1 INTRODUCTION

Sea cucumbers，also known as holothurians，are marine invertebrates in the Phylum Echinodermata (Iniguez-Martinez et al.，2005) . The Class Holothuroidea is divided into three subclasses，i.e. Dendrochirotacea，Aspidochirotacea，and Apodacea，and six orders，i.e. Aspidochirotida，Apodida，Dactylochirotida，Dendrochirotida，Elasipodida and Molpadiida (Bordbar et al.，2011) . Many species of sea cucumber are harvested and dried commercially for human consumption or for medicinal use，particularly in Asia. Like many other commercially important marine organisms，sea cucumbers continue to be widely exploited because of their perceived unique biological and pharmaceutical properties. Recent scientific efforts have focused on searching for the bioactive components of sea cucumbers for nutritional use in the food industry or as potential properties of sea cucumbers，including a discussion on their biological and pharmaceutical potential.

2 BIOACTIVE COMPOUNDS AND THEIR THERAPEUTIC EFFECTS 2.1 Nutritive value

Sea cucumbers contain high protein levels，low sugar and fat content，and no cholesterol (Lu and Wang，2009) . Nutritionally，sea cucumbers have an impressive profile of valuable nutrients，such as vitamin A，vitamin B1 (thiamine) ，vitamin B2 (riboflavin) ，vitamin B3 (niacin) ，minerals，especially calcium，magnesium，iron，zinc，selenium，germanium，strontium，copper，manganese，molybdenum，and other microelements beneficial to human health (Bordbar et al.，2011) . Sea cucumbers are also rich in amino acids，with their essential amino acid content，including threonine，valine，methionine，tryptophan，phenylalanine，isoleucine，leucine and lysine，being significantly higher than in fish. The most abundant amino acid in all sea cucumber species is glycine，with high levels of glutamic acid，aspartic acid，alanine and arginine also being recorded (Wen et al.，2010) .

A low lysine/arginine ratio is an important feature of the amino acid composition of sea cucumbers (Wen et al.，2010) . Previous studies have suggested that a low lysine/arginine ratio can significantly reduce cholesterol levels by exerting a hypocholesterolemic effect (Rajamohan and Kurup，1997) ，and sea cucumbers are thus considered an ideal food for people with hyperlipidemia.

2.2 Anticancer activity

Sea cucumbers are believed to contain several compounds with anticancer properties. Triterpene glycosides，commonly known as holothurins，are currently one of the most studied anticancer agents. These glycosides are the predominant secondary metabolites of holothurians (Liu et al.，2007; Liu et al.，2008) and accumulating evidence indicates that they have a wide spectrum of biological activities，including cytotoxic，hemolytic，antifungal and immunomodulatory properties (Maier et al.，2001; Chludil et al.，2002) . At present，more than 100 types of glycosides have been recorded (Zhang et al.，2006) .

There is increasing evidence that triterpene glycosides have anticancer functions. The cytotoxic activity of sea cucumber glycosides against different types of cancer cell lines has been under investigation for many years. Omran and Khedr (2015) showed that bivittoside extracted from the sea cucumber Holothuria polii exhibited significant cytotoxic activity against two cultured tumor cell lines: colon adenocarcinoma cell line (HCT116) and breast adenocarcinoma cell line (MCF7) . Zhao et al. (2010) compared the effects of two sulfated triterpene glycosides isolated from the sea cucumber Pearsonothuria graeffei on carcinoma cell metastasis in vitro and in vivo. The results showed that triterpene glycoside treatment significantly suppressed adhesion of human hepatocellular liver carcinoma (HepG2) cells to both Matrigel^® and human endothelial cells，and inhibited HepG2 cell migration and invasion in a dose-dependent manner. In addition，the antimetastatic activity of triterpene glycosides was mediated by the inhibition of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression. Subsequent studies have demonstrated that triterpene glycosides exhibit anticancer activity in HepG2 cells by inhibiting cell-cycle progression and inducing apoptosis through the mitochondrial pathway (Zhao et al.，2012) . The mechanism by which triterpene glycosides induce apoptosis of HepG2 cells in a nuclear factor κB (NF-κB) -dependent or NF-κB-independent manner depends on their structure. Additional evidence indicated that triterpene glycoside isolated from the sea cucumber H. hilla showed significant cytotoxicity against eight human tumor cell lines (Wu et al.，2007) .

