Bioactive Compound and Functional Properties of Sea Cucumbers as Nutraceutical Products

Abstract

Indonesia has very rich biological resources and is diverse in both land and sea areas, so it is known as a mega biodiversity country. Sea cucumbers are one of the potential export commodities in the fisheries sub-sector. The use of sea cucumbers in Indonesia as a food ingredient compared to other fishery products is relatively low and less popular because they have low aesthetic value judging from their disgusting physical appearance. This review aims to provide an overview of sea cucumbers’ bioactive compounds and functional properties so that this information will provide a comprehensive perspective in developing sea cucumber-based nutraceuticals. The nutritional content of dried sea cucumbers was 82% protein, 1.7% fat, 8.9% water, 8.6% ash, 4.8% carbohydrates, phosphorus, iron, iodine, sodium, and vitamins A and B (thiamin, riboflavin, and niacin). Bioactive components in sea cucumbers contain collagen, glycosides, polysaccharides, glycosaminoglycans, N-acetylglucosamine, chondroitin sulfate, steroids, lectins, omega-3 fatty acids and phenolic compounds. Sea cucumbers have functional properties such as antioxidative, anticancer, anti-inflammatory, antithrombotic, antimicrobial, anti-atherosclerosis, antiosteoporosis, anti-diabetic, antiaging, and anti-obesity. The functional properties provide an excellent opportunity to develop high-value nutraceuticals from sea cucumbers. The main factors for producing and developing nutraceuticals based on sea cucumbers are organoleptic, bioaccessibility, and bioavailability.

1. Introduction

Indonesia is the largest archipelagic country in the world, which has 17,504 islands with a coastline length of 81,000 km and a sea area of about 5.8 million km² (75% of Indonesia’s total area) stretching along the equator. Indonesia has very rich biological resources and is diverse in both land and sea areas, so it is known as a mega biodiversity country. One of the marine products that have important economic value is sea cucumbers. Sea cucumbers are a source of potential biopharmaceuticals from marine products and as a functional food [1].

Sea cucumbers are one of the potential export commodities in the fisheries sub-sector. The use of sea cucumbers in Indonesia as a food ingredient compared to other fishery products is relatively low and less popular because they have low aesthetic value judging from their disgusting physical appearance [2]. However, sea cucumbers contain quite high protein. Several countries, such as Hong Kong, Taiwan, Singapore, and the United States, have more advanced processing techniques, so sea cucumbers have become one of the most popular food components. Sea cucumbers are invertebrates with an elongated cylindrical body with the oral and aboral lines as the axis connecting the anterior and posterior parts [3]. The shape resembles a cucumber, which is known as a sea cucumber. The mouth and anus are located at opposite ends of the axis. The mouth in the anterior and the anus in the posterior, around the mouth of the sea cucumber, some tentacles can be extended and pulled quickly. Tentacles are modified tube feet that catch food [4, 5, 6].

Sea cucumbers are invertebrate sea-shaped in Holothuridae, Stichopodidae, and Cucumaridae and are the most valuable for the commercial market. There are more than 1,100 varieties of sea cucumbers in the world, among others, about 40 species available on the commercial market [7]. Sea cucumbers are one of the thorn-skinned animals of Echinodermata [8], but the spines on sea cucumbers cannot be seen with the naked eye because they are very small and can only be seen using a microscope. Sea cucumber spines are microscopic chalk grains scattered in the epidermal layer. The body wall of sea cucumbers is elastic, with a mouth in the anterior and anus in the posterior part, with an adult body length for the smallest species of 2.54 cm, the longest size is 90 cm [4]. In comparison, the sand sea cucumber species has a size of 25–35 cm. When alive, they can weigh up to 500 g [6]. According to Bandaranayake and Rocher [9], the length of sea cucumbers can reach 60 cm with a weight of 2 kg.

