Biological Functionality of Soyasaponins and Soyasapogenols

Review pubs.acs.org/JAFC

Biological Functionality of Soyasaponins and Soyasapogenols Cuie Guang,*,† Jie Chen,† Shangyuan Sang,† and Shuiyuan Cheng*,§ †

State Key Laboratory of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, People’s Republic of China § Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University, Huanggang, Hubei 438000, People’s Republic of China ABSTRACT: Soyasaponins are a group of structurally complex oleanane triterpenoids primarily found in soybeans and have diverse biological properties. The recent investigations and findings (since 2000) regarding the biological functions of soyasaponins and their aglycones, including their anti-inflammatory, antimutagenic, anticarcinogenic, antimicrobial, and hepatoand cardiovascular-protective activities, are herein summarized. The primary conclusion is that the use of soyasaponins and soyasapogenols in functional foods should be considered. KEYWORDS: soyasaponin, soyasapogenol, anti-inflammatory, anticarcinogenic, hepatoprotective, cardiovascular

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INTRODUCTION

main metabolites, soyasapogenol A and soyasapogenol A 3-β-Dglucuronide, despite the different metabolic activities and pathways among individuals.9 When group B soyasaponins were digested by healthy women, the metabolite was soyasapogenol B and was excreted in the feces.10 In particular, soyasaponin I was metabolized to soyasapogenol B by human fecal microorganisms via soyasaponin III or, alternatively, via soyasaponin III and soyasapogenol B 3-β-D-glucuronide with apparent first-order kinetics.8,11 The transepithelial transfer of soyasaponin I across a human colon cancer Caco-2 cell monolayer was concentration independent and saturable with an intermediate apparent permeability coefficient (Papp) of (0.9−3.6) × 10−6 cm/s, whereas soyasapogenol B was transported across Caco-2 cells in a concentration-dependent manner with a low Papp of (0.3−0.6) × 10−6 cm/s.10 Due to its tighter paracellular route, the Caco-2 model often underestimates the permeability of compounds in the human intestine.12 With diverse chemical structures, soyasaponins and soyasapogenols have been reported to possess a wide range of health benefits, including anticancer, antivirus, and antioxidant activities, as well as hepatoprotective and cardiovascularprotective effects.2,4 In this review, recent studies (since 2000) concerning the biological functions of these compounds have been summarized (Table 1).

Soyasaponins are found in soybeans (Glycine max) and other legumes, such as lentils (Lens culinaris) and green peas (Pisum sativum L). Soyasaponins are amphiphilic oleanane triterpenoid glycosides with polar sugar chains conjugated to a nonpolar pentacyclic ring1 and are generally classified into four major groups according to their aglycones (soyasapogenols): groups A, B, E, and DDMP (2,3-dihydro-2,5-dihydroxy-6-methyl-4Hpyran-4-one). Group A soyasaponins are characterized as having a hydroxyl group at C-21 and two sugar moieties separately attached at the C-3 and C-22 positions of soyasapogenol A,2 with an exceptional compound, A3, that contains one sugar moiety at C-3.3 In addition to a starting glucoronyl residue, the C-3 side chain has one or two more sugar residues, and the C-22 sugar moiety contains two sugar residues: a starting arabinosyl and an ending xylosyl or glycosyl residue.4 Group A soyasaponins can be further grouped into acetylated and deacetylated forms.1 Group B soyasaponins differ from those in group A by the presence of a hydrogen atom at C-21 and only one sugar moiety at the C-3 position of soyasapogenol B,2 with the exception of three soyasaponins that, in addition to the C-3 sugar chain, contain a sugar moiety at C-22.5,6 Additionally, soyasaponin Bh, which has a unique five-membered ring exhibiting hemiacetal activity, has been identified.7 With a DDMP group connected to group B at C-22, DDMP soyasaponins are sometimes categorized as B-type soyasaponins.1 Unlike DDMP soyasaponins, group E soyasaponins have a carbonyl group at C-22 that may be produced by the photo-oxidation of group B. Approximately 36 soyasaponins have been found in soybean.2,4 As aglycones of soyasaponins, soyasapogenols A, B, and E do not occur in soybean naturally but can be formed by the acid or alkaline hydrolysis of soyasaponins and therefore may exist in processed soy products. Soyasapogenols C and D may result from the acid hydrolysis of soyasapogenol B and are not genuine aglycones of soyasaponins.2,4 The physiological effects of soyasaponins are dependent on their metabolism and absorption.8 The anaerobic incubation of soyasaponin Ab with human fecal specimens produced two © 2014 American Chemical Society

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ANTI-INFLAMMATORY EFFECTS A crude extract of soyasaponins significantly inhibited the production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and chemokine monocyte chemoattractant protein (MCP)-1, the inflammatory mediators prostaglandin E2 (PGE2) and nitric oxide (NO), and the inflammatory enzymes cyclooxygenase (COX)-2 and inducible nitric oxide Received: Revised: Accepted: Published: 8247

December 30, 2013 July 25, 2014 July 29, 2014 July 29, 2014 dx.doi.org/10.1021/jf503047a | J. Agric. Food Chem. 2014, 62, 8247−8255