Frondoside A，a triterpene glycoside derived from the orange-footed sea cucumber，Cucumaria frondosa，has demonstrable anticancer activity in several models. Recently，frondoside A has been shown to potently inhibit pancreatic cancer cell growth and induce apoptosis both in vitro and in vivo (Al Shemaili et al.，2014) . Frondoside A also has potent antimetastatic activity; for example，Ma et al. (2012) reported that frondoside A，given intra-peritoneally to mice bearing mammary gland-implanted mammary tumors，inhibited spontaneous tumor metastasis to the lungs. Additional evidence has demonstrated that frondoside A inhibited human breast cancer and lung cancer cell survival，migration，invasion，and metastasis (Al Marzouqi et al.，2011; Attoub et al.，2013) .

Other extracts of sea cucumbers have also been shown to display anticancer activity. Acid mucopolysaccharide is an important biologically active component in the body wall of sea cucumbers and plays an important chemical and physiological role. Lu et al. (2010) provided a theoretical basis for the utilization of acid mucopolysaccharide isolated from the sea cucumber Stichopus japonicus as a potential anticancer component for the treatment of hepatocellular carcinoma. They reported that acid mucopolysaccharide inhibited the proliferation of HepG2 cells in a dose-and time-dependent manner，and induced apoptosis of HepG2 cells through decreasing the expression of Bcl-2 and increasing the expression of nm23-H1. In an experimental hepatocellular carcinoma rat model，Stichopus japonicus acid mucopolysaccharide effectively inhibited the growth of hepatocellular carcinoma through protecting the immune organs，and stimulating the proliferation of tissues from the immune organs and enhancing cell-mediated immunity (Song et al.，2013) . Acid mucopolysaccharide from Holothuria leucospilota also has antimetastatic properties，possibly via its anti-angiogenesis induced by downregulation of VEGF and suppression of the invasive ability of cancer cells mediated by downregulation of MMP-2，-9 expression and their activities (Zhang et al.，2009) . Sphingoid bases are other important extracts from sea cucumbers. Sugawara et al. (2006) determined the structure of sphingoid bases extracted from the sea cucumber Stichopus variegatus and established its cytotoxicity against human colon cancer cell lines. Sphingoid bases reduced cell viability and caused apoptosis of human colon cancer cell lines by increasing caspase-3 activity. Additional experimentation investigating the apoptosis-inducing effects of sphingoid bases using HepG2 cells (Hossain et al.，2013) indicated that sphingoid bases from sea cucumbers induced HepG2 cells apoptosis through upregulation of Bax，death receptor-5 (DR5) ，growth arrest and DNA damage-inducible gene 45 (GADD45) and peroxisome proliferator activator receptor-γ (PPARγ) and downregulation of p-AKT. These results showed for the first time the functional properties of sphingoid bases from sea cucumbers as inducers of apoptosis in HepG2 cells.

Janakiram et al. (2010) appraised the chemopreventive effects of frondanol A5，a glycolipid extracted from Cucumaria frondosa，using in vivo and in vitro models of colon cancer. Roginsky et al. (2010) investigated the effects and mechanism of frondanol A5P activity from C. frondosa on growth inhibition and apoptosis in human pancreatic cancer cells. Yang et al. (2003) demonstrated that 12-methyltetradecanoic acid (12-MTA) ，a branched-chain fatty acid isolated from C. frondosa，inhibited proliferation of prostate cancer cells via caspase-3-mediated apoptosis. There is mounting evidence that a variety of sea cucumber extracts display wide-ranging anticancer effects and，because these extracts are derived from edible，nontoxic sea cucumbers，they may be valuable for nutritional therapy or prevention of various cancers.

