Saponins from Sea Cucumber and Their Biological Activities - Journal

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Cite This: J. Agric. Food Chem. 2018, 66, 7222−7237

Saponins from Sea Cucumber and Their Biological Activities Ying-Cai Zhao,† Chang-Hu Xue,†,‡ Tian-Tian Zhang,*,† and Yu-Ming Wang*,†,‡ †

College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong China Qingdao National Laboratory for Marine Science and Technology, Laboratory of Marine Drugs & Biological Products, Qingdao 266237, China

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‡

ABSTRACT: Sea cucumbers, belonging to the phylum Echinodermata, have been valued for centuries as a nutritious and functional food with various bioactivities. Sea cucumbers can produce highly active substances, notably saponins, the main secondary metabolites, which are the basis of their chemical defense. The saponins are mostly triterpene glycosides with triterpenes or steroid in aglycone, which possess multiple biological properties including antitumor, hypolipidemic activity, improvement of nonalcoholic fatty liver, inhibition of fat accumulation, antihyperuricemia, promotion of bone marrow hematopoiesis, antihypertension, etc. Sea cucumber saponins have received attention due to their rich sources, low toxicity, high efficiency, and few side effects. This review summarizes current research on the structure and activities of sea cucumber saponins based on the physiological and pharmacological activities from source, experimental models, efficacy, and mechanisms, which may provide a valuable reference for the development of sea cucumber saponins. KEYWORDS: sea cucumber, saponins, bioactivities, mechanism, marine foods

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INTRODUCTION Sea cucumber, belonging to the phylum Echinodermata, is a valuable marine food as well as important source of medicine. Nearly 1400 species of sea cucumbers are found in the world,1 of which more than 40 species are edible.2 The sea cucumber has high edible and medicinal values due to its various active substances including polysaccharides, saponins, peptides, proteins, lipids, etc. These active ingredients have important physiological functions to human beings. For example, sea cucumber polysaccharides can enhance the immune function of cells, inhibit the activity of tumor cells, and effectively accelerate their death.3 The phospholipids extracted from sea cucumber possess lipid-lowering, hypoglycemic activities,4 antiatherosclerosis,5 and brain functions improvement.6 Small molecule peptides from sea cucumber also have many functions, such as lowering blood pressure and lipid,7 enhancing immunity,8 antifatigue,9 and antibacterial and antioxidant activities.10,11 Sea cucumber can produce highly active substances, saponins, the main secondary metabolites, which are the basis of their chemical defense. Saponins, glycosides of triterpenoid or steroidal aglycones, can form a colloidal solution by shaking with water, resulting in white and stable foam that will not disappear by heating. Among terrestrial organisms, saponins are mainly present in higher plants such as Panax spp., Glycyrrhiza spp., Polygala spp., Platycodon spp., Anemarrhena spp., Bupleurum spp., etc. In marine life, the vast majority of saponins exist in sea cucumbers, starfish and other organisms, of which the sea cucumber exhibits the most abundant content. Saponins have important physiological functions. Ginsenoside could delay the aging of the brain.12 Senegenin could alleviate cognitive impairment in animals.13 Saponins extracted from Yucca schidigera exhibited lowering cholesterol, antibacterial, and other bioactivities.14 Studies have shown that saponins extracted from animals especially from sea cucumber also had significant biological activities including © 2018 American Chemical Society

improvement of the metabolic syndrome, promotion of marrow hemopoiesis, antitumor and antiradiation activity. For example, crude saponins extracted from Ophicoma erinaceus could inhibit the proliferation, metastasis, and proliferation of cervical cancer cells.15 Sea cucumber saponin echinoside A exhibited antiobesity activity by promoting the fatty acids β-oxidation as well as inhibiting their biosynthesis.16 Sea cucumber saponins extracted from Holothuria leucospilota possessed antifungal and antibacterial activity to human pathogens.17 Crude saponins of Pearsonothria graef fei could promote animal marrow hematopoietic function.18 It is necessary to summarize the current research on the structure and activities of sea cucumber saponins based on the wide range of physiological and pharmacological activities.

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STRUCTURE OF SEA CUCUMBER SAPONINS

Sea cucumber saponins exhibit a unique chemical structure due to the marine environment compared with terrestrial plants, which determine the diversity of biological activities. The chemical structure of sea cucumber saponins is usually triterpenoid oligoglycoside, which is connected by aglycone and sugar chains through the β-glycosidic bond.19,20 The carbon skelecton of the aglycone, with the molecular weight of 500−1500 Da, is composed of 30 carbon atoms.21 Sea cucumber saponins are usually divided into the holostane and the nonholostane types on the basis of the different locations of the aglycone lactones, in which the majority of sea cucumber saponins are present in the holostane form (Figure 1).22,23 Received: Revised: Accepted: Published: 7222

April 10, 2018 June 18, 2018 June 22, 2018 June 22, 2018 DOI: 10.1021/acs.jafc.8b01770 J. Agric. Food Chem. 2018, 66, 7222−7237

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Journal of Agricultural and Food Chemistry

The 3-hydroxyl group study was designed to synthesize stable structure of the saponin. Aglycone of sea cucumber saponins is connected with the sugar chain (2−6 monosaccharides) including xylopyranose, glucose, quinose, 3methyl xylose, 3-methyl glucose in general by the β-Oglycosidic bond and the first glycosyl group linked with the aglycone is usually xylose.24 It has been considered that the structural diversity of sea cucumber saponin is caused by the combination of the different positions of functional groups on the aglycone and the hydroxyl groups on the monosaccharide. Sea cucumbers usually contain many structurally similar saponins. The saponins in sea cucumber Holothuria forskali are holostane triterpene glycoside, which can be divided into at least 16 different compounds, of which the substituents R1 and R2 on the aglycone is usually OH or H, the R3 substituent on the sugar chain is H, Glc, Glc-Qui, Glc-MeOGle (Glc, glucose; MeGlc, 3-O-methylglucose; Qui, quinovose), and the R4

Figure 1. Basic structure of holostane saponins extracted from sea cucumber.