8248

anti-inflammatory

anti-inflammatory hepatoprotective adjuvant

anti-inflammatory

anticarcinogenic

soyasaponin Ab

soyasaponin A1/ soyasaponin A2

soyasaponin A3

soyasapogenol A

soyasaponins B + E + DDMP

anticarcinogenic

soyasaponins A2 + I + II + III + V + Be

antimutagenic

antiviral

hepatoprotective

anticarcinogenic

soyasaponins with no soyasapogenols

lung-protective

hepatoprotective

anticarcinogenic

Chinese hamster ovary cells

Vero cells

HT-29 cells Hep-G2 cells breast cancer MDA-MB-231 cells breast cancer MCF-7 cells Hep-G2 cells mice injected with Con A

THP-1 monocytic leukemia cells

LPS-stimulated macrophages mice mice

LPS-stimulated macrophages TNBS-induced colitic mice

cervical carcinoma HeLa cells

hepatocarcinoma Hep-G2 cells

colon cancer DLD-1 cells mice injected with colon carcinoma CT-26 cells fibrosarcoma HT-1080 cells mice mice with acute alcoholinduced liver damage rats with silicotic pulmonary fibrosis

S. typhimurium Hep-G2 cells colon cancer HT-29 cells

antimutagenic

in vitro/in vivo LPS-stimulated macrophages helper T cells

effect

anti-inflammatory

material

total soyasaponins

mechanism

ref

inhibit 2AAAF-induced DNA damage by interception of reactive molecules

39 43 46

estrogen-like activity protect against aflatoxin B1-induced cytotoxicity reduce the number of infiltrating inflammatory cells in the liver and apoptotic bodies in the liver parenchymal cells, plasma TNF-α level and ALT activity anti-HSV-1 activity

21

57

26 32 39

18

15 44 62

inhibit growth inhibit proliferation; induce a sub-G1 buildup of apoptotic cells and morphological changes inhibit growth

inhibit the TNF-α-induced expression of ICAM-1

inhibit TNF-α, NO. and iNOS production, iNOS enzyme activity and NF-κB activity decrease lipid peroxidation in the liver stimulate antiovalbumin total-IgG and IgG1 antibody responses

14 14

34, 35

cytotoxic; change cell cycle distribution; increase NO content, the activities of NOS, and iNOS and intracellular Ca2+ levels; cause a loss of mitochondrial transmembrane potential; induce apoptosis inhibit TNF-α, PGE2, NO, and IL-1β production, IκB-α degradation and binding of LPS to TLR4 inhibit colon shortening, myeloperoxidase activity, the expression of TNF-α, IL-1β, COX-2, iNOS and TLR4, and the phosphorylation of IRAK1, IKK-β and p65; increase IL-10 expression

33

59, 60

23 44 45

27 23

20 20 22−25

13 17

inhibit proliferation; induce a sub-G1 buildup of apoptotic cells and morphological changes

inhibit the expression and secretion of MMP-2 and MMP-9; increase TIMP-2 secretion; suppress cell migration decrease lipid peroxidation in the liver by increasing the secretion of thyroid hormones protect plasma membrane integrity; increase liver regenerative capacity; decrease serum levels of hepatic marker enzymes and hepatic TG, TC, and MDA contents; activate the hepatic antioxidant system; prevent hepatic steatosis necrosis, inflammation, and swelling decrease serum NO and ROS contents and pulmonary MDA level; increase serum SOD level; inhibit Fas/FasL expression and lung cell apoptosis

inhibit TNF-α, MCP-1, PGE2, NO, COX-2, and iNOS production and IκB-α degradation increase p27KIP1 expression and stability; inhibit cyclin D and cyclin E expression, cell cycle transition and proliferation, and secretion of IL-2 and IFN-γ inhibit aflatoxin B1-induced mutagenicity by scavenging electrophiles inhibit the formation of aflatoxin B1-induced DNA adducts by changing membrane permeability alter membrane structure; inhibit cell growth and migration, IκB-α degradation, COX-2 and PKC expressions, and PKC activity; increase AP activity and CEA levels; induce autophagic death elicit cell cycle arrest at the G2 phase along with early apoptosis decrease the incidence of metastatic tumor colonization in lungs

Table 1. Biological Effects of Soyasaponins and Soyasapogenols

Journal of Agricultural and Food Chemistry Review

dx.doi.org/10.1021/jf503047a | J. Agric. Food Chem. 2014, 62, 8247−8255

8249

anti-inflammatory anticarcinogenic hepato-protective adjuvant

anti-inflammatory

soyasaponin III

soyasapogenol B

antimutagenic

hepatoprotective cardiovascular protective antiviral adjuvant

soyasaponin II

antimicrobial antioxidative adjuvant kidney protective

cardiovascular protective

hepatoprotective

MCF-7 cells

anticarcinogenic

THP-1 monocytic leukemia cells Chinese hamster ovary cells

inhibit 2AAAF-induced DNA damage by intercepting reactive molecules

inhibit the TNF-α-induced expression of ICAM-1

anticomplementary activity inhibit growth decrease lipid peroxidation in the liver by increasing the secretion of thyroid hormones stimulate antiovalbumin total-IgG and IgG1 antibody responses

anti-HSV-1 activity stimulate antiovalbumin total-IgG and IgG1 antibody responses

