ISSN 0377-9556 (PRINT) ISSN 2383-9457 (ONLINE) 약학회지 제63권 제5호 259~267 (2019) Yakhak Hoeji Vol. 63, No. 5 DOI 10.17480/psk.2019.63.5.259 Review Beneficial Effects of Fermented Soybean through PPARs Activation in Metabolic Syndrome Radha Arulkumar*, EunJin Bang**, Sang-Gyun Noh*, Hee Jin Jung***, Dae Hyun Kim***, Takako Yokozawa****, and Hae Young Chung*,**,***,# *Interdisciplinary Research Program of Bioinformatics and Longevity Science, Pusan National University **College of Pharmacy, Pusan National University ***Longevity life Science and Technology Institutes, Pusan National University ****Graduate School of Science and Engineering for Research, University of Toyama (Received September 17, 2019; Revised October 11, 2019; Accepted October 14, 2019) Abstract Fermented soybean is an important fermented soybean food in Korea as it has many health benefits. The phytochemicals that are modified and concentrated by fermentation with Bacillus subtilis are isoflavone aglycones, flavonols, and gallic acid, which were produced by the activity of β-glucosidase and esterase. On the other hand, isoflavone glycosides and flavanol gallates were decreased. It possesses various biological activities such as anti-oxidative, anti-microbial, anti-cancer, anti-diabetic and neuroprotective effects. Therefore, recent research has paid great attention to fermented soy food products to improve human health. We performed in silico molecular docking simulation of increased phytochemical components during soybean fermentation for peroxisome proliferator-activated receptors (PPARs), which is a well-known nuclear receptor family for preventive roles in metabolic and inflammatory diseases. The results demonstrated that components such as epicatechin, daidzein, catechin, and genistein showed strong binding affinity with PPARs, suggesting their potential therapeutic effects. In this review, we highlighted the recent studies and possible action mechanisms of phytochemical extracts during the fermentation process of soybean and their potential health benefits to humans, especially for the treatment of the metabolic syndrome. Keywords Fermented soybean, Bacillus subtilis, phytochemicals, in silico docking simulation, PPARs Introduction contribute to enhanced biological properties of fermented soybeans as well as their nutritional contents.5) The phytochemicals contests Soy foods are one of the most common beneficial health foods are modified by fermentation by Bacillus subtilis (B. subtilis) with an exceptional source of essential nutrients provided in 100 converting soybean with greater healthy properties. For example, grams, serving high contents of the daily nutrition value, in these fermented soybean products include soybean cake (meju), particular, for protein (36%), dietary fiber (37%), iron (121%), soybean paste (Cheonggukjang), soybean sauce (kanjang).6) manganese (120%), phosphorus (101%) and several B vitamins, Fermented soybean is a popular fermented soybean, which is including folate (94%). High contents exist for vitamin K, used as one of the major dietary sources in Korea. Fermented magnesium, zinc and potassium with several biological properties soybean is generally considered to be a healthy consumption as it contains various phytochemicals such as isoflavones, saponins, product as is rich in sources of vitamins, lipids, protein, phytic acid, catechins, and trypsin inhibitors.1-3) Commercially, hydrolyzed peptides and other diverse nutrients.7) It possesses fermentation is the enzymatic decomposition process by microbes beneficial pharmacological characteristics and exerts anti-oxidative, used to increase biologically active compounds that potentially anti-microbial, anti-cancer and anti-diabetic activities.3,8) In addition, benefit human health.4) Previous reports suggest that microbes can it has the capability to modulate cholesterol in the human physiological system. It also has been demonstrated that fermented # soybeans consumption significantly correlate with a reduction of Corresponding author 9) Hae Young Chung, Department of Pharmacy, College of Pharmacy, the occurrence rate of breast and prostate cancer. Pusan National University, 2, Busandaehak-ro 63beon-gil, Geumjeong- Peroxisome proliferator-activated receptors (PPARs), a nuclear gu, Busan, 46241, Republic of Korea Tel: +82-51-510-2814; Fax: +82-51-518-2821 receptor protein family, is well-known to play an important role in E-mail: [email protected] lipid and glucose homeostasis.10) Therefore, PPARs targeting 259 260 Radha Arulkumar et al. molecules are developed as therapeutic target molecules to treat Biotransformation during Soybean diseases such as metabolic syndrome and inflammatory diseases. Fermentation We performed in silico docking simulation of PPARs for fermented