The body surface of sea cucumbers is not ciliated and is covered with a layer of lime whose thickness is affected by age. The mouth’s condition that extends to the anus has five rows of tube feet (ambulacral), and three rows of sucking tube feet (trivium) in the stomach play a role in movement and attachment [7, 10]. Sea cucumbers can walk slowly using tube feet or ambulacral feet. Sea cucumbers breathe with gills in the form of long, branching tubes. The genitals of sea cucumbers are separate. Sea cucumber eggs are fertilized outside the mother’s body in the water. The eggs hatch into larvae, and the larvae grow into adult sea cucumbers. Generally, the reproductive system of sea cucumbers is classified as Dioecious. The bioactive components in sea cucumbers produce a variety of specific functional properties, such as characterization and molecular mechanisms related to immunity [11]. Triterpene glycosides have anticancer characteristics [12, 13, 14] and other broader biological activities [15], so sea cucumbers are a source of potential nutraceutical products. This review aims to provide an overview of sea cucumbers’ bioactive compounds and functional properties so that this information will provide a comprehensive perspective in developing sea cucumber-based nutraceuticals.

2. Nutritional properties of sea cucumbers

Sea cucumbers are food ingredients that contain enough nutrition. Sea cucumbers are an excellent source of protein. The protein content in dried sea cucumbers is 82 g per 100 g, with a high digestibility value. Of that amount, about 80% is in the form of collagen. Collagen functions as a tissue binder in the growth of bones and skin. Calcium supplements alone are insufficient for bone growth because bones comprise calcium phosphate and collagen. Without collagen, bones will become brittle and break easily [1]. The nutrients contained in sea cucumbers include 6.16% protein, 0.54% fat, 6.41% carbohydrates, and 0.01% calcium (new conditions 86.73% moisture content). Dried sea cucumbers have a high protein content of 82%, complete amino acid content, and saturated fatty acids, which are important for heart health. In addition, sea cucumbers also contain phosphorus, iron, iodine, sodium, and vitamins A and B (thiamin, riboflavin, and niacin) [2]. Sea cucumber body fluids and fluids contain more than 44% protein, carbohydrates between 3–5% and 1.5% fat [3]. Reported that the nutritional content of dried sea cucumbers was 82% protein, 1.7% fat, 8.9% water, 8.6% ash and 4.8% carbohydrates. Compared to other fish, the fat content of sea cucumbers is relatively low, namely 1.7 g/100 g of dried sea cucumbers, but it is quite rich in omega-3 fatty acids. Thus, sea cucumber meat is safe for consumption by those with high serum cholesterol levels. The dominant mineral content in sea cucumbers is sodium, calcium, potassium, phosphorus, and iron [1]. The proximate, amino acid and nutritional composition of sea cucumbers can be seen in Table 1, Supplementary Table 2, and Supplementary Table 3.

Sea cucumbers have a high protein content and low lipids. The protein content reaches 40–60% by weight material dry sea cucumbers [4]. Most of the protein in sea cucumbers is collagen, reaching 70% [5], glutamic acid [6, 7, 8] and glycine [4, 5]. The fatty acids in sea cucumbers exist in relatively small amounts. Total fatty acids account for 2–8% by weight in the dry matter of sea cucumbers, of which unsaturated fatty acids can be up to 70%. Eicosapentaenoic or eicosapentaenoic acid (EPA) in total fatty acids can reach 56.7%, while the content of docosahexaenoic acid (DHA) is much lower (up to 5.8% of total fatty acids) [7, 8, 9, 10]. Sea cucumbers contain about 15% by weight of carbohydrates in the body wall and 8% by weight in the muscle bands [8]. In addition to these three main components, sea cucumbers are rich in elements such as Ca, Mg, and Fe, with varying contents among different species [4, 11, 12]. Other compounds in sea cucumbers include peptides [13], phenols [14], triterpene glycosides or saponins [15], fucoidan [16], fucosylated chondroitin sulfate [17], cerebroside [18], and sphingoid [19].

3. Bioactive compounds in sea cucumbers

The bioactive ingredients in sea cucumbers are also known as antioxidants which help reduce damage to cells and body tissues. Sea cucumbers’ antibacterial and antifungal properties can enhance their ability for skin care. Sea cucumbers are also known to have antinociceptive (painkilling) and anti-inflammatory (against inflammation and reduces swelling) effects [2]. The results also show that sea cucumbers have other benefits. Namely, they can improve blood circulation, prevent cholesterol blockage in blood vessels, improve kidney function, increase metabolic levels, help arthritis, diabetes mellitus, and hypertension, and accelerate the healing of external and internal wounds.