Figure 2. Structures of saponins from Holothuria forskali. 7223

DOI: 10.1021/acs.jafc.8b01770 J. Agric. Food Chem. 2018, 66, 7222−7237

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Figure 3. Structure of saponins from Apostichopus japonicus.

substituent is CH3 or CH2OH (Figure 2).25 The saponins isolated from Apostichopus japonicus consist of eight nonholostane saponins (Figure 3), two of which, 17 and 18 have no lactone bond in the aglycone (compounds 1 and 2).26 La et al.27 elucidated the structures of three triterpene glycosides

frondoside A6, frondoside A, and frondoside A1 from Cucumaria frondosa on the basis of chemical evidence and spectral data. Yu et al.28 established the fingerprint chromatograms of triterpene glycosides in Stichopus japonicus for its quality control. Sulfated triterpene glycosides were also found 7224


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associated factors (TRAF) could inhibit apoptosis in the caspase-8 pathway and inhibit the activation of key enzymes such as caspase-3, 7, 9 in the apoptotic pathway via regulating the activity of IAP (inhibitor of apoptosis protein) family. Furthermore, NF-κB could inhibit MAPK (mitogen-activated protein kinase) for anticancer signaling pathways.41 Zhao et al.42 found that ds-echinoside A isolated from Pearsonothuria graef fei could promote apoptosis by activating NF-κB to exhibit marked anticancer activity in HepG2 cells. Matrix metalloproteinases (MMPs) family can promote cancer cell migration and angiogenesis. MMPs have the following roles in tumor metastasis: (i) MMPs can affect the activity of many growth factors and play an important role in the growth of the tumor through promoting their mitogenic activity or cell survival ability; (ii) MMPs can affect the cell adhesion and promote the dissociation and migration of tumor cells as well as the movement of tumor cells in the matrix and blood vessels; (iii) MMPs can release bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial growth factor) bound to matrix components via degrading ECM (extracellular matrix) and basement membrane components to eliminate the physical barrier; and (iv) MMPs can boost the expression of endogenous VEGF, thereby promoting angiogenesis.43,44 Zhao et al.45 studied the antitumor activity of 24-dehydroechinoside A extracted from Pearsonothuria graef fei and found that it could inhibit HepG2 cell migration and invasion via decreasing MMP-9 and inhibiting VEGF. Moreover, Tong et al.46 assessed the effects of philinopside A from Pentacta quadrangulari on angiogenesis and tumor growth in a series of models in vitro and in vivo. Results suggested that philinopside A was a promising anticancer agent with dual cytotoxic and antiangiogenic effects, which might be attributed to the inhibition on VEGF receptor. Table 1 presents the sea cucumber saponins with antitumor activity and the possible underlying mechanisms.42,45−73 Inhibition of Hyperlipidemia and Fatty Liver. Hyperlipidemia is the abnormalities of blood lipids with excessive triglycerides, cholesterol, and low-density lipoprotein due to a variety of causes.74 It has been reported that the sea cucumber could effectively reduce the serum cholesterol, low density lipoprotein, triglyceride levels, and atherosclerosis index in the model rats with hyperlipidemia. Diets containing sea cucumber (Isostichopus badionotus) exhibited hypocholesterolemic activity in the model.75 Wen et al.76 found that sea cucumber saponin significantly reduced serum lipid level.16 Another study was conducted to evaluate the effect of sea cucumber saponin liposomes in mice on a high-fat diet. The results indicated that saponin liposomes exhibited better effects on antiobesity and antihyperlipidemia activities than the common form of sea cucumber saponins. The liver is of crucial significance for lipid metabolism in the metabolic activity of an organism. The physiological or pathological changes in the liver lead to the accumulation of lipids, causing fatty liver.77 Fatty liver can be divided into acute fatty liver and chronic fatty liver in accordance with the incidence and duration of disease. The acute fatty liver is small vesicular fatty liver with high risk, which can cause jaundice, hepatic encephalopathy, and renal failure. The chronic fatty liver is bullous or bullae-dominated fatty liver. The most common is chronic fatty liver with the characteristics of occult onset, slow development, and longer duration.78 Fatty liver can be divided into alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD), in

in sea cucumber and Philinopsides A and B, belonging to sulfated triterpene glycosides, were isolated from Pentacta quadrangularis.29−31

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DIGESTION AND ABSORPTION OF SEA CUCUMBER SAPONINS The triterpenes glycosides can be digested and absorbed into tissues and organs. Joo et al.32 assessed the digestion and absorption of ginsenoside in serum after oral administration and found two peaks for the presumed absorption in stomach and intestines. A pharmacokinetic study investigated the digestion and absorption of two sulfated triterpenoid saponins echinoside A and holothurin A from Pearsonothuria graef fei. Results showed that serum echinoside A concentration rapidly declined in 5 min after intravenous administration, while holothurin A serum concentration decreased to its lowest level after 1 h. Further study indicated that echinoside A reached its peaks at 3 and 7 h in serum after oral administration, while the first peak of holothurin A occurred at 3 h and reached a second peak at 9 h, suggesting that echinoside A and holothurin A could be absorbed directly into the blood through the intestinal tract.33,34 Most food compounds undergo metabolic transformation into other forms and structures by the intestinal microorganism before being absorbed into the body. A previous study elucidated the metabolic characteristics of echinoside A and holothurin A by gut microflora. Results indicated that deglycosylation was the main intestinal microflora-mediated metabolic pathway for sea cucumber saponins and obtained deglycosylated metabolites could be absorbed by intestine.35

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BIOLOGICAL ACTIVITIES OF SEA CUCUMBER SAPONINS Sea cucumber saponins exhibit a variety of biological activities, including antitumor, improving hyperlipidemia, ameliorating fatty liver, restraining fat accumulation, regulating blood sugar, preventing gout, relieving hyperuricemia, promoting hematopoietic function of bone marrow, and antibacterial and antiviral activities. Antitumor Activity. Tumors are caused by the abnormal proliferation of tissue cells under the action of tumorigenic factors. A malignant tumor is a serious disease which endangers human life.36 Chemotherapy as the main means of cancer treatment has good curative effect. However, it often causes side effects such as myelosuppression and immune dysfunction, which makes it difficult for patients to adhere to the treatment.37 Moreover, resistance to chemotherapy drugs has become a difficult problem in the current clinical treatment.38 Therefore, it is necessary to seek remedies and therapeutic drugs with good curative effect, low toxicity, and side effects. Studies have shown that many sea cucumber saponins exhibit good antitumor activity and inhibition of tumor angiogenesis.39 There could be metastasis and tumor angiogenesis after the tumor development and the proliferation to a certain extent. Nuclear factor-kappa B (NF-κB) is one of the factors associated with tumor cell metastasis, which plays an important role in tumor cell apoptosis.40 It has been found that NF-κB could bind to the κB sites on the Bcl-2 (B-cell lymphoma-2), Bcl-xl (B-cell lymphoma-extra-large) gene, which could decrease the permeability of mitochondrial membrane and inhibit the release of cytochrome C. In addition, NF-κB acting as signaling pathway for TNF (tumor necrosis factor) receptor7225


name of saponin

experimental model

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STC in mouse CT-26 subcutaneous tumor and HL-60 leukemia xenograft models Human tumor cell lines (HL-60, NB4, THP-1) HL-60, HCT-116, BEL-7402, MKN-45 Human tumor cell lines (A549, HCT-116, HepG2, and MCF-7)