soybean extracts for their potential action mechanism. The previous report suggests that phytochemical contents such And we highlight the nutritional contents and active compounds as isoflavones, flavonols, and phenolic acids are changed during from fermented soybean and elaborate on possible action the process of fermentation of soybean by using B. subtilis CS90.27) mechanisms through PPARs activation for health benefits to Among phytochemical constituents, 15 isoflavone, flavonols, and human beings. phenolic acids either increased or decreased during fermentation. Specifically, the levels of isoflavone aglycones, and flavonols, and Roles of PPARs in Diseases gallic acid increased significantly, while the isoflavone glycosides, malonylglycosides, and flavonol gallates decreased (Table 1). In The PPARs are a subfamily of three transcription factors that addition, garlic affected the soybean fermentation by B. belong to the superfamily of nuclear hormone receptors.11) PPAR amyloliquefaciens MJ1-4. It altered the total amount of phenolic subfamily consists of three members: PPARα, PPARβ/δ, and and 12 isoflavones or isoflavone glycodise, including daidzin, PPARγ.11) PPARs regulates the expression of a large number of glycitin, genistin, malonyldaidzin, malonylglycitin, acetyldaidzin, genes involved in metabolic homeostasis, lipid, glucose, and malonylgenistin, acetylglycitin, daidzein, glycitein and genistein, energy metabolism, adipogenesis, and inflammation.12-14) As which correlated with the higher anti-oxidative activity.3) Phytochemicals PPARs regulate a large number of genes and metabolic pathways, like isoflavones, flavonols, and phenolic acids have shown many its involvement in the pathogenesis is implicated in diseases such potential health benefits. It is well established that isoflavones as metabolic syndrome, type 2 diabetes mellitus (T2DM), have been reported to prevent atherosclerosis, osteoporosis, and nonalcoholic fatty liver disease (NAFLD), and cardiovascular postmenopausal syndrome.28,29) Flavonols act as excellent antioxidants disease.15-17) Therefore, they represent critical molecular targets for and chelating agents.30) Moreover, phenolic acids, such as the the development of new therapeutic drugs to treat these metabolic gallic acid and its derivatives are demonstrated to have anti- diseases. oxidative and anti-carcinogenic activities and exert various other PPARα is activated by ligand and plays a role as a nuclear health benefits.31,32) transcriptional factor.18,19) PPARα particularly regulates the expression of genes involved in fatty acid beta-oxidation and acts as an Biological Importance of Fermented important regulator of energy homeostasis.20) PPARγ contributes to Soybean the regulation of adipogenesis, lipid and glucose homeostasis and other pathophysiological processes.21) Commercial medications such As previously mentioned, fermented soybean has excellent as pioglitazone and rosiglitazone function as insulin sensitizers health benefits as it is a rich source of proteins, amino acids, and enhance insulin action and improve hyperglycemia in patients vitamins, minerals, and lipids. Fermented soybean’s characteristic with T2DM.22,23) Likewise, several PPARγ agonists have been fibrous texture comes from the release of γ-aminobutyric acid shown to effectively lower increased plasma free fatty acid levels, during fermentation.33) It has exhibited various biological activities improve excessive lipid accumulation in peripheral tissues such as and health benefits (Fig. 1). For example, it showed a potent in liver, skeletal muscle, heart, and hyperinsulinemia/insulin resistance vitro anti-cancer effect by inhibiting cancer cell growth and and modulate the expression of adipokines and inflammatory inducing apoptosis. Recently, Go et al.34) reported that fermented cytokines that impact hepatic and muscle metabolism and whole- soybean produced by mixed culture growth of both B. subtilis body insulin sensitivity.24,25) In addition, pharmacological modulation MC31 and Lactobacillus sakei 383 has exhibited neuroprotective of the PPARα/δ nuclear receptors by elafibranor, a dual agonist of effects in trimethyltin (TMT)-induced cognitive defects mice. The PPARα/δ, improved the histological resolution of non-alcoholic neuroprotective effects of fermented soybean were the result of steatohepatitis (NASH), and the cardiometabolic risk profile.26) inducing the release of nerve growth factor (NGF) and the Currently, elafibranor is on phase 3 trials in the target population promotion of superoxide dismutase (SOD) activity as well as of patients with moderate to severe symptoms. Therefore, PPARs inhibition of acetylcholinesterase (AChE) activity.34) Among are an important therapeutic target for intervention