Several bioactive compounds contained in sea cucumbers, namely sea cucumber S. japonicus contains the enzyme arginine kinase [60], sea cucumber H. glaberrina contains serum amyloid A [61], sea cucumber S. mollis contains glycosides [62], and sea cucumber S. japonicus contains fucan sulfate as an inhibitor of osteoclastogenesis [63]. Kaswandi et al. [64] and Lee et al. [65] reported the active ingredient produced by Holothuria sp. as antibacterial and antifungal. The results showed that the active ingredient from the sea cucumber H. tubeless could inhibit the growth of S. cerevisiae. Besides having antibacterial properties, sea cucumbers also contain various unsaturated fatty acids such as linoleic, oleic, EPA, and DHA [66].

Putri [67] reported the results of research on extracting antibacterial components from sea cucumbers (H. vacabunda), which were quite effective in inhibiting the growth of Escherichia coli, Vibrio damsel, Vibrio harveyi, Vibrio parahaemolyticus, and Vibrio cercariae bacteria. Sea cucumber extract also showed antiprotozoal activity and inhibition of tumor cell growth [68]. Based on some of the research results that have been carried out, it is clear to us that sea cucumbers contain various bioactive components that are very beneficial for human health. Several bioactive components include glycosaminoglycans (GAGs), N-acetylglucosamine and chondroitin sulfate, minerals and trace minerals, steroids, collagen, Omega3 - DHA and EPA, and holoturin.

Table 1: Proximate and macronutrient composition (%) of sea cucumbers (mean values ± standard deviation)

Species	Moisture	Protein	Lipid	Ash	Carbohydrates	Ref.
Apodida lecanora (fresh)	87.78 ± 0.9	65.53 ± 11.77	1.76 ± 0.04	23.03 ± 2.95	-	[20]
Apodida mauritiana (fresh)	84.71 ± 0.70	48.27±0.10	4.99 ± 0.10	2.12±0.10	44.62±0.30	[21]
Bohadschia argus (fresh)	85.82 ± 0.09	68.75 ± 17.29	1.34 ± 0.30	20.30 ± 0.41	-	[20]
Bohadschia marmorata (fresh)	83.17 ± 0.20	43.23±0.10	4.83 ± 0.10	6.03±0.30	45.91±0.10	[21]
Holothuria arenicola (fresh)	93.01± 0.01	4.40±0.88	0.60±0.42	2.01±0.05	-	[22]
Holothuria leucospilota (fresh)	81.41 ± 0.60	45.71±0.20	4.60 ± 0.30	4.3±0.20	44.96±0.30	[21]
Holothuria scarba (fresh)	85.76 ± 0.30	43.43±0.20	5.66 ± 0.09	2.26±0.15	48.65±0.20	[21]
Holothuria fuscogilva (fresh)	84.34±0.72	63.64±4.56	1.12±0.28	30.45±6.79	-	[20]
Stichopus horns (fresh)	92.8 ± 0.03	3.47±0.15	0.41±0.01	3.33±0.06	-	[22]
Thelenota ananas (fresh)	90.81 ± 2.08	48.26 ± 2.32	2.35	37.40 ± 4.60	-	[20]
Apodida caerulea (dried)	0.81±0.03	56.9±0.36	10.1±0.25	28.4±0.32	-	[23]
Apodida echinites (dried)	9.30 ± 0.10	60.20 ± 0.20	1.25 ± 0.01	29.25 ± 0.25	-	[24]
Apodida mauritiana (dried)	11.60±0.31	63.30±0.43	1.40±0.02	15.40±0.18	-	[23]
Bohadschia argus (dried)	13.0±0.26	62.1±0.39	1.1±0.01	17.7±0.20	-	[23]
Holothuria atra (dried)	9.90±0.01	58.20±0.72	1.32±0.00	31.58±0.42	-	[24]
Holothuria fuscogilva (dried)	11.6±0.28	57.8±0.41	0.3±0.01	26.4±0.31	-	[23]
Holothuria fuscopunctata (dried)	7.0±0.14	50.1±0.38	0.3±0.01	39.6±0.20	-	[23]
Bohadschia scabra (dried)	8.20 ± 0.15	68.67 ± 0.37	1.11 ± 0.01	22.02 ± 0.27	-	[24]
Stichopus hermanni (dried)	10.20±0.32	47.00±0.36	0.80±0.02	37.90±0.33	-	[23]
Stichopus vastus (dried)	19.46	38.70	0.38	34.04	7.42	[25]
Thelenota ananas (dried)	15.10±0.29	55.20±0.38	1.90±0.01	25.10±0.30	-	[23]
Thelenota anax (dried)	1.20±0.06	40.70±0.33	9.90±0.27	39.20±0.28	-	[23]