2.3 Anticoagulant/antithrombotic activity

Thromboembolic diseases continue to be the major cause of death throughout the world (Streiff et al.，2011) . Because of the high incidence of thrombosis，unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) have been the cornerstone in antithrombotic prophylaxis and treatment for the last 60 years (Luo et al.，2013) . Because the source of heparin is limited，there is now more interest in therapeutics prepared from non-mammalian sources. Marine organisms are abundant in sulfated polysaccharides with anticoagulant and antithrombotic activities (Glauser et al.，2008; Pomin and Mourao，2008; Bordbar et al.，2011; Pomin，2012) . Fucosylated chondroitin sulfate (FucCS) ，a glycosaminoglycan extracted from the sea cucumber Ludwigothurea grisea，has the same structure as mammalian chondroitin sulfate; however，some of the glucuronic acid residues display sulfated fucose branches. This new polysaccharide has high anticoagulant activity and is able to potentiate the inhibitory activities of both antithrombin and heparin co-factor II (Mourao et al.，1996) . In addition，this polysaccharide also has serpin-independent anticoagulant activities (Fonseca et al.，2009) . FucCS has broad effects on the coagulation system. In addition to its serpin-dependent anticoagulant activity，it also inhibits the factor Xa generation and thrombin by the intrinsic tenase and prothrombinase complexes，respectively (Glauser et al.，2008) .

FucCS has a chondroitin sulfate-like core containing side chains made up of sulfated α-l-fucose attached at the carbon-3 position of β-d-glucuronic acid (Mourao et al.，1996) . Mourao et al. (1998) ，reporting the effect of FucCS from Ludwigothurea grisea in the prevention of experimental stasis thrombosis in rabbits，showed that its antithrombotic activity could be assigned mainly to the sulfated fucose branches linked to the chondroitin sulfate-like core. Borsig et al. (2007) indicated that removal of the sulfated fucose branches on FucCS abolished the inhibitory effect of the polysaccharide both in vitro and in vivo. Previous studies also indicated that the sulfated fucose branches were required for the anticoagulant and antithrombotic activities of FucCS (Mourao et al.，1996; Zancan and Mourao，2004) . Fonseca and Mourao (2006) reported that intravascular injection of FucCS inhibited thrombus formation in an arterial and a venous shunt model in rats，and oral administration of FucCS to rats increased plasma anticoagulant activity in a dose-dependent manner. FucCS has more advantages over heparin and other anticoagulant drugs now used clinically in the treatment of thrombosis. FucCS is absorbed after oral administration and，about 2 h later，the drug concentration in plasma and the antithrombotic effect peak simultaneously (Fonseca and Mourao，2006) . Its carboxyl-reduced derivative does not cause bleeding and maintains its anticoagulant activity，indicating a better antithrombotic effect than the native polysaccharide (Zancan and Mourao，2004) . Pacheco et al. (2000) also reported that intravascular injection of FucCS at the dose totally preventing thrombus formation produced a much more intense modification of plasma anticoagulant activity than antithrombotic doses of heparin. In addition，experimental evidence has indicated that FucCS had a more favorable effect than heparin on vascular cell growth (Tapon-Bretaudiere et al.，2002) . FucCS inhibited smooth muscle cell proliferation on a par with heparin，and it had a potent enhancing effect on endothelial cell proliferation and migration in the presence of heparin-binding growth factors.

2.4 Antimicrobial activity

Marine echinoderms are considered a potential source of novel antibiotics (Haug et al.，2002) . In several studies，sea cucumbers extracts have been confirmed as important antibacterial agents (Villasin and Pomory，2000; Kiani et al.，2014) . Ghanbari et al. (2012) detected antibacterial activity in Actinopyga lecanora hydrolysates. Actinopyga lecanora，a sea cucumber known as stonefish，contains relatively high protein levels and has been investigated as a raw material for bioactive peptide production. The results revealed that A. lecanora hydrolysates could be a valuable natural antibacterial agent and that its antibacterial activity was strongly related to the type of enzyme employed (Ghanbari et al.，2012) . Papain and bromelain were found to be the most effcient enzymes for the production of hydrolysates with antibacterial properties. Beauregard et al. (2001) isolated a novel antimicrobial peptide from the coelomic fluid of Cucumaria frondosa. The data demonstrated that fractionated coelomic fluid had a broad range of antimicrobial activity against both Gram negative and Gram positive bacteria. Several crucial enzymes，such as lysozyme (Wang et al.，2011) and phenoloxidases (Jiang et al.，2014) ，purified from the coelomocytes of sea cucumbers，have also been shown to exhibit antimicrobial activity.