Vero cells mice in vitro HT-29 cells mice mice

decrease lipid peroxidation in the liver by increasing secretion of thyroid hormones inhibit renin activity

protect against immunological liver injury decrease lipid peroxidation in the liver by increasing secretion of thyroid hormones inhibit renin activity reduce blood pressure, plasma levels of LDLC, AST, ALT, and blood urea nitrogen inhibit growth scavenge DPPH radicals; inhibit lipid peroxidation in liposomes stimulate antiovalbumin total-IgG and IgG1 antibody responses reduce kidney weight, water content, and plasma creatinine and urea levels; impede kidney enlargement and cyst growth

inhibit TNF-α, IL-1β, PGE2, NO, COX-2, and iNOS productions, IκB-α phosphorylation, NF-κB activity, and iNOS enzyme activity anticomplementary activity inhibit colon shortening, myeloperoxidase activity, the expression of TNF-α, IL-1β, COX-2, iNOS, PGE2, and IL-6; and the activation of NF-κB and lipid peroxides; increase the glutathione content and SOD and catalase activities inhibit α2,3-sialyltransferase activity, ST3Gal IV sialyltransferase expression and the secretion of cell surface α2,3-sialic acids; stimulate cell adhesion decrease migration ability inhibit the expression of α2,3-sialic acids; increase cell adhesion; reduce cell migration decrease ability to grow into tumors in lungs

inhibit growth; induce apoptosis

28, 29

increase p27KIP1 content; decrease CDK-2 activity; inhibit cell cycle transition and proliferation; suppress Akt activity; activate ERK 1/2; induce macroautophagy cytotoxic; induce a significant accumulation of sub-G1 apoptotic cells inhibit growth and invasion; decrease S phase; cause loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into the cytosol, up-regulation of Apaf-1, activation of caspase-9 and caspase-3, and cleavage of polyADP-ribose polymerase and apoptosis inhibit α-glucosidase increase the fecal excretion of total bile acid and neutral sterols; lower the TC, non-HDLC, and TG concentrations and the TC-to-HDLC ratio

21

18

19 26 44 62

56 62

44 51

41 41 49, 51 54 55 16 62 63

38 40 40

38

15, 16 19 16

32

48 53

31 36

ref

mechanism

mice in vitro

MDA-MB-231 cells melanoma B16F10 cells mice injected with B16F10 cells cultured rat hepatocytes mice in vitro SHRs E. coli and C. albicans in vitro mice mice with PKD

LPS-stimulated macrophages in vitro TNBS-induced colitic mice

anti-inflammatory

soyasaponin I

Hep-G2 cells

in vitro hamsters

Hep-G2 cells glioblastoma SNB19 cells

colon cancer HCT-15 cells

in vitro/in vivo

anticarcinogenic


anticarcinogenic

effect

soyasaponins I + III

group B soyasaponins

material

Table 1. continued



effect


antiviral

anticarcinogenic

antioxidative

soyasapogenol E

DDMP soyasaponins

soyasaponin βg

antiviral

anti-inflammatory

antiviral

hepatoprotective

anticarcinogenic

group E soyasaponins

soyasapogenol C

material

Table 1. continued in vitro/in vivo

8250

in vitro

Hep-G2 cells

Vero cells

in vitro

THP-1 monocytic leukemia cells Vero cells

HT-29 cells Caco-2 cells Hep-G2 cells HeLa and lung cancer A549 cells MDA-MB-231 and MCF-7 cells Hep-G2 cells mice injected with Con A Vero cells

31

58

induce differentiation and morphological changes scavenge O2− and DPPH radicals

56

48

inhibit α-glucosidase

anti-HSV-1 activity

57

18

43 47 56, 57

anti-HSV-1 activity

inhibit TNF-α-induced expression of ICAM-1

protect against aflatoxin B1-induced cytotoxicity and actinomycin D-TNF-α-induced apoptosis; increase MLR lower plasma ALT level anti-HSV-1 activity

8, 39

inhibit proliferation

ref 26 10, 30 8, 33 8

mechanism inhibit growth inhibit proliferation and reduce viability inhibit proliferation; induce a sub-G1 buildup of apoptotic cells and morphological changes cytotoxic



Journal of Agricultural and Food Chemistry

Review

reducing the levels of the lipid peroxides malondialdehyde (MDA) and 4-hydroxy-2-nonenal and increasing the glutathione content as well as the superoxide dismutase (SOD) and catalase activities.16 These results indicate that soyasaponin I may ameliorate colitis by inhibiting NF-κB activation and consequently diminishing its ability to scavenge the lipid peroxides produced by TNBS. Soyasaponin Ab increased the expression of IL-10, an immunosuppressive and anti-inflammatory cytokine that inhibits NF-κB activation and consequently suppresses the production of pro-inflammatory cytokines. Soyasaponin Ab also inhibited the expression of TLR4 and the phosphorylation of IRAK1, the inhibitor of NF-κB kinase (IKK)-β, and the NF-κB subunit p65 in the colon of TNBSinduced colitic mice.14 Phosphorylated IRAK1 activates a multimeric protein complex, and the activated subunit, transforming growth factor-β activated kinase-1, phosphorylates IKKs. IKKs phosphorylate IκB-α, leading to its ubiquitination and subsequent degradation by the proteasome.14