Note: - : not determined

3.1 Collagen

Collagen is the main structural protein in sea cucumber body tissues and contributes to the excellent taste of sea cucumbers [69]. Collagen in sea cucumbers generally consists of three polypeptide chains, each containing a Glycine-XY repeating motif where X and Y represent each amino acid [70]. Consequently, glycine is the most abundant amino acid in sea cucumber collagen [69, 71, 72, 73, 74]. Covalent cross-linking between collagens. Electrophoretic tests revealed that the sea cucumber fiber network is a thin, uniform, and tightly woven collagen fibril [69]. External factors such as temperature, salt concentration, sun exposure, and nutritional deficiencies can cause autolysis of the sea cucumber body wall and drastic changes in tissue mechanical properties such as contraction, relaxation, and mucoid degeneration [75].

Sea cucumbers are also rich in nutrients. Most of the active compounds are antioxidants, which can prevent cancer and repair the human body’s cells. Sea cucumbers contain 86% protein. About 80% of that amount is in the form of collagen, which functions as a tissue binder in the growth of bones and skin. The protein is also easily broken down by the enzyme pepsin. In general, collagen in the human body decreases with age. Collagen is needed for hair, bones, nails, skin and metabolism. Natural collagen intake will help grow skin, muscle, and bone tissue, prevent premature aging, beautify the skin, relieve stomach ulcers, increase body immunity, and heal wounds [15].

3.2 Glycosides

Sea cucumbers contain triterpene glycosides as abundant secondary metabolites. The unique structure of triterpene glycosides contributes to their biological activity and can be used as a taxonomic marker [76, 77]. The triterpene glycoside carbohydrate chains generally contain xylose, glucose, quinovose, 3-O-methyl glucose, and in rare cases, 3-O-methyl xylose, 3-O-methyl glucuronic acid, 3-O-methylquinovose, and 6-O-acetyl-glucose [76, 78]. The holostan-type triterpene glycoside (a lanostan derivative with 18(20)-lactone) is the most common [79].

3.3 Polysaccharides

Sea cucumbers contain various polysaccharides such as fucoidan, fucosylated chondroitin sulfate, and fucan. Fucoidan in sea cucumbers is built up by (1–3) -linked tetrafucose repeat units, with each fucose unit having one or two HSO4 substitutions in its cyclic structure [80, 81, 82, 83]. Several studies reported that fucan consists of repeating units of 1–3 and 1–2 tetrasaccharides with sulfated or non-sulfate fucose residues attached to the sea cucumber backbone chain [84, 85, 86].

The complex structure of the polysaccharides is responsible for their physiological function, such as the fucose sulfate branch in fucosylated chondroitin sulfate is essential in exerting the anticoagulant activity of sea cucumbers [87]. Trisaccharide units with 2,4-O-desulfated fucose branches in fucosylated chondroitin sulfate are crucial in facilitating neurite outgrowth. [88]. Chondroitin sulfate and fucoidan with linear chains show more muscular anti-hyperlipidemic activity than random chains [89].

3.4 Glycosaminoglycans (GAGs)

GAGs is a cartilage builder and is important in preventing joint disorders. These substances can restore joint diseases and rebuild cartilage. In addition, it can eliminate joint pain caused by sitting too long. GAGs provide a slime effect on the cell wall. Sea cucumbers function as anti-thrombogenic to prevent clotting through blood dilution [90]. GAGs relieve arthritis and joint pain and help increase insulin levels [91]. The body and skin of the sea cucumber S. japonicus contain a lot of glycosaminoglycan, which is useful for healing kidney disease, anaemia, diabetes, pneumonia, anti-tumour, anti-inflammatory, prevention of aging of body tissues, and preventing arteriosclerosis. Meanwhile, the pure extract helps blood circulation, relieves pain, helps reduce inflammation, and speeds up wound healing.