Some triterpene glycosides isolated from sea cucumbers have exhibited significant antifungal activity. Han et al. (2009) reported that three triterpene glycosides isolated from Holothuria scabra displayed antifungal activity. Kumar et al. (2007) revealed that marine natural products (triterpene glycosides) isolated from Actinopyga lecanora could be an interesting source of antifungal compounds.Triterpene glycosides isolated from Bohadschia marmorata and Holothuria (Microthele) axiloga were shown to have antifungal activity against six strains (Yuan et al.，2009a，b) . Careaga et al. (2011) investigated the antifungal activity of triterpene glycosides isolated from an ethanolic extract of Psolus patagonicus. Their results indicated that triterpene glycosides and their desulfated analogs had antifungal activity against the phytopathogenic fungus Cladosporium cladosporioides in a dose-dependent manner. Yano et al. (2013) ，in a double-blind，randomized controlled study of the elderly，investigated the effect of the consumption of jelly containing sea cucumber extract on their oral Candida albicans load. The jelly contained a hydrolysate of Stichopus japonicus，which contained triterpene glycosides known as holotoxins. The results indicated that the sea cucumber jelly showed inhibitory effects on oral Candida，suggesting that daily consumption of S. japonicus jelly had the potential to reduce the oral Candida load in elderly patients in nursing homes.

Sea cucumbers extracts also have antiviral and antiparasitic activities. A recent study，using a crude water extract of a Holothuria sp. from the Persian Gulf，evaluated its possible antiviral activity against herpes simplex virus type 1 (HSV-1) in a cell culture system (Farshadpour et al.，2014) . The extract exhibited remarkable antiviral activity not only against virus adsorption to the cells but also on virus intracellular replication. Huang et al. (2013) evaluated the anti-human immunodeficiency virus type-1 (anti-HIV) activity of FucCS obtained from the pineapple sea cucumber Thelenota ananas. Their results suggested that FucCS might be developed further as a novel HIV-1 entry inhibitor for treatment of HIV/ AIDS patients，particularly for those infected by T-20-resistant variants. Mona et al. (2012) and Melek et al. (2012) demonstrated that holothurins and echinosides isolated from sea cucumbers possessed potential in vitro schistosomicidal activities. Yoshida et al. (2007) generated transgenic Anopheles stephensi mosquitoes that express the C-type lectin CEL-Ⅲ from Melek2 in a midgut-specific manner and，ultimately，CEL-Ⅲ impaired malaria parasite development. In these transgenic mosquitoes，sporogonic development of Plasmodium bergheii was severely impaired. Moderate but significant inhibition was found against Plasmodium falciparum. All these results suggest that sea cucumbers can be considered as a natural source for a new adjuvant antiparasitic drug with conventional therapy，such as praziquantel.

2.5 Antioxidant activity

Sea cucumbers are now considered to be potential sources of valuable antioxidants (Esmat et al.，2013; Yu et al.，2014) . Polysaccharides have been prepared from Apostichopus japonicus via protease hydrolysis and their antioxidant activity investigated in vitro (Liu et al.，2012) . Polysaccharides showed potent，free radical-scavenging activities，and were demonstrated to be potential candidates as natural antioxidants. Althunibat et al. (2013) ，investigating the antioxidant properties of aqueous and organic extracts from two sea cucumber species，showed that both extracts were capable of scavenging free radicals. Zhong et al. (2007) initially evaluated the antioxidant activity of fresh and rehydrated Cucumaria frondosa samples with/without internal organs; all samples exhibited free radical-scavenging properties. Rehydrated samples，especially those with internal organs，possessed higher antioxidant activity than their fresh counterparts. Hawa et al. (1999) described a lipid peroxidation process and antioxidant activity in three species of sea cucumber. Their study revealed that the coelomic fluid contained high levels of superoxide dismutase (SOD) protein and total antioxidant activities (AOA) ，indicating that some form of antioxidant activity was present in the coelomic fluid of these holothurians.