Frondoside A

Stichoposide C

Cucumariosides A2-2

Arguside A Arguside B, argusides c

stichorrenosides A−D

Total saponins Leucospilotaside D, holothurin B, holothurin B2

Human tumor cell lines (Hep-G2, KB (epidermoid carcinoma), LNCaP (prostate cancer), MCF7 (breast cancer), and SK-Mel2 (melanoma)) B16F10 Melanoma cells Human tumor cell lines (HeLa, BEL-7402, MCF-7)

Total saponins

Holothuria moebii Stichopus horrens

Holothuria leucospilota

Human tumor cell lines (HCT-8, HCT-15, HCT-116, CT-26)

Stichoposide D

Thelenota anax

Human leukemic K562 and HL-60 cell lines

Human tumor cell lines (A549, JB6 Cl41)

Okhotoside B1−B3

Cucumaria japonica Bohadschia argus

Human tumor cell lines (THP-1, HeLa, and JB6 Cl41)

Intercedenside A

Human cell lines (HepG2, HL-7702, H22), normal BALB/c male mice

Echinoside A and ds-echinoside A

Mensamaria intercedens Cucumaria okhotensis Cucumaria frondosa Thelenota anax

Human tumor cell lines (HepG2, HUVEC), CAM Human tumor cell line (ECV-304), CAM

Echinoside A 24-dehydro echinoside A

Mouse S180 sarcoma mouse liver cancer H22 Several tumor cell lines Mouse Lewis lung cancer and mouse S180 sarcoma

Human tumor cell lines (HepG2, ECV-304) Human tumor cell lines (HepG2, ECV-304), CAM

Holothurin A Ds-echinoside A

Colochiroside A

Tumor cell lines (P-388, A-549, MCF-7, MKN-28, HCT-116, and U87MG) Human tumor cell lines (Hep3B, MDA-MB231, A549)

Human tumor cell line HMECs

Human tumor cell line HMECs, rat aortas culture assay, chick embryo chorioallantoic membrane assay(CAM), mouse sarcoma 180 tumor Tumor cell lines (HMECs, HUVECs), CAM

Pentactasides I and II, philinopsides A and B Patagonicoside A

Philinopside E

Philinopside A

Colochirus anceps

Psolus patagonicus Pearsonothuria graef fei

Pentacta quadrangularis

source (sea cucumber) efficacy

Induce Apoptosis to resistant B16F10 Melanoma cells Show marked antitumor activity in vitro

Inhibit the proliferation of four different human colorectal cancer cells Show strong cytotoxicity

Suppress proliferation Show high cytotoxicities to A549 and HCT-116 cell lines Inhibit growth of leukemia xenografts

Induce apoptosis of leukemic cells

Suppress the PAK1-dependent growth of A549 lung cancer Induce apoptosis, reduce tumor growth

Reduce cell activity

Reduce cell activity, inhibit tumor growth Exhibit remarkable antineoplastic activities in vitro Antineoplastic activity

Exhibit marked anticancer activity in HepG2 cells

Suppress adhesion of tumor cells Inhibit the proliferation of HepG2, suppress HepG2 cell adhesion, migration, and invasion Inhibit tumor metastasis Inhibit angiogenesis

Show significant cytotoxicities against six tumor cell lines in vitro Inhibit tumor cell proliferation

Reduce cell viability, induce apoptosis, inhibit tumor blood neogenesis and tumor growth in vitro and in vivo Inhibit tumor cell proliferation, decrease proliferation of tumor cells and increase apoptosis of both endothelial cells and tumor cells Inhibit tumor angiogenesis

Table 1. Sea Cucumber Saponins with Anti-Tumor Activity and the Possible Underlying Mechanisms mechanism

Up-regulate caspase-3 and caspase-9l Not mentioned

Not mentioned

Activate Fas/ceramide synthase 6/p38 kinase lipid rafts Not mentioned

Not mentioned Not mentioned

Not mentioned

Activate acid and neutral SMase

Inhibit PAK1 in a selective manner

Not mentioned

Inhibit MMP-9 and VEGF expression Inhibit NF-κB-dependent MMP-9 and VEGF expressions Inhibit the expression of VEGF protein Promote the apoptosis of endothelial cells and inhibit the formation of endothelial cells in vitro Block cell-cycle progression and induce apoptosis through the mitochondrial pathway Not mentioned Not mentioned Not mentioned

Induce the activation of NF-kB

Block the interaction between kinase insert domain containing receptor (KDR) andαvβ3 integrin Not mentioned

Inhibit VEGFR2 signal

Inhibit RTKs pathway

ref

67 68

66

65

64

62 63

61

60

59

58

54 55,56 57

42

52 53

45 51

50

49

48

47

46

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73 show marked antineoplastic activity in vitro Human tumor cell lines (MKN-45, HCT-116)