3.5 N-acetylglucosamine

Naturally, sea cucumbers contain N-acetylglucosamine compounds, additional nutrients that can overcome joint inflammation. N-acetylglucosamine is one of the important components of the body. These compounds belong to a class of macromolecules called GAGs. GAGs are normally found in the synovial fluid in joints [92]. N-acetylglucosamine (C₆H₁₃NO₅) is an amino sugar and an important precursor in the biochemical synthesis of glycosylated proteins and lipids. N-acetylglucosamine is a major component of the exoskeleton of crustaceans, arthropods, and fungi. N-acetylglucosamine is one of the most common monosaccharides. In industry, N-acetylglucosamine is produced by hydrolysis of crustacean exoskeleton [93]. N-acetylglucosamine is commonly used to relieve symptoms of osteoarthritis, although its therapeutic effect is still debated. Taking N-acetylglucosamine orally is usually used to reduce the symptoms of osteoarthritis. As a precursor of glycosaminoglycans that make up joint cartilage tissue, N-acetylglucosamine supplementation is expected to be able to rebuild cartilage tissue and reduce the risk of osteoarthritis [93].

3.6 Chondroitin sulfate

Chondroitin sulfate is also a glycosaminoglycan that acts as a shock breaker and holds water. Chondroitin sulfate functions as a lubricant in the joints for better joint movement. The mechanism of action of chondroitin sulfate is almost the same as that of N-acetylglucosamine, where chondroitin is the material needed to form proteoglycans. Combining chondroitin sulfate and N-acetylglucosamine will positively affect joints [1]. Chondroitin, known as chondroitin sulfate, is a sulfated glycosaminoglycan (GAG) comprising branched sugar chains (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of proteoglycan compounds. Chondroitin sulfate chains can have more than 100 sulfathiazole sugars in each variable section. Chondroitin sulfate is an important structural component of cartilage tissue and increases its resistance to pressure. With N-acetylglucosamine, chondroitin sulfate is used extensively as a dietary supplement to prevent osteoarthritis.

3.7 Steroids

Sand-type sea cucumber steroids are higher than gnat and black. Sea cucumber extract has great potential as a source of natural testosterone. Testosterone is a steroid hormone from the androgen group. The main producers of testosterone are the testes in males and the ovaries in females, although the adrenal glands also produce small amounts of this hormone. This hormone is the main male sex hormone and is an anabolic steroid. Both in males and females, testosterone plays an important role in health. Its functions include increasing libido, energy, immune function, and protection against osteoporosis. On average, adult males produce about twenty times more testosterone than adult females. Sea cucumber extract contains steroid compounds. Quantitatively, the innards of wet sea cucumbers contain more steroid compounds than dried meat and innards [94]. Sea cucumber steroid compounds have biological activity as an aphrodisiac due to the high concentration of cholesterol and testosterone in the blood serum of male chicks that were given sea cucumber extracts [95].

Meanwhile, the effectiveness of sea cucumber steroid extracts in manipulating the sex of giant prawns was by administering testosterone hormone from sea cucumber innards extract through injection and dipping methods can effectively affect the zygote and larvae develop into males [96]. Furthermore, the sand sea cucumber (H. scabra) contains three dominant steroid compounds, namely 12β-hydroxy-20,24-dimethyl-12,18-oxa-25-norscalarane, 12, oleanane-3,16,21, 22,28-pistol and 24-O-(2,4-Di-O-methyl-D-xylopyranosyl-(12)-D-xylofuranoside) [69]. The results of the bioassay test showed that sea cucumbers can be used as an aphrodisiac which can provide value to the sand sea cucumbers [97].

3.8 Lectins

Lectins are proteins that bind body cells to glycoproteins and glycolipids expressed on the cell surface, especially glucose molecules, and can make these cells clump. Lectins act as biological markers at the cellular and molecular levels. Some viruses use lectins to attach their cell membranes to their host organisms during the infection process [116]. In chemical tests, the lectin isolated from the body wall of the brown sea cucumber was a non-blood type - a specific lectin that agglutinated blood types A, B, AB, and O. In addition, it also agglutinated the blood cells of cattle and goats [98]. Non-Blood-Lectins are classified as complete lectins, not requiring prior assay with trypsin to demonstrate lectin activity. The lectin agglutination activity increases with the addition of trypsin, while the addition of calcium accelerates the process of agglutination activity. Lectins isolated from sea cucumbers were found to have mitogenic activity or cell proliferation. It was also effective against mouse and human lung cancer at levels of 5 and 50 micrograms, respectively [98].