synthase (iNOS) and the degradation of IκB-α, an inhibitor of nuclear transcription factor kappa B (NF-κB), in lipopolysaccharide (LPS)-stimulated macrophages.13 The phosphorylation and degradation of IκB-α allowed NF-κB to translocate to the nucleus, bind to specific promoter sequences, and induce the expression of inflammatory genes. Thus, it may be through the inhibition of NF-κB activation that soyasaponins exert their anti-inflammatory effects. Soyasaponins Ab, A1, A2, and I were confirmed to contribute to these anti-inflammatory properties.14−16 Furthermore, soyasaponins A1, A2, and I were found to inhibit iNOS enzyme activity and NF-κB transcriptional activity in LPS-stimulated murine RAW 264.7 macrophages.15 Soyasaponins Ab and I also suppressed the release of the proinflammatory cytokine interleukin (IL)-1β in LPS-stimulated mouse peritoneal macrophages.14,16 The IC50 values of soyasaponin Ab for inhibiting the production of PGE2 and NO and the expression of TNF-α and IL-1β were 2.0 ng/mL, 1.6 μM, 1.3 ng/mL, and 1.5 pg/mL, respectively. In addition, soyasaponin Ab prevented the binding of LPS and Alexa-Fluor594-conjugated LPS to Toll-like receptor 4 (TLR4),14 a receptor on macrophages that is linked to the NF-κB pathway via IL-1 receptor-associated kinases (IRAKs) and that recognizes pathogen-associated molecular patterns such as LPS. In contrast to soyasaponins A1, A2, and I, soyasapogenols A and B exhibited no inhibitory effect on the production of NO, iNOS, and TNF-α or on the iNOS enzyme activity in LPS-stimulated macrophages,15 indicating that the sugar chains in the structures of soyasaponins are critical to their antiinflammatory activities. Excessive helper T (Th) cell activity occurs during severe inflammation. Soyasaponins were found to enhance the expression and increase the stability of the negative regulator of cyclin-dependent kinases (CDKs) p27KIP1 and to decrease the expression of the positive CDK regulators cyclin D and cyclin E in Th cells. CDKs are key molecules for cell cycle progression. Soyasaponins were thus confirmed to block the G1-to-S phase cell cycle transition and inhibit the proliferation of Th cells, leading to the decreased mRNA transcription and secretion of cytokine IL-2 and interferon (IFN)-γ in Th cells.17 As a member of the immunoglobulin family of adhesion molecules, intercellular adhesion molecule (ICAM)-1 appears to cause acute and chronic inflammatory disease. Soyasaponin A3 mildly inhibited the TNF-α-induced expression of ICAM-1 on THP-1 human monocytic leukemia cells, soyasapogenols B and C exhibited strong inhibitory activities, and soyasapogenol A slightly activated ICAM-1 expression. These results indicate that the hydroxyl group at C-21 and the glycosyl group at C-3 influence the inhibition of ICAM-1.18 The excessively activated complement system acts fatally on organ transplantation, and its modulation is important in the treatment of inflammatory diseases. Soyasaponin III showed a stronger anticomplementary activity than did soyasaponin I, and their activities were influenced by the nature of glucuronic acid; the free acid forms (−COOH) displayed much more potent activity than did the sodium salt forms (−COO−Na+), methyl ester forms (−COOCH3), or reduced forms (−CH2OH).19 In addition to down-regulating the expression of TNF-α, IL1β, COX-2, and iNOS, orally administered soyasaponins Ab and I potently ameliorated body weight reduction, colon shortening, macroscopic score, and myeloperoxidase activity in the colon of 2,4,6-trinitrobenzenesulfonic acid (TNBS)induced colitic mice.14,16 Soyasaponin I also suppressed the expression of PGE2 and another potent pleiotropic inflammatory cytokine, IL-6, and suppressed the activation of NF-κB,

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ANTI-MUTAGENIC AND ANTI-CARCINOGENIC EFFECTS Crude soyasaponins strongly inhibited aflatoxin B1-induced mutagenicity and blocked the initiation step of carcinogenesis by inhibiting the formation of aflatoxin B1-induced DNA adducts.20 Additionally, an ethanol extract consisting of group B, E, and DDMP soyasaponins, as well as the purified soyasapogenol B, both repressed 2-acetoxyacetylaminofluorene (2AAAF)-induced DNA damage in Chinese hamster ovary cells and thus exhibited antigenotoxic activity against 2AAAF.21 Crude soyasaponins changed the membrane structure and inhibited the growth of WiDr human colon cancer cells (the same cell line as HT-29) by reducing the activity of protein kinase C (PKC) while increasing the activity of alkaline phosphatase (AP) at lower concentrations or by inducing autophagic death at higher concentrations.22 PKC activity increases as cells undergo the proliferation process, and AP activity is a marker of cell differentiation. For the HT-29 cell line, crude soyasaponins were additionally found to inhibit cell migration and increase the level of another differentiation marker, carcinoembryonic antigen (CEA).23,24 In addition, crude soyasaponins suppressed the degradation of IκB-α and down-regulated the expression of COX-2 and PKC in HT-29 cells,25 indicating that the anti-inflammatory activity of soyasaponins is involved in their anticarcinogenic function. Soyasapogenols A and B were found to inhibit the growth of HT-29 cells more strongly than did soyasaponin III.26 For DLD-1 colon cancer cells, treatment with soyasaponins also elicited cell cycle arrest at the G2 phase and early apoptosis.27 Group B soyasaponins, at physiologically relevant doses, increased the protein content of the CDK inhibitor p27KIP1 and the inhibitory phosphorylation of CDK-2 at Tyr15 and decreased the activity of CDK-2, leading to an accumulation of HCT-15 colon cancer cells in S phase and, through this delay, suppressed cell proliferation. Group B soyasaponins also induced type II nonapoptotic programmed cell death or macroautophagy in the HCT-15 cell line, as indicated by the elevated concentration of microtubule-associated protein light chain-3 I and II, by the increased incorporation of monodansylcadaverine into autophagic vacuoles, and by morphological alterations, including reduced cytoplasmic density and prominent vacuolization.28 The autophagyinducing action in HCT-15 cells was due to the suppression of Akt activity by reducing the Akt phosphorylation at Ser473 8251