Not mentioned

72 Not mentioned Show antitumor activity in vitro Human tumor cell lines (HL-60, MOLT-4, A-549)

71 Not mentioned Exhibit significant cytotoxicity against cancer cells

which NAFLD is the leading cause of chronic liver disease.79 NAFLD is a clinical pathological syndrome characterized by hepatocellular steatosis and lipid storage, excluding hereditary, extra-virulent, excessive alcohol consumption, and other factors. The disease spectrum mainly consists of four processes including simple fatty liver, nonalcoholic steatohepatitis, fatty liver fibrosis, and fatty liver cirrhosis.80 Animal experiments have proved that sea cucumber saponin has a good lipid-lowering effect to improve liver function. Han et al.81 studied the effect of the saponins extracted from Cucumaria f rondosa on improvement of nonalcoholic fatty liver in rats induced by orotic acid and found that liver TG, cholesterol, and TC levels decreased remarkably. Further mechanistic study suggested that sea cucumber saponins could inhibit the orotic acid-induced nonalcoholic fatty liver through inhibiting the activity of fatty acid synthase, down-regulating the expression of fatty acid synthesis related genes, and enhancing the activity of fatty acid β-oxidation related enzymes. Sterol regulatory element binding protein 2 (SREBP-2) is one of the important nuclear transcription factors in lipid metabolism, which is related to cholesterol synthesis and regulation.82 Inhibition of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase could suppress cholesterol synthesis.83 Wang et al.82 found that saponins extracted from Pearsonothria graef fei could significantly improve orotic acid-induced NAFLD by reducing liver lipid levels, which might be attributed to the inhibition of SREBP-2 and HMG-CoA reductase. Table 2 shows the effect of sea cucumber saponins on improvement of hyperlipidemia and NAFLD.16,81,82,84−89 Inhibition of Fat Accumulation. Obesity is associated with a series of physiological and pathological changes in the body due to an imbalance of energy metabolism including excessive intake or insufficient energy consumption. Obesity can be divided into visceral obesity (central obesity) and subcutaneous obesity (peripheral obesity) according to the site of fat accumulation. Central obesity is closely related to insulin and metabolic syndrome.90 Obese patients often have insulin resistance, dyslipidemia, hypercoagulable blood, and low-grade inflammatory state, which are the major risk factors for diabetes and cardiovascular disease, posing a significant threat to human health.91 Obesity is associated with the accumulation of fat in the body, which is closely implicated to the lipid metabolism in vivo. Fat Digestion and Absorption. The fat in food is usually triglycerides, which must be metabolized by lipase to be absorbed, and stored in adipose tissue, thereby leading to obesity (Figure 4). The digestion of fat mainly depends on the lipase in the digestive tract, in which the pancreatic lipase plays an important role. It has been considered that the inhibition of pancreatic lipase activity can suppress the digestion and absorption of fat in the small intestine and thus reduce the intake of exogenous fat to lose weight.92 It has been reported that sea cucumber saponins play an important role in lipid metabolism and can reduce fat accumulation. LXRs including LXR-β and LXR-α play essential roles in the regulation of cholesterol, triglycerides, fatty acids, and glucose homeostasis.93 Guo et al.89 found that sea cucumber saponins extracted from Pearsonothuria graef fei exhibited an antiobesity effect through inhibition of pancreatic lipase activity and upregulation of LXR-β signaling in C57BL/6 obese mice induced by high-fat diets.

Holothuria scabra

17-dehydroxyholothurinoside A and griseaside A Scabraside C, holothurin A1, echinoside A, 24-dehydroechioside A, holothurin A 24-dehydroechinoside A, echinoside B, echinoside A, holo thurin B and holothurin A Holothuria grisea

nobiliside D

ref

70 Not mentioned Promote cellular apoptosis

Induce DNA double strand breaks in a Top2-dependent manner.

mechanism efficacy

Inhibit the growth of tumors in mouse models and nude mouse models

Several cancer cell lines, mouse models inoculated tumor cells and human prostate carcinoma xenografts in nude mouse models Human tumor cells lines (K562, U937, A-549, HeLa, MCF-7 and HepG2) Cancer cell lines (HL-60, BEL-7402, Molt-4, and A-549)

experimental model name of saponin

Echinoside A Holothuria nobilis

source (sea cucumber)

Table 1. continued

69


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10 different species of sea cucumbers

Cucumaria f rondosa

Pearsonothuria graeffei


Total saponins

Total saponins

Echinoside A Total saponins

Total saponins

Total saponins

Total saponins

Total saponins

Total saponins

name of saponin

High fat diet mice model, HepG2

NAFLD rat model induced by orotic acid NAFLD rat model induced by orotic acid NAFLD rat model induced by orotic acid NAFLD rat model induced by orotic acid High-Fat Diet−Fed Mice Normal male ICR mice High fat model of SD rats Normal Wistar rats

experimental model

Lower the levels of TC and TG in both serum and liver Suppress adipose accumulation and reduced serum and hepatic lipids Reduce the accumulation of perirenal adipose tissue in rats, decrease the TC and TG concentrations in serum and liver Reduce the serum TC, TG and LDL-c

Ameliorate obesity, hepatic steatosis, and glucose intolerance

Reduce serum TG and TC, reduce fatty liver degeneration

Improve fatty liver

Inhibit cholesterol synthesis in the liver and reduce serum cholesterol levels

Alleviate NAFLD induced by orotic acid in rats, decrease the level of serum TG

efficacy

Table 2. Improvement of Hyperlipidemia and NAFLD by Sea Cucumber Saponins

Inhibit pancreatic lipase activity, up-regulate LXR-β signaling

89

81

16 88

Impair fatty acid synthesis and enhanced mitochondrial fatty acid β-oxidation Inhibit pancreatic lipase activity Suppress the activities of FAS

87

86

Enhance β-oxidation via PPARa activation.inhibit SREBP-1c-mediated lipogenesis increase adiponectin production and decrease tumor necrosis factor alpha level

85

82

84

ref

Not mentioned

Inhibit cholesterol synthesis rate-limiting enzyme HMG-CoA reductase, and cholesterol regulatory element binding protein SREBP-2 gene expression

Inhibit the enzymes activities and gene expressions involved in hepatic lipogenesis and enhance the activities of peroxisomal β-oxidation enzymes in liver

mechanism

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Figure 4. Possible underlying mechanism of sea cucumber saponins on fat digestion and obesity induced by fat accumulation. Sea cucumber saponins could repress the pancreatic lipase activity and increase fatty acid excretion in the feces to reduce the accumulation of adipose tissue.

Table 3. Improvement of Lipid Accumulation and Metabolism by Sea Cucumber Saponins source (sea cucumber) Pearsonothuria graef fei

10 different species of sea cucumbers

name of saponin

experimental model

efficacy

mechanism

ref

Inhibit the synthesis of fatty acids, and promote β-oxidation of fatty acids, lower serum TC, TG Reduce the body weight and tissue adipose Reduce the accumulation of mouse adipose tissue

Inhibit the expression of SREBP-1c gene, inhibit the activity of fatty acid synthase and glucose-6phosphate synthase Promote adiponectin secretion and β-oxidation of fatty acids Repress the pancreatic lipase activity and increase fatty acid excretion in the feces.