3.9 Omega-3 Fatty Acids

As a seafood product, sea cucumbers also contain omega-3 fatty acids that the body needs. These omega-3 fatty acids are EPA and DHA. Both omega-3 fatty acids are beneficial in inhibiting the aging process, lowering bad Low-Density Lipoprotein (LDL) and Very Low-Density Lipoprotein (VLDL) cholesterol in the body, thereby reducing the risk of heart disease [99]. EPA and DHA in sea cucumbers can also reduce blood viscosity, prevent blood clots, and reduce the risk of cardiovascular disorders. EPA and DHA, with long chains and double bonds, restore damaged tissue and improve brain and eye performance. Besides that, the content of important fatty acids such as EPA and DHA also play an important role as a wound healing agent and antithrombotic to reduce blood clots in the blood vessels. This can reduce the risk of stroke and heart disease. The two acids above can also help slow down the process of cell degeneration and the aging process [90].

The efficacy of sea cucumbers in overcoming heart disease is thought to be due to the DHA content in sea cucumbers. Intake of DHA-the main fatty acid in sperm, brain, and retina of the eye-high can reduce blood triglycerides that cause heart disease [95]. The results of other studies show that the efficacy of sea cucumbers H. atra, H. sabra, and Bohadshia argus kills Streptococcus faecalis, the cause of swelling of the inner lining of the heart, and S. viridans, destroyer of heart valves. EPA and DHA content is relatively high, 25.69% and 3.69%, respectively [100]. A large EPA value indicates the speed at which sea cucumbers repair damaged tissue and inhibit the formation of prostaglandins that cause high inflammation. At the same time, DHA is the main fatty acid in sperm, the brain, and the eye’s retina. High DHA intake can reduce blood triglycerides that cause heart disease. DHA deficiency causes a decrease in brain serotonin which triggers Alzheimer’s disease and depression [94].

3.10 Phenolic compounds

Sea cucumbers are a good source of phenolic compounds essential to antioxidant activity. The phenolic composition of sea cucumbers differs from that of fruits and vegetables. Chlorogenic acid (up to 93% by weight) is the main phenolic component in sea cucumbers, while the ascorbic acid content is minimal [14, 101, 102]. Other phenolic components such as pyrogallol, rutin, coumaric acid, and catechins were also detected in sea cucumbers [14, 101, 102]. The phenolic compound content in various sea cucumber tissues also varies greatly [103].

4. Functional properties of sea cucumbers

4.1 Sea cucumbers as antioxidative

Radical Oxygen Species (ROS) or species oxygen reactive produced from various sources (mitochondria, peroxisomes, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, cytokines, UV radiation, chemotherapeutic agents, and hyperthermia) can cause oxidative stress and interfere with physiological functions of the human body, such as protein structure modification, Deoxyribonucleic acid (DNA) damage, cell aberration. Signaling decreased proliferative response, and impaired host defense [104]. Sea cucumbers exert a solid ability to scavenge ROS. For example, fresh sea cucumbers and rehydrated S. japonicus were reported to scavenge Amidinopropane Hydrochloride (AAPH) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals [7], whereas organic/aqueous extracts from H. atra showed chelating activity Fe⁺ and the ability to repress lipid [14], [102].

Protein hydrolyzate from sea cucumbers exhibits antioxidant activity depending on the peptides’ molecular weight, amino acid composition, and hydrophobicity [105]. Peptide-rich enzymatic hydrolyzate from sea cucumber Actinopyga lecanora scavenges DPPH radicals and shows great [106]. Low molecular weight antioxidant peptides containing 46.7% hydrophobic amino acids in the order Gly-Pro-Glu-Pro-Thr-Gly-Pro-Thr-Gly-Ala-Pro-Gln-Trp-Leu-Arg [13], where three sea cucumber antioxidant peptides, Val-Thr-Pro-Tyr, Val-Leu-Leu-Tyr, and Val-Gly-Thr-Val-Glu-Met, each contain 50%, 75%, and 50% hydrophobic amino acids [107].

The polysaccharides in sea cucumbers also have functional properties as antioxidative activity, with the main components being N-acetylglucosamine, galactosamine, glucuronic acid, mannose, glucose, galactose, and fucose [97]. Sea cucumber fucoidan does not inhibit the expression of enzymes p-JNK and p-ERKs, but inhibits their phosphorylation [108]. Fucosylated chondroitin sulfate derived from two sea cucumber species (A. molpadioidea and H. nobilis) also showed moderate antioxidant activity [105]. Apart from protein and polysaccharides, other compositions in sea cucumbers such as polyphenols [109, 110], flavonoids [103], phospholipids, and cerebrosides [111, 112] also showed antioxidative activity. The coelomic fluid collected from sea cucumbers contains superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR) with high potential activity [113].