Alzheimer’s disease is a common neurodegenerative disorder in which oxidative stress plays an important role (Fukasawa et al.，2012) . Extracts of several sea cucumbers have been identified as potential therapeutic agents against nervous system oxidative damage. Wu et al. (2014) investigated the effect of eicosapentaenoic acid-enriched phospholipids (EPA-enriched PL) from Cucumaria frondosa on oxidative injury in the rat pheochromocytomaline cell line (PC12) induced by hydrogen peroxide (H₂O₂) and tert-butylhydroperoxide (t-BHP) . In vitro，pretreatment with EPA-enriched PL enhanced the survival of H₂O₂ or t-BHP damaged PC12 cells in a dose-dependent manner. EPA-enriched PL pretreatment reduced leakage of lactate dehydrogenase，and increased intracellular total antioxidant capacity (T-AOC) and superoxide dismutase activity compared with the H₂O₂ or t-BHP group. In vivo，the administration of EPA-enriched PL also prevented the development of learning and memory impairments in senescence-accelerated prone mouse strain 8 (SAMP8) mice. Sea cucumber cerebrosides (SCC) also have been demonstrated to play an important protective role in H₂O₂-and t-BHP-induced damage of PC12 cells (Wu et al.，2013) . SCC may exert its protective function against oxidative damage by inhibiting the mitochondria-mediated apoptosis pathway.

2.6 Antihyperlipidemic activity

Several studies have shown that sea cucumber extracts have beneficial effects on lipid metabolism (Olivera-Castillo et al.，2013) . Hu et al. (2010) examined the effect of saponins extracted from Pearsonothuria graeffei on the preventive activity of fatty liver in rats. Their results indicated that the lipids-lowering effect of dietary saponins might be partly associated with the enhancement of β-oxidation via PPAR activation. In addition，the inhibited sterol-regulatory element binding protein (SREBP-1c) -mediated lipogenesis caused by saponins might also contribute to alleviating fatty liver. Hu et al. (2012b) also indicated that dietary saponin supplementation significantly suppressed adipose accumulation，and reduced serum and hepatic lipids in rats. The possible mechanism could be related to the pancreatic lipase-inhibiting effect of saponins，which ultimately suppressed and delayed triglyceride and total cholesterol absorption. To investigate the effects of sea cucumber saponins on high-fat diet-induced obesity，insulin resistance and fatty liver，C57/BL6 mice were fed a high-fat diet (Hu et al.，2012a) . The data demonstrated that saponins could improve certain metabolic parameters associated with obesity，mainly in alleviating hepatic steatosis and reducing serum total cholesterol and triglyceride concentrations.

Liu et al. (2012) investigated the antihyperlipidemic activity of polysaccharides prepared from Apostichopus japonicus. Serum total cholesterol，triglyceride and low-density lipoprotein levels decreased significantly，and high-density lipoprotein cholesterol increased significantly after treatment of hyperlipidemic Wistar rats with polysaccharides. Cerebrosides are another important bioactive substance found in sea cucumbers. Dietary sea cucumber cerebroside could attenuate hepatic steatosis because of its inhibition of hepatic lipogenic gene expression and enzyme activity，and the enhancement of triglyceride secretion from liver (Zhang et al.，2012) . Xu et al. (2011) purified AMC-2，a novel cerebroside，from the less-polar lipid fraction of Acaudina molpadioides，and investigated the anti-fatty liver activity of AMC-2 in rats with fatty liver induced by orotic acid. AMC-2 ameliorated nonalcoholic fatty liver disease through suppression of stearoyl-CoA desaturase (SCD) activity and impaired the biosynthesis of monounsaturated fatty acids in the livers of the rats. Sea cucumbers are rich in sulfated polysaccharides called glycosaminoglycans (GAGs) ，which are widely distributed in the connective tissues of members of the Holothuroidea. Liu et al. (2002) demonstrates that sea cucumber GAGs had potential in reducing the incidence of cholesterol-related diseases，such as atherosclerosis and cholesterol fatty liver.