16

Inhibit the activity pancreatic lipase

99

C57BL/6 mice in high fat diet and low fat diet Normal ICR male mice

Suppress adipose accumulation, reduce serum and hepatic lipids Relieve metabolic disorders induced by obesity Improve lipids metabolism

100

High fat diet mice model, HepG2

Reduce body weight and serum lipid concentration

Inhibit lipid synthesis and accelerate lipid βoxidation and glycolysis in liver Regulate circadian rhythm of target genes expression or related hormones secretion Inhibit pancreatic lipase activity and up-regulate LXR-beta signaling

Echinoside A

Male ICR mice

Holothurin A, Echinoside A Echinoside A, Holothurin A Total saponins

C57/BL6 mice in high-fat diet Male Wistar rats orally administered the lipid emulsion Normal SD rat

Echinoside A, Holothurin A Total saponins Total saponins

Fatty Acid Anabolism. Fatty acid synthase (FAS), expressed in both human liver and adipose tissue, is one of the key enzymes involved in the synthesis of fatty acids mainly through slow regulation. Many studies have found that FAS is positively correlated with obesity, therefore the inhibition of FAS activity has become an important target for controlling obesity and lowering blood lipids. Furthermore, glucose-6-phosphate dehydrogenase (G-6PDH) is a key enzyme and the first ratelimiting enzyme catalyzing the pentose phosphate pathway, which can catalyze the conversion of glucose 6-phosphate to glucono-6-phosphate lactone, thereby generating NADPH.94 Moreover, malic enzyme (ME) can catalyze the formation of pyruvate from malic acid, converting NAD(P)+ to NAD(P)H which is mostly used for fatty acid synthesis.95 Fatty Acid Catabolism. Carnitine palmitoyl transferase (CPT) catalyzes the entry of long-chain fatty acids into the mitochondria through carnitine transport, and this process is a rate-limiting step in the fatty acids β-oxidation.96 Peroxisomes play an important role in the β-oxidation of long-chain fatty acids.97 A previous study has found that a sea cucumber saponin echinoside A could suppress fatty acid biosynthesis and stimulate hepatic fatty acid β-oxidation through the inhibition of G-6PDH and ME as well as the activation of CPT.16

87 98

101 89

Table 3 shows the effect of sea cucumber saponins on improvement in lipid accumulation and metabolism.16,87,89,98−101 Regulation of Blood Glucose Concentrations. Individuals with glucose metabolism disorders including impaired fasting glucose and/or impaired glucose tolerance have been referred as prediabetes, indicating the relatively high risk for the future development of diabetes.102 Hyperglycemia is the main manifestation of diabetes mellitus, which in turn impair the structure and function of many tissues in the body, especially the vascular system. Diabetes mellitus-induced longterm complications including diabetic coronary artery disease, diabetic retinopathy, and diabetic neuropathy may lead to severe morbidity or death.103 Diabetics usually cannot regulate blood glucose properly, which is mainly attributed to insufficient insulin or insulin resistance.104 Insulin resistance is a pathological condition in which cells fail to respond normally to the hormone insulin. Excess glucose is not sufficiently absorbed by cells even in the presence of insulin, thereby causing an increase in the level of blood sugar.105 Studies have shown that the saponins from terrestrial plants produce great improvement on the regulation of blood glucose and diabetes. It has been found that ginsenoside Rb3 could 7229


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Journal of Agricultural and Food Chemistry Table 4. Regulation of Blood Glucose by Sea Cucumber Saponins source (sea cucumber) Pearsonothuria graeffei

name of saponin Total saponin liposomes Total saponins Holothurin A, Echinoside A Total saponins Total saponins

Holothuria thomasi

Total saponins

experimental model High-fat-dietfed mice Spontaneous diabetic mice ICR mice and adrenal cells High-Fat dietFed mice STZ-induced diabetic rats STZ-diabetic rats

efficacy

mechanism

ref

Improve insulin resistance

Alter the uptake and utilization of glucose

76

Reduce the fasting blood glucose and serum insulin, improve the glucose tolerance Inhibit alpha-glucosidase activity but cannot attenuate postprandial blood glucose level within short time periods Normalize glucose tolerance, enhance insulin sensitivity Reduce postprandial blood glucose level

Inhibit α-glucosidase activity

110

increased serum corticosterone level

111

increase adiponectin production and decrease tumor necrosis factor alpha Inhibit the activity of alpha amylase, promote glycogen synthesis, and inhibit the gluconeogenesis Stimulate the release of insulin from β-cell or insulinomimetic activities of the extract giving rise to direct peripheral glucose uptake

87

Reduce serum blood glucose, cholesterol, triacylglycerol, liver L-MDA and significantly increase serum insulin level

significantly improve the blood glucose concentration in diabetic mice induced by streptozotocin (STZ).106 Sea cucumber saponins with similar structures play an important role in the regulation of blood glucose107 and exhibited a protective effect on impaired glucose tolerance in high-fat diet induced mice.76 Wen et al.108 studied the effects of saponins extracted from Pearsonothuria graef fei on glycometabolism in spontaneous diabetic mice. The results suggested that the sea cucumber saponins had a good hypoglycemic effect and could improve insulin resistance, which might be attributed to the inhibition of α-glucosidase, α-amylase and other enzymes related to glucose metabolism. Amira et al.109 found that saponins extracted from Holothuria thomasi significantly decreased serum glucose, α-amylase activity, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) concentrations and liver malondialdehyde (MDA) level in white female albino rats. The histopathological results also showed that saponins markedly reduced the degenerative change in β-cells. Table 4 summarizes the regulation of saponins on blood glucose.76,87,109−112 Antihyperuricemic Activity. Hyperuricemia is a metabolic disorder caused by increased production and/or reduced excretion of uric acid due to purine metabolic disorders. Hyperuricemia with elevated serum uric acid, as a metabolic disease, is closely related to cardiovascular disease, chronic kidney disease, and metabolic syndrome.113 It has been found that hyperuricemia is an important biochemical basis for gout, which can cause acute gouty arthritis while affecting renal function, triggering chronic interstitial nephritis, uric acid kidney stones, etc.114 Hyperuricemia is divided into primary hyperuricemia and secondary hyperuricemia. URAT1 (uric acid transporter l), expressed on the brush border of the kidney, plays a crucial role in uric acid reabsorption. There are three single nucleotide polymorphisms in the N-terminus of the hURAT1 gene in patients with primary hyperuricemia, which is significantly correlated with the reduction in uric acid fractionation excretion and is an important genetic mechanism for primary hyperuricemia.115 The mutation of the urinary regulator gene can reduce the excretion of uric acid and induce hyperuricemia of the kidney, which is an autosomal genetic syndrome. Lossof-function mutants result in defective uric acid transport and defects in uromodulin expression on the apical membrane. The misfolding of proteins could lead to decreases in uromodulin and permeability, thereby increasing uric acid levels.116