Review

collagen I and the Matrigel matrix. Soyasaponin I showed no effect on the migration of MCF-7, but it did significantly decrease the migration ability of highly metastatic MDA-MB231 breast cancer cells.38 Soyasapogenol B reduced the proliferation of both estrogen-responsive MCF-7 cells8,39 and estrogen-insensitive MDA-MB-231, and soyasapogenol A inhibited the growth of MDA-MB-231 but stimulated MCF-7 cell proliferation. Soyasapogenol A also increased estrogeninduced pS2 mRNA expression and activated the estrogen receptor in MCF-7 cells,39 indicating an estrogen-like activity of soyasapogenol A that might have the same in vivo anticarcinogenic and health-promoting functions as those reported for the soybean phytoestrogen genistein. Soyasaponin I inhibited the expression of α2,3-sialic acids on the surface of highly metastatic B16F10 melanoma cells; increased cell adhesion to the extracellular matrix proteins collagen IV, fibronectin, and laminin; and reduced cell migration. Additionally, soyasaponin I-treated B16F10 cells showed a markedly decreased ability to grow into tumors in the lungs of experimental mice that had harbored the cells for a 2 week period after tail-vein delivery.40 Soyasapogenol B exhibited potent cytotoxicity against A549 lung cancer cells.8

and the activation of ERK 1/2, in part modulated by enhanced raf-1 activity.29 Soyasapogenol B was found to inhibit the proliferation and reduce the viability of Caco-2 cells.10,30 Feeding with dietary soyasaponins also decreased the incidence of metastatic tumor colonization in the lungs of mice injected with colon carcinoma CT-26 cells.23 A reflux extract consisting of group B soyasaponins was cytotoxic to hepatocarcinoma Hep-G2 cells with an LC50 value of 0.55 mg/mL and produced a significant accumulation of subG1 apoptotic cells, and a room temperature extract containing a greater amount of DDMP soyasaponins induced differentiation and morphological changes.31 Another extract containing a majority of soyasaponins I and III inhibited Hep-G2 growth with an LC 50 value of 0.39 mg/mL. The significant accumulation of sub-G1 cells, mid- and late-apoptotic cells, and dead cells confirmed the apoptosis-inducing effects of soyasaponins I and III, with the cellular protein expression of the caspase family of enzymes being a main trigger of the apoptotic pathway.32 Soyasapogenols A and B more strongly inhibited Hep-G2 proliferation than did a soyasaponin extract containing no soyasapogenols, with LC50 values of 0.052, 0.128, and 0.594 mg/mL, respectively, and induced a greater sub-G1 buildup of apoptotic cells.8,33 All three compounds also induced morphological changes in Hep-G2 cells, such as nuclear condensation and fragmentation.33 The treatment of human fibrosarcoma HT-1080 cells with crude soyasaponins inhibited the mRNA expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9, increased the secretion of tissue inhibitor of metalloproteinase (TIMP)-2, and reduced cell migration.23 TIMP-2 contributes to the inhibition of pro-MMP-2 and acts as a specific inhibitor of MMP-2, and MMP-2 and MMP-9 degrade extracellular matrix components and contribute to the invasion and metastasis of cancer cells. A mixture containing soyasaponins A2, I, II, III, V, and Be had obvious cytotoxic effects on human cervical carcinoma HeLa cells, changing the cell cycle distribution and inducing apoptotic features, including nuclear fragmentation, cytoplasm shrinkage, and decreased cell volume.34 The apoptosis of HeLa cells might be due to the increased NO content and the activities of NOS and iNOS, the loss of mitochondrial transmembrane potential, or the increase in intracellular Ca2+ induced by the fraction released through the mitochondrial pathway.35 Soyasapogenol B also inhibited the proliferation of HeLa cells.8 For the SNB19 human glioblastoma cell line, group B soyasaponins inhibited cell growth and invasion and decreased the S phase of the cell cycle with a concomitant increase in the G0/G1 phase. The apoptosis of SNB19 cells induced by group B soyasaponins was due to the loss of mitochondrial transmembrane potential, the release of mitochondrial cytochrome c into the cytosol, and the subsequent upregulation of Apaf-1, the activation of caspase-9 and caspase3, and the specific cleavage of poly-ADP-ribose polymerase.36 Sialyltransferases catalyze the transfer of sialic acids to the nonreducing terminal positions on the sugar chains of glycoconjugates, and the increased sialylation is associated with oncogenic transformation and metastasis. Soyasaponin I, a sialyltransferase inhibitor,37 was predicted to inhibit the α2,3sialyltransferase activity of nonmetastatic MCF-7 breast cancer cells and depressed the mRNA expression of ST3Gal IV sialyltransferase and the secretion of cell surface α2,3-sialic acids. Soyasaponin I also stimulated MCF-7 cell adhesion to

