vitro. 2008;22(7):1749-1753.
45. Uifalean A, Schneider S, Ionescu C, Lalk M, Iuga CA. Soy isoflavones and breast cancer cell lines: molecular mechanisms and future perspectives. Molecules. 2016;21(1):13.
46. Carroll KK. Review of clinical studies on cholesterol-lowering response to soy protein. J. Am. Dietetic Assoc. 1991;91(7):820-827.
47. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. New Eng. J. Med. 1995;333(5):276-282.
48. Endres JG. Soy protein products: characteristics, nutritional aspects, and utilization. The American Oil Chemists Society. 2001.
49. Sathyapalan T, Aye M, Rigby AS, Fraser WD, Kilpatrick ES, Atkin SL. Effect of soy on bone turn-over markers in men with type 2 diabetes and hypogonadism–a randomised controlled study. Scientific Reports. 2017;7(1):15366.
50. Sathyapalan T, Aye M, Rigby AS, Thatcher NJ, Dargham SR, Kilpatrick ES, et al. Soy isoflavones improve cardiovascular disease risk markers in women during the early menopause. Nutrition Metabol. Cardiovas. Dis. 2018;28(7):691-697.
51. Tsai JS, Lin YS, Pan BS, Chen TJ. Antihypertensive peptides and γ-aminobutyric acid from prozyme 6 facilitated lactic acid bacteria fermentation of soymilk. Process Biochem. 2006;41(6):1282-1288.
52. Vermaak I, Viljoen AM, Hamman JH. Natural products in anti-obesity therapy. Natural Product Reports. 2011;28(9),1493-1533.
53. Pan MH, Tung YC, Yang G, Li S, Ho CT. Molecular mechanisms of the anti-obesity effect of bioactive compounds in tea and coffee. Food Function. 2016;7(11):4481-4491.
54. Pallottini V, Bulzomi P, Galluzzo P, Martini C, Marino M. Estrogen regulation of adipose tissue functions: involvement of estrogen receptor isoforms. Infectious Disorders-Drug Targets. 2008;8(1):52-60.
55. Park HJ, Della-Fera MA, Hausman DB, Rayalam S, Ambati S, Baile CA. Genistein inhibits differentiation of primary human adipocytes. J. Nutr. Biochem. 2009;20(2):140-148.
56. Harmon AW, Harp JB. Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis. American J. Physiol. 2001;280(4):C807-C813.
57. Szkudelska K, Nogowski L, Szkudelski T. Genistein, a plant-derived isoflavone, counteracts the antilipolytic action of insulin in isolated rat adipocytes.  J. Steroid Biochem. Mol. Biol. 2008;109(1-2):108-114.
58. Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, et al. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 2005;338(2):694-699.
59. Agarwal R. Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochemical Pharmacol. 2000;60(8):1051-1059.
60. Wang S, Wang Y, Pan MH, Ho CT. Anti-obesity molecular mechanism of soy isoflavones: weaving the way to new therapeutic routes. Food Function. 2017;8(11):3831-3846.
61. Yoon G, Park S. Antioxidant action of soy isoflavones on oxidative stress and antioxidant enzyme activities in exercised rats. Nutr. Res. Practice. 2014;8(6):618–624.
62. Hirota K, Morikawa K, Hanada H, Nonaka M, Nakajima Y, Kobayashi M, et al. Effect of genistein and daidzein on the proliferation and differentiation of human preadipocyte cell line. J. Agricul. Food Chem. 2010;58(9):5821-5827.
63. Crespillo A, Alonso M, Vida M, Pavón FJ, Serrano A, Rivera P, et al. Reduction of body weight, liver steatosis and expression of stearoyl‐CoA desaturase 1 by the isoflavone daidzein in diet‐induced obesity. British Journal of Pharmacology. 2011;164(7):1899-1915.
64. Ali AA, Velasquez MT, Hansen CT, Mohamed AI, Bhathena SJ. Effects of soybean isoflavones, probiotics, and their interactions on lipid metabolism and endocrine system in an animal model of obesity and diabetes. J. Nutr. Biochem. 2004;15(10):583-590.
65. Kim MH, Park JS, Jung JW, Byun KW, Kang KS, Lee YS. Daidzein supplementation prevents non-alcoholic fatty liver disease through alternation of hepatic gene expression profiles and adipocyte metabolism. Intl. J. Obesity. 2011;35(8):1019-1030.
66. Velasquez MT, Bhathena SJ. Role of dietary soy protein in obesity. Intl. J. Med. Sci. 2007;4(2):72-82.
67. Takabayashi T, Imoto Y, Sakashita M, Kato Y, Tokunaga T, Yoshida K, et al. Nattokinase, profibrinolytic enzyme, effectively shrinks the nasal polyp tissue and decreases viscosity of mucus. Allergology Intl. 201766(4):594-602.
68. Lee SJ, Rim HK, Jung JY, An HJ, Shin JS, Cho CW, et al. Immunostimulatory activity of polysaccharides from Cheonggukjang. Food Chemical Toxicol. 2013;59:476-484.
69. Zhang T, Pan W, Takebe M, Schofield B, Sampson H, Li XM. Therapeutic effects of a fermented soy product on peanut hypersensitivity is associated with modulation of T-helper type 1 and T-helper type 2 responses. Clin. Experimental Allergy. 2008;38(11):1808-1818.
70. Masilamani M, Wei J, Bhatt S, Paul M, Yakir S, Sampson HA. Soybean isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut. J. Allergy Clin. Immunol. 2011;128(6):1242–1250.
71. Mirahmadi SMS, Shahmohammadi A, Rousta AM, Azadi MR, Fahanik-Babaei J, Baluchnejadmojarad T, et al. Soy isoflavone genistein attenuates lipopolysaccharide-induced cognitive impairments in the rat via exerting anti-oxidative and anti-inflammatory effects. Cytokine. 2018;104:151-159.
72. Kerwin SM. Soy saponins and the anticancer effects of soybeans and soy-based foods. Curr. Med. Chem. Anti-Cancer Agents. 2004;4(3):263-272.
73. Srikanth S, Chen Z. Plant protease inhibitors in therapeutics-focus on cancer therapy. Frontiers Pharmacol. 2016;7:470.