109 112

Secondary hyperuricemia is mainly caused by kidney disease, blood diseases, and drug treatment. The body releases large amounts of DNA or RNA accompanied by tissue decomposition, which leads to a large amount of purine substances attached to the liver, causing a significant increase of uric acid. Rapid increase of plasma uric acid concentration results in uric acid crystal induced renal tubular obstruction and acute renal failure. If this obstruction is delayed, it may lead to local inflammation and interstitial fibrosis.117 The purine bases contained in foods are also factors that increase the body’s uric acid level.118 The current treatments of hyperuricemia mainly include the xanthine oxidase inhibitor allopurinol, nonsteroidal antiinflammatory drugs, colchicine, and uric acid excretion drug probenecid.117 However, hyperuricemia cannot be cured at present, which can lead to many complications and its clinical treatment is difficult. Therefore, it is of great significance to screen more safe and effective ingredients from natural sources for preventing and treating hyperuricemia. Zhang et al.119 have studied the effects of sea cucumber and its active ingredients on uric acid and the activity of enzymes related to uric acid metabolism in hyperuricemic mice induced by yeast extract. They found that sea cucumber saponins obviously improved hyperuricemia, and its effect might be related to the saponins and polysaccharides. Xanthine oxidase is a key enzyme for uric acid which can catalyze hypoxanthine to generate xanthine, thereby producing uric acid. Adenosine deaminase can catalyze adenosine to form carnine and then produce hypoxanthine. Further research studied the effect of sea cucumber saponins extracted from Pearsonothuria graef fei on uric acid metabolism and related enzyme activities in hyperuricemic mice. The results suggested that the saponins could improve the yeast-induced hyperuricemia, which might be attributed to the inhibition of xanthine oxidase and adenosine deaminase in the liver.120 Promotion of Bone Marrow Hematopoiesis. The hematopoietic process is an active, continuous cell proliferation, differentiation, and release process. Pluripotent hematopoietic stem cells maintain their numbers through selfrenewal, proliferate and differentiate into various progenitor cells and further transform into mature blood cells, which is released into the peripheral blood circulation.121 There are a large number of blood cells mainly generated in the bone marrow in peripheral blood. Although the blood cells die successively, the bone marrow is continuously outputting new cells to maintain a constant number of mature blood cells in 7230


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Journal of Agricultural and Food Chemistry the body.122 The major cell types in the hematopoiesis process include hematopoietic stem cells, hematopoietic progenitor cells, precursors, and mature blood cells, which exhibit their own functions and morphological features. There are a variety of cell regulators for hematopoietic function of bone marrow cells, in which interleukin-3, granulocyte-macrophage colony stimulating factor, interleukin 11 could promote the growth of granulocyte and macrophage colony. Erythropoietin, known early as erythrocyte colony stimulating factor, plays an important role in the normal division, differentiation, and maturation of erythroid cells in the bone marrow. Thrombopoietin, also known as megakaryocyte colony stimulating factor, is secreted mainly by hepatic parenchymal cells and renal distal tubules.123 There are a variety of active substances could regulate the function of hematopoietic cells, among which saponins could improve the hematopoietic function of bone marrow. Interestingly, Li et al.18 investigated the regulatory effect of saponins isolated from Pearsonothuria graef feii on hematopoiesis in cyclophosphamide-induced bone marrow injury mice. The results showed that the saponins exhibited significant promotion on hematopoiesis by regulating the body’s immune function, inducing the body to produce a variety of hematopoietic cytokines, promoting the proliferation of hematopoietic stem cells, and inducing differentiation of granulosa, erythroid, and megakaryocyte progenitor cells. In addition, previous studies found that saponins extracted from P. graef fei could promote effectively the hematopoietic function by up-regulating the level of hemopoietic growth factors in myelosuppressed mice.124,125 Immunity Improvement. Sea cucumber saponin has gradually become the research focus as an important marine bioactive substance, which can improve the body’s immunity.126 Macrophages as a significant immunocyte exhibit important functional diversity in immunity system, which are essential for the maintenance of physiological balance. As the most efficient phagocytic cells, macrophages can engulf a considerable number of microorganisms or other cells by the binding of bacterial substances to receptors on the surface of macrophages. Macrophages can produce chemokines and enhance cellular immunity.127 There are various kinds of lymphocytes in the spleen, mainly composed of B cells (about 60%) and T cells, and also a small number of natural killer cells. When the body is invaded by pathogens, the immune cells in the spleen will make an immune response.128 It has been reported that bioactive components from Isostichopus badionotus, I. f uscus, and Cucumaria f rondosa can significantly improve the cellular immune and nonspecific immune function, increase the plantar thickening, and promote phagocytic capacity of peritoneal macrophages in normal mice.129 It also has been found that Pearsonothuria graef fei saponins increased the number of antibody-forming cells and serum hemolysin levels in immunocompromised mice to promote humoral immune function, promote delayed allergic reaction, increase the proliferation ability of splenic lymphocytes, and promote the phagocytic rate and index of mouse peritoneal macrophages on chicken red cells to improve the nonspecific immune function.130 Aminin et al.131 found that low dose of Cucumaria frondosa saponin could increase the antibody production to promote monocyte phagocytosis and the release of cytokines such as IL-6, thereby improving the humoral immunity and nonspecific immune function in mice, whereas it had no significant effect on Th1-mediated delayed-