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HEPATOPROTECTIVE EFFECTS Soyasaponin I exhibited protective activity toward immunological liver injury in primary cultured rat hepatocytes as measured by the reduced alanine aminotransferase (ALT) activity in the medium.41 The immunological liver injury was considered to be caused by complement-mediated cell damage.19 Soyasaponin III and soyasapogenol B exerted weak protective effects against the cytotoxicity of tert-butyl hydroperoxide to human liver-derived cells.42 Soyasapogenols A and B were found to protect against aflatoxin B 1-induced cytotoxicity to liver cells and, furthermore, soyasapogenol B protected against actinomycin D-TNF-α-induced apoptosis and increased the mixed lymphocyte reaction (MLR) in cultured cells. The marked decrease in MLR is proportional to the decrease in immune system function in patients and therefore increases the chance of infectious diseases; thus, soyasapogenol B may be a candidate therapeutic agent for chronic hepatitis.43 When total soyasaponins were administered to mice orally and intraperitoneally, significantly decreased lipid peroxidation was observed in the liver, with the effect of the intraperitoneally injected soyasaponins being comparable to that of αtocopherol. Soyasaponins increased the levels of serum thyroid hormones, which then restrained NADPH-dependent lipid peroxidation in vitro in liver microsomes more strongly than did α-tocopherol. Propylthiouracil, an antithyroid drug, decreased the effect of the soyasaponins, suggesting that the in vivo inhibition of lipid peroxidation by soyasaponins might be mediated through the secretion of thyroid hormones. Constituent group B soyasaponins (I, II, and III) showed much stronger in vivo reducing effects on hepatic lipid peroxidation than did group A soyasaponins (A1 and A2), and only group B soyasaponins induced a significant increase in thyroid hormones.44 The administration of crude soyasaponins in mice with acute alcohol-induced liver damage decreased the serum levels of the hepatic marker enzymes aspartate transaminase (AST), ALT, AP, and lactate dehydrogenase by stabilizing the plasma membrane and repairing the hepatic tissue damage as well as the hepatic triglyceride (TG), total cholesterol (TC), and MDA contents. A better profile of the antioxidant system with normal SOD, glutathione S-transferase, 8252



Review

respectively; thus, the hydroxyl group at C-21 and the carbonyl group at C-22 seem to reduce anti-HSV-1 activity; soyasapogenol C, with a double bond at C-21 and C-22 instead of the hydroxyl group in soyasapogenol A, showed moderate anti-HSV-1 activity.56,57

and glutathione peroxidase activities was also observed, which was associated with an increase in the hepatic glutathione level. In addition, crude soyasaponins prevented hepatic steatosis necrosis, inflammation, and swelling in acutely alcohol-treated mice.45 Concanavalin (Con) A injection into mice can lead to autoimmune or viral hepatitis. Soyasapogenol A reduced the number of infiltrating inflammatory cells in the liver and the elevated level of plasma TNF-α and then reduced the elevated plasma ALT activity and the number of apoptotic bodies in the liver parenchymal cells, resulting in the prevention of liver damage in the Con A-induced hepatitis mouse model.46 Similarly, soyasapogenol B lowered the elevated plasma ALT level in a mouse model, with two hydroxyl groups on the A ring of soyasapogenol B required for the amelioration.47

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ADDITIONAL EFFECTS Soyasaponin I showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity with a 50% inhibitory concentration of 70.2 μM, which is comparable to that of α-tocopherol (IC50 = 52.1 μM). Soyasaponin I also suppressed lipid peroxidation in liposomes prepared from L-α-phosphatidylcholine, with an IC50 of 19.5 μM.16 Soyasaponin βg at 1 mM showed an 8% O2− scavenging activity and at 25 μM exhibited a 20.9% DPPH radical-scavenging activity (IC50 = 63.8 μM), which is comparable to that of tert-butylhydroxytoluene (21%; IC50 = 67.5 μM). When a low concentration of gallic acid was added, a synergistic effect was observed, with an unpaired electron located on the carbons at C-4 and C-6 and on the ketone group at C-4 of the DDMP moiety of soyasaponin βg and a twoelectron reduction from gallic acid related to the synergistic scavenging action toward O2− and DPPH radicals.58 The treatment of rats with silicotic pulmonary fibrosis with soyasaponins decreased the serum NO and reactive oxygen species (ROS) contents as well as the MDA level in pulmonary tissue, increased the serum SOD level, and inhibited the expression of Fas and FasL and the apoptosis of lung cells, which thus retarded the progress of SiO2-induced pulmonary fibrosis.59,60 Soyasaponins bearing sugar chain(s) showed strong adjuvant activities and stimulated anti-chicken ovalbumin total-IgG and IgG1 antibody responses in mice.61 Among the bisdesmosidic soyasaponins, soyasaponin A1, with a long sugar side chain, induced stronger total IgG and IgG1 antibody responses than did soyasaponin A2. For the monodesmosidic soyasaponins, the antibody response decreased in the order soyasaponin I > II > III. The adjuvant activity of these soyasaponins increased with the ratio of hydrophilic sugar side chain(s) to lipophilic aglycone (HLB). Therefore, the number, length, and composition of sugar side chains affecting the HLB value would indicate the overall conformation of each saponin molecule, and the amphipathic structure would define the fundamental adjuvanticity of soyasaponins.62 Soyasaponin I also impeded kidney enlargement and cyst growth in the pyc mouse model of polycystic kidney disease (PKD), as indicated by the reduced kidney weight, water content, and plasma creatinine and urea levels.63 Human beings have consumed soybeans as a source of highquality protein and other nutrients for hundreds of years. This review summarizes recent findings regarding the health effects of soyasaponins and soyasapogenols. Clearly, the biological functionality of these compounds largely depends on the testing materials, methodology, and dose. Before they are used as components of functional foods, further studies of the in vivo and clinical effects of soyasaponins and soyasapogenols are necessary.