2.7 Antihyperglycemic activity

Several sea cucumbers extracts may offer an adjunctive therapy for diabetes mellitus. FucCS is one component of sulfated polysaccharides in the body wall of sea cucumbers. Hu et al. (2013b) investigated the effect of FucCS from Acaudina molpadioides on hyperglycemia in the skeletal muscle of insulin-resistant mice. The results indicated that FucCS could alleviate hyperglycemia via activation of the PKB/ GLUT4 signaling pathway in skeletal muscle of insulin-resistant mice. Their subsequent research investigated the effects of a combination of FucCS and rosiglitazone (RSG) on glucose metabolism in the liver of insulin-resistant C57BL/6J mice fed a high-fat high-sucrose diet for 19 weeks (Hu et al.，2013a) . They found that FucCS/RSG treatment improved glucose metabolism by modulating metabolic enzymes and strengthening the PI3K/PKB/ GSK-3β signal pathway mediated by insulin at the transcriptional level. Therefore，dietary supplementation with FucCS may provide an adjunctive therapy for the treatment of diet-induced insulin resistance.

Eicosapentaenoic acid-enriched phosphati-dylcholine was isolated from Cucumaria frondosa and its effects on streptozotocin (STZ) -induced hyperglycemic rats were investigated (Hu et al.，2014) . Eicosapentaenoic acid-enriched phosphati-dylcholine also exhibited significant anti-hyperglycemic activity via up-regulating the PI3K/ PKB signal pathway mediated by insulin. Nguyen et al. (2011) purified two unsaturated fatty acids from the body wall of Stichopus japonicus，which exhibited a mixed type of inhibition against α-glucosidase. Because of their strong α-glucosidase inhibitory activity，these unsaturated fatty acids could potentially be developed as novel，natural nutraceuticals to prevent diabetes mellitus .

2.8 Anti-inflammatory activity

Studies indicate that sea cucumber extracts possess potent anti-inflammatory activity. Tissue fractions of sea cucumbers could be exploited as potentially potent therapeutic agents for the treatment of inflammation. The anti-inflammatory activity and related molecular mechanisms of an ethyl acetate solvent fraction of Stichopus japonicus (SCEA-F) were investigated in lipopolysaccharide (LPS) -stimulated RAW264.7 cells (Himaya et al.，2010) . In this study，SCEA-F inhibited the LPS-induced inflammatory response via blocking of the mitogen-activated protein kinases (MAPK) signaling pathway in murine macrophages; thus demonstrating its in vitro anti-inflammatory potential. This study suggested that SCEA-F has potential in anti-inflammation therapy and could be used as an effective functional food.

2.9 Other properties

In addition to the pharmacological and therapeutic functions described above，other studies have revealed that sea cucumbers also possess antihypertension and radioprotective properties. An angiotensin I-converting enzyme (ACE) inhibitory peptide was isolated from a hydrolysate of Acaudina molpadioides (Zhao et al.，2009) . The purified ACE inhibitory peptide was a novel peptide，which had very low similarity to other ACE inhibitory peptide sequences. The experimental results showed that the ACE inhibitory peptide displayed a clear antihypertensive effect in spontaneously hypertensive rats (SHR) . Cumaside is a complex of monosulfated triterpene glycosides isolated from Cucumaria japonica by Aminin et al. (2011) ，and shown to possess moderate radioprotective properties at low prophylactic doses.

3 SUMMARY

Sea cucumbers have been the subject of intense research in recent decades because of their valuable bioactive components and their potential therapeutic benefits (Table 1) . An extensive literature search has revealed that sea cucumbers have a long history as a traditional food and folk medicine. In addition，the health benefits of sea cucumbers have been validated through scientific and ethno-pharmacological research. In conclusion，sea cucumbers are a valuable and effective functional food with great potential to physiologically benefit human health and well-being. The current review emphasizes the biological and pharmaceutical potential of sea cucumbers and highlights the numerous bioactive compounds that can be isolated and purified to act as natural sources of new multifunctional drugs.