type hypersensitivity. Moreover, sea cucumber saponin cucumarioside A2-2 showed a strong immunomodulatory effect.132 The regulatory effects on immunity of sea cucumber saponins are presented in Table 5.129,131,133−139 Lowering Blood Pressure. The regulation of blood pressure is a complex process involving multiple systems, and the occurrence and development of hypertension are closely related to multiple genes and factors. Thus, the pathogenesis of hypertension remains unclear. Currently, the positive blood pressure regulating factors mainly include the nervous system,140 renin-angiotensin-aldosterone system,141 adrenergic system,142 bradykinin-prostaglandin system,143 endotheliumderived vasoactive substances, etc.144 Saponin active substances exhibit improvement on hypertension. Zhang et al.145 had studied the effect of saponins extracted from Pearsonothuria graef fei on the blood pressure of C57BL/KsJ (db/db) obese mice. The result suggested that the sea cucumber saponins might improve hypertension during obesity progression through the renin-angiotensin system. Other Bioactivities. Antibacterial and Antivirus Activities. The saponins from sea cucumber have good antibacterial effect.146−150 Mohamed et al.151 found that the saponins extracted from Bohadschia cousteaui showed a good antifungal activity against Candida albicans. Moreover, a previous study has found that water-soluble saponins from Apostichopus japonicas exhibited a strong inhibitory effect on Candida albicans and Schizosaccharomyces pombe.152 Careaga et al.153 also found that two new triterpene glycosides (patagonicosides B and C), patagonicoside A and their desulfated analogues extracted from sea cucumber Psolus patagonicus showed good antifungal activities against the phytopathogenic fungus Cladosporium cladosporoides in a dose-dependent fashion. Chludil et al.154 proved that the triterpene saponins extracted from Patagonian sea cucumber Hemoiedema spectabilis exhibited the antiviral activity, which might be related to their functional groups including the structure of the sugar chain. Anti-HIV Activity. The chemokine receptor subtype 5 (CCR5) has been a particularly attractive target since it is the most commonly used receptor by HIV-1 strains and is thought to be important in viral transmission. Much attention has been focused on the blockade of CCR5 for antiviral therapy. Hegde et al.155 found that the aqueous methanolic extract of a sea cucumber containing two triterpene glycosides exhibited inhibitory activity on CCR5 with selectivity. Contraceptive activity. Saponins content in sea cucumber is the highest before and after ovulation. Saponins can inhibit the maturation of oocytes to regulate the reproduction of sea cucumber. Mats et al.156 found that the sum of triterpene glycosides of the Far Eastern holothurian Stichopus japonicus Selenka (holotoxins A1 and B1) possessed contraceptive activity by inhibiting ovulation and stimulating the contractile activity of the uterus. Safety of Saponins from Sea Cucumber. There are no strict boundaries between drugs and poisons, and their efficacy depends on the dose used. Medicinal value becomes toxicity if it exceeds the therapeutic dose range. As an active ingredient extracted from sea cucumber, saponins have a variety of biological functions. It is necessary to evaluate the toxicological safety for its potential toxicity to provide reference for the application of sea cucumber saponins. It has been proved that sea cucumber saponin is readily absorbable after peroral 7231


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Enhance the function of cellular immunity and humoral immunity

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PROBLEMS AND PROSPECTS Sea cucumber has potential for development and utilization as a health care product in the market. Saponins of sea cucumber as a secondary metabolite have drawn more and more attention in the prevention and treatment of diseases. They will provide great economic value and application prospects for the clinical medicine, pharmaceutical, and functional health food industry due to various biological activities and pharmacological effects such as inhibition of tumor cells, the alleviation of metabolic syndrome and hyperuricemia, improvement of immune function, etc. However, there are still some problems. It is difficult to separate and purify the saponin monomers and identify their structures due to their low content, high levels of other secondary metabolites produced by complicated metabolic processes in the body of sea cucumbers, and a large number of saponin isomers. The elucidation of the underlying mechanism on the effects of sea cucumber saponins is still very limited. The specific mechanism and their safety in human body are not clearly defined. Most of the sea cucumber saponins have a strong hemolytic effect, which means that intravenous injection cannot be directly applied in the clinic. Moreover, the oral absorption rate of saponin is low and it would be decomposed in the gastrointestinal tract. The toxicity of saponins from sea cucumber will limit its development and application as a functional food or medicine. Therefore, it is of great significance for the development and utilization of sea cucumber saponins to reduce toxicity while maintaining activity. The composition and medical function of bioactive substances in sea cucumber are receiving increased attention and utilization with gradual expansion of research. Apart from saponins, there are other active components including phospholipids, polysaccharides, and polypeptides in sea cucumber. Recent studies have showed that sea cucumber phospholipids possessed the improvements on degenerative disease such as Alzheimer’s disease.160 Sea cucumber polypeptides have shown significant antifatigue and immune functions161 and have appeared in many functional foods. In addition, sea cucumber fucosylated chondroitin sulfates have strong anticoagulant activity and can be used in pharmaceutical industry as marine drugs.162 Sea cucumber is a high-quality

Total saponins

Mouse Ehrlich carcinoma cells and Mouse peritoneal macrophages Normal mice and hypoimmune mice

Frondoside A1, okhotoside B1, okhotoside A1-1, frondoside A, okhotoside A2-1, and cucumarioside A2-5 cucumariosides I2, H, A5, A6, B2 and B1

Mouse peritoneal macrophages

129

139

Depend on structures of both aglycone and carbohydrate chain Not mentioned

138

131

administration and it does not accumulate in organs of experimental animals over long-time administration.157 Wang et al.158 evaluated the toxicological safety of sea cucumber saponins from Pearsonothria graef fei by an acute toxicity test, bone marrow cell micronucleus test, and 30-days feeding test. They found that the saponins had no significant toxicity on body weight, peripheral blood, myocardium, liver and renal function in rats, but slight toxic effects on rat testis. Moreover, Belousov et al.159 found that saponins extracted from Cucumaria japonica exhibited weak toxicity in the acute toxicity test, while saponin treatment for 3 months did not produce any toxic effect on the experimental animals in the chronic toxicity experiment. The toxicity of sea cucumber saponins is relatively weak in its dose range. Cytotoxicity experiments have proved that the sea cucumber saponin has some hemolytic activity, while animal experiments showed that low doses of sea cucumber saponins would not affect the physiological indicators of experimental animals, providing reference for the subsequent application of sea cucumber saponins.

Cucumaria frondosa Cucumaria okhotensis Eupentacta f raudatrix Pearsonothuria graef fie

Mouse peritoneal macrophages

BALB/C mice and The total blood mode

Cucumarioside A2-2 and its desulfated derivative, cucumarioside A4-2 and its desulfated derivative, cucumariosides A3 and A6-2 and cucumarioside A7-1 Frondoside A

Possess potent immunomodulatory properties

Stimulate reactive oxygen species formation in macrophages Stimulate ROS formation in macrophages

136

Increase the number of cells with increased adhesion properties as well as the spreading reaction and motility velocity Induce macrophage lysosomal activity, inhibit release of tumor necrosis factor-α Mouse peritoneal macrophages cucumariosides A2‑2

Stimulate lysosomal activity of mouse macrophages in vivo and enhance macrophage phagocytosis Stimulate spreading and lysosomal activity of mouse macrophages Increase lysosomal activity of macrophages

134 135 Enhance the natural cellular defense barrier Interact with immune cells and increase the cellular biomembrane microviscosity Cucumarioside A2-2, and Frondoside A cucumarioside A2-2