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CARDIOVASCULAR PROTECTIVE EFFECTS α-Glucosidase is involved in the development of diabetes. Group B, E, and DDMP soyasaponins showed strong inhibitory activities against this enzyme in vitro, with IC50 values of 10−40 μM.48 Renin is the rate-limiting enzyme in the renin− angiotensin system, and its overactivation leads to hypertension. A soybean embryo extract showed approximately 3fold higher human renin inhibitory activity than did a soybean cotyledon extract, and the active compound was shown to be soyasaponin I. Kinetic analysis indicated partial noncompetitive inhibition, with a Ki value comparable to that of synthetic tetradecanoyl acetal sodium sulfate, an analogue of sodium houttuynin.49,50 Following a simple structure and activity analysis of 14 saponins and sapogenols, the 3-O-β-Dglucopyranosiduronic moiety in saponins was found to be essential for renin inhibition. In addition to soyasaponin I, soyasaponin II contains such a structure and has a similar human renin inhibitory activity.51 Due to the bile acid- or cholesterol-binding ability in the digestive tract,52 group B soyasaponins increased the fecal excretion of total bile acid, primarily including cholic acid, and neutral sterols, including cholestane, coprostanol, lathosterol, and campesterol, and therefore improved the plasma cholesterol status by lowering the TC, non-high-densitylipoprotein cholesterol (HDLC), and TG concentrations as well as the TC-to-HDLC ratio in hamsters. Greater production of group B soyasaponin metabolites was associated with better plasma cholesterol status in hamsters, indicating that gut microbial variation in soyasaponin metabolism influences the health effect of group B soyasaponins.53 The oral administration of commercially purified soyasaponin I in spontaneously hypertensive rats (SHRs) significantly decreased their blood pressure and led to reductions in the plasma levels of low-density lipoprotein cholesterol (LDLC), AST, ALT, and blood urea nitrogen, indicating that soyasaponin I may exert its liver and kidney protective functions by lowering blood pressure.54

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ANTIMICROBIAL AND ANTIVIRAL EFFECTS

Soyasaponin I was found to have moderate activities against Escherichia coli and Candida albicans, whereas soyasaponin III showed only weak activity against E. coli.55 Soyasaponin II showed much higher in vitro anti-herpes simplex virus type I (HSV-1) activity than did soyasaponin I, indicating the contribution of the glucosyl unit in the central sugar moiety to the antiviral activity.56 The activities of soyasapogenols A and E were less than 1/20 and 1/10 that of soyasapogenol B,

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AUTHOR INFORMATION

Corresponding Authors

*(C.G.) E-mail: [email protected]. Phone: 86-51085197883. *(S.C.) E-mail: [email protected]. Phone: 86-713-8833866 8253



Review

Funding

metabolites by human fecal microflora. J. Pharm. Biomed. 2010, 52, 752−756. (10) Hu, J.; Reddy, M. B.; Hendrich, S.; Murphy, P. A. Soyasaponin I and sapongenol B have limited absorption by Caco-2 intestinal cells and limited bioavailability in women. J. Nutr. 2004, 134, 1867−1873. (11) Hu, J.; Zheng, Y. L.; Hyde, W.; Hendrich, S.; Murphy, P. A. Human fecal metabolism of soyasaponin I. J. Agric. Food Chem. 2004, 52, 2689−2696. (12) Masungi, C.; Borremans, C.; Willems, B.; Mensch, J.; Dijck, A. V.; Augustijns, P.; Brewster, M. E.; Noppe, M. Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prrediction of the absorption potential of passively diffused compounds. J. Pharm. Sci. 2004, 98, 2507−2521. (13) Kang, J.; Sung, M.; Kawada, T.; Yoo, H.; Kim, Y.; Kim, J.; Yu, R. Soybean saponins suppress the release of proinflammatory mediators by LPS-stimulated peritoneal macrophages. Cancer Lett. 2005, 230, 219−227. (14) Lee, I.; Park, Y.; Joh, E.; Kim, D. Soyasaponin Ab ameliorates colitis by inhibiting the binding of lipopolysaccharide (LPS) to Tolllike receptor (TLR) 4 on macrophages. J. Agric. Food Chem. 2011, 59, 13165−13172. (15) Zha, L.; Mao, L.; Lu, X.; Deng, H.; Ye, J.; Chu, X.; Sun, S.; Luo, H. Anti-inflammatory effect of soyasaponins through suppressing nitric oxide production in LPS-stimulated RAW 264.7 cells by attenuation of NF-κB-mediated nitric oxide synthase expression. Bioorg. Med. Chem. Lett. 2011, 21, 2415−2418. (16) Lee, I.; Park, Y.; Yeo, H.; Han, M. J.; Kim, D. Soyasaponin I attenuates TNBS-induced colitis in mice by inhibiting NF-κB pathway. J. Agric. Food Chem. 2010, 58, 10929−10934. (17) Lee, S.; Bae, J.; Kim, S.; Jeong, S.; Choi, C.; Choi, S.; Kim, H.; Jung, W.; Imm, J.; Kim, S.; Chun, T. Saponins from soy bean and mung bean inhibit the antigen specific activation of helper T cells by blocking cell cycle progression. Biotechnol. Lett. 2013, 35, 165−173. (18) Ahn, K.; Kim, J.; Oh, S.; Min, B.; Kinjo, J.; Lee, H. Effects of oleanane-type triterpenoids from fabaceous plants on the expression of ICAM-1. Biol. Pham. Bull. 2002, 25, 1105−1107. (19) Oh, S.; Kinjo, J.; Shii, Y.; Ikeda, T.; Nohara, T.; Ahn, K.; Kim, J.; Lee, H. Effects of triterpenoids from Pueraria lobata on immunohemolysis: β-D-glucuronic acid plays an active role in anticomplementary activity in vitro. Planta Med. 2000, 66, 506−510. (20) Jun, H.; Kim, S.; Sung, M. Protective effect of soybean saponins and major antioxidants against aflatoxin B1-induced mutagenicity and DNA-adduct formation. J. Med. Food 2002, 5, 235−240. (21) Berhow, M. A.; Wager, E. D.; Vaughn, S. F.; Plewa, M. J. Characterization and antimutagenic activity of soybean saponins. Mutat. Res. 2000, 448, 11−12. (22) Tsai, C.; Chen, Y.; Chien, Y.; Huang, W.; Lin, S. Effect of soy saponin on the growth of human colon cancer cells. World J. Gastroenterol. 2010, 16, 3371−3376. (23) Kang, J.; Han, I.; Sung, M.; Yoo, H.; Kim, Y.; Kim, J.; Kawada, T.; Yu, R. Soybean saponin inhibits tumor cell metastasis by modulating expressions of MMP-2, MMP-9 and TIMP- 2. Cancer Lett. 2008, 261, 84−92. (24) Oh, Y.; Sung, M. Soybean saponins inhibit cell proliferation by suppressing PKC activation and induce differentiation of HT-29 human colon adenocarcinoma cells. Nutr. Cancer 2001, 39, 132−138. (25) Kim, H.; Yu, R.; Kim, J.; Kim, Y.; Sung, M. Antiproliferative crude soy saponin extract modulates the expression of IκB-α, protein kinase C, and cyclooxygenase-2 in human colon cancer cells. Cancer Lett. 2004, 210, 1−6. (26) Gurfinkel, D. M.; Rao, A. V. Soyasaponins: the relationship between chemical structure and colon anticarcinogenic activity. Nutr. Cancer 2003, 47, 24−33. (27) Jorud, I. N. The effect of generational feeding of soy and genistein-supplemented diets on progression of precancerous lesions in colon of second generation male rats. Master’s thesis, University of Illinois at Urbana−Champaign, USA, 2012.

This work was supported by the National Natural Science Foundation of China (Project 31201289), the Research Programs of the State Key Laboratory of Food Science and Technology (Jiangnan University, No. SKLF-ZZB-201208), and the Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization (No. 2011BLKF241). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Robert Phillips of the University of Georgia, Griffin, GA, USA, for his helpful comments.

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ABBREVIATIONS USED DDMP, 2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one; TNF, tumor necrosis factor; MCP, monocyte chemoattractant protein; PGE2, prostaglandin E2; NO, nitric oxide; COX, cyclooxygenase; iNOS, inducible nitric oxide synthase; NF-κB, nuclear transcription factor kappa B; IκB, inhibitor of NF-κB; LPS, lipopolysaccharides; IL, interleukin; TLR4, Toll-like receptor 4; IRAKs, IL-1 receptor-associated kinases; Th, helper T; CDKs, cyclin-dependent kinases; IFN, interferon; ICAM, intercellular adhesion molecule; TNBS, 2,4,6-trinitrobenzenesulfonic acid; MDA, malondialdehyde; SOD, superoxide dismutase; IKK, inhibitor of NF-κB kinase; 2AAAF, 2acetoxyacetylaminofluorene; PKC, protein kinase C; AP, alkaline phosphatase; CEA, carcinoembryonic antigen; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; ALT, alanine aminotransferase; MLR, mixed lymphocyte reaction; AST, aspartate transaminase; TG, triglyceride; TC, total cholesterol; Con, concanavalin; H(L)DLC, high (low)-density lipoprotein cholesterol; SHRs, spontaneously hypertensive rats; HSV-1, herpes simplex virus type I; DPPH, 1,1-diphenyl-2-picrylhydrazyl; ROS; reactive oxygen species; PKD, polycystic kidney disease

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Biological Functionality of Soyasaponins and Soyasapogenols

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