137

ref

133

mechanism

Act as Ca2+ agonists due to their membranotropic properties

efficacy experimental model name of saponin

cucumariosides A2-2 and A7-1 Cucumaria japonica


Table 5. Immunomodulatory Effect of Sea Cucumber Saponins

Embryos of the sea urchin Strongylocentrotus nudus and Balb/c line mouse peritoneal macrophages Mouse splenocyte Mouse splenocyte and peritoneal macrophage

Stimulate lysosomal activity and induce a rapid short-term increase in cytosolic Ca2+ content in mouse macrophages Express their immunostimulatory effects Exhibit strong cytotoxic effect in the micromolar range of concentrations and show immunomodulatory activity in the nanomolar concentration range Enhance macrophage morphology parameters and behavior


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related factors in the sea cucumber Apostichopus japonicus. Fish Shellfish Immunol. 2018, 72, 342−347. (12) Zhu, J.; Mu, X.; Zeng, J.; Xu, C.; Liu, J.; Zhang, M.; Li, C.; Chen, J.; Li, T.; Wang, Y. Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of Dgalactose-induced aging. PLoS One 2014, 9, e101291. (13) Vincken, J. P.; Heng, L.; de Groot, A.; Gruppen, H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry 2007, 68, 275−297. (14) Sun, Y.; Long, R.; Zhang, T.; Yang, Q.; Zhou, H. Advances in the study of alfalfa saponin. Acta Pratacult. Sin. 2013, 22, 274−283. (15) Amini, E.; Nabiuni, M.; Baharara, J.; Parivar, K.; Asili, J. In-vitro pro apoptotic effect of crude saponin from Ophiocoma erinaceus against cervical cancer. Iran. J. Pharm. Res. 2017, 16, 266−276. (16) Wen, M.; Fu, X.; Han, X.; Hu, X.; Dong, P.; Xu, J.; Xue, Y.; Wang, J.; Xue, C.; Wang, Y. Sea Cucumber Saponin Echinoside A (EA) Stimulates Hepatic Fatty Acid β-Oxidation and Suppresses Fatty Acid Biosynthesis Coupling in a Diurnal Pattern. J. Nutr. Sci. Vitaminol. 2016, 62, 170. (17) Mashjoor, S.; Yousefzadi, M. Holothurians antifungal and antibacterial activity to human pathogens in the Persian Gulf. J. Mycol. Med. 2017, 27, 46−56. (18) Li, B.; Wang, J.; An, M.; Liu, Y.; Zhang, Z.; xue, C. Study on the effect of saponin of Pearsonothuria graeffei on hematopoiesis in myelosuppression mice. Acta Pratac. Sin. 2011, 33, 173−177. (19) Caulier, G.; Mezali, K.; Soualili, D. L.; Decroo, C.; Demeyer, M.; Eeckhaut, I.; Gerbaux, P.; Flammang, P. Chemical characterization of saponins contained in the body wall and the Cuvierian tubules of the sea cucumber Holothuria (Platyperona) sanctori (Delle Chiaje, 1823). Biochem. Syst. Ecol. 2016, 68, 119−127. (20) Bahrami, Y.; Zhang, W.; Chataway, T.; Franco, C. Structural elucidation of novel saponins in the sea cucumber Holothuria lessoni. Mar. Drugs 2014, 12, 4439−4473. (21) Ruan, W.; Su, Y.; Wu, C. The research actuality of sea cucumber glycosides. J. Fujian Fish. 2011, 33, 74−78. (22) Mondol, M.; Shin, H. J.; Rahman, M. A.; Islam, M. T. Sea cucumber glycosides: chemical structures, producing species and important biological properties. Mar. Drugs 2017, 15, 317. (23) Sun, P.; Yi, Y.; Li, L.; Tang, H. Resource, Chemical structure and characteristics of triterpene glycosides from sea cucumbers (Order Aspidochirotida). Chin. J. Nat. Med. 2007, 5, 463−469. (24) Kwak, J. Y. Corrigendum: Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers. Front. Chem. 2014, 2, 77. (25) VanDyck, S.; Gerbaux, P.; Flammang, P. Elucidation of molecular diversity and body distribution of saponins in the sea cucumber Holothuria forskali (Echinodermata) by mass spectrometry. Comp. Biochem. Physiol., Part B: Biochem. Mol. Biol. 2009, 152, 124− 134. (26) Gomes, A. R.; Freitas, A. C.; Rocha-Santos, T. A. P.; Duarte, A. C. Bioactive Compounds Derived from Echinoderms. RSC Adv. 2014, 4, 29365−29382. (27) La, M.; Yi, Y.; Li, L.; Lu, B.; Han, H.; Wang, Z.; Gong, W. Three tritserpene glycosides from sea cucumber Cucumaria f rondosa gunnerus. Chin. J. Nat. Med. 2008, 6, 254−258. (28) Yu, L.; Dong, P.; Xue, C.; Wang, Y.; Xu, J.; Li, Z.; Xue, Y. High performance liquid chromatographic fingerprints of triterpene glycosides from Stichopus japonicus. Chin. J. Chromatogr. 2010, 28, 885− 888. (29) Han, H.; Yi, Y.; Liu, B.; Wang, X.; Pan, M. Leucospilotaside C, a new sulfated triterpene glycoside from sea cucumber Holothuria leucospilota. Chin. Chem. Lett. 2008, 19, 1462−1464. (30) Han, H.; Yi, Y.; Li, L.; Wang, X.; Liu, B.; Sun, P.; Pan, M. A new triterpene glycoside from sea cucumber Holothuria leucospilota. Chin. Chem. Lett. 2007, 18, 161−164. (31) Yi, Y.; Xu, Z.; Li, L.; Zhang, S.; Wu, H.; Ding, J.; Tong, Y.; Tan, W.; Li, M.; Tian, F.; Wu, J.; Liaw, C. C.; Bastow, K. F.; Lee, K. H. Philinopsides A and B, Two new sulfated triterpene glycosides from

stuff with low-fat, low-cholesterol, rich in minerals, and rich in vitamins. We should take full advantage of other active components in sea cucumber when we develop saponinsderived functional products. As for saponins, the biosynthesis and biological activity of sea cucumber saponin will be further elucidated, which will indicate the direction for the large-scale industrial production of sea cucumber saponins, the research and development of marine health foods and drugs.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone: +86 532 82032597. *E-mail: [email protected]. Phone: +86 532 82032597. ORCID

Tian-Tian Zhang: 0000-0001-7127-8593 Yu-Ming Wang: 0000-0001-7315-9934 Notes

The authors declare no competing financial interest.

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