4.2 Sea cucumbers as anticancer

Cancer is a complex disease caused by many factors. Physiologically, the cell growth system in an individual is regulated by a balance system, namely apoptosis and proliferation. If there is excessive apoptosis, it will experience a decline in the function of an organ system which can cause muscle wasting (hypotrophy). Conversely, excessive proliferation will form a tumor mass (malignancy), leading to cancer [114]. Tong et al. [115] demonstrated the efficacy of sea cucumbers in preventing cell proliferation and expelling tumors. Tong isolated sulfate saponins from a sea cucumber Pentancta quadrangular called philinopside A by injecting 2–10 microliters of philinopside A into the rat aorta. He was able to prevent the formation of new micro blood vessels (angiogenesis) in tumor cells. As a result, the tumor cells do not get enough nutrients, so the cells fail to grow and eventually die. These results prove that philinopside A in sea cucumbers has the potential as an antitumor. Popov AM also reported the efficacy of sea cucumbers in overcoming tumors. He compared the cytotoxic effects of sea cucumber and ginseng by giving 5–20 micrograms of ginsenosides-carbohydrates in ginseng does not have a significant cytotoxic effect. Meanwhile, glycosides from sea cucumbers, such as echinoids A and B, holothurin A and B, holotoxin A1, and curcumarioside G1, have significant cytotoxic activity. This confirms the efficacy of sea cucumbers, which have the potential functional properties to be antitumor and anticancer. Various bioactive compounds in sea cucumbers play a role in treating gastric polyps, and gastric tumors [116].

A recent phase II clinical trial demonstrated the anticancer effectiveness of sea cucumber extract in vivo [117]. In general, several bioactive compounds in sea cucumbers have the potential to be used as anticancer products. For example, cerebrosides induce apoptosis of tumor cells through the mitochondrial pathway [118, 119]. H. parva extract induces chronic lymphocytic leukemia death via the mitochondrial pathway without damaging healthy B lymphocytes [120]. Extracts from sea cucumbers also show curative effects on skin cancer [121].

Sulfated saponins extracted from sea cucumbers Pentacta quadrangularis were observed to have an anti-angiogenesis effect by inhibiting the vascular endothelial growth factor receptor [122]. The anticancer activity of sulfated saponins was further reported by suppressing the interaction between the receptor-containing kinase insert a domain and the αvβ3 [123]. Triterpene glycosides from sea cucumber Neothyonidium magnum showed a cytotoxic effect on DLD-1 cells and synergism with the antiproliferative effect of radioactive irradiation [15].

4.3 Sea cucumber as anti-inflammatory

The Central Nervous System (CNS) is often accompanied by inflammation. Sulfated polysaccharide isolated from sea cucumber S. japonicas relieves CNS injury by recruiting neural stem cells to the site of injury and increasing levels of MMP-2, MMP-9, and iNOS proteins [124]. Fucoidan and fucosylated chondroitin sulfate have been reported to regulate inflammatory cytokines in vivo [116, 125]. Extract from two sea cucumbers, H. forskali and Parastichopus tremulus, confers anti-inflammatory activity on endothelial cells and subcutaneous adipose tissue but not on epicardial adipose tissue [126].

4.4 Sea cucumbers as anti-thrombotic

A thrombus is the human body’s exaggerated response to injury and often results in a clot and obstruction of blood flow. Medications usually heal thrombus by blocking platelet aggregation, prolonging freeze formation, and dissolving the clot. Fucosylated chondroitin sulfated and sulfated fucan in sea cucumbers has shown anticoagulant and antithrombotic activity [127, 128, 129]. Fucan compounds isolated from sea cucumbers have high antithrombotic activity and are used to treat thrombosis with a reduced risk of bleeding [85]. Fucosylated chondroitin sulfate compounds exhibit a similar effect [130].

The antithrombotic activity of sea cucumber polysaccharides is closely related to its structure, such as monomer composition, sulfate content, molecular size, and sulfate pattern [89, 131]. For example, fucosylated chondroitin sulfate exhibits unusual procoagulant activity related to charge density, sugar composition, and molecular mass [132]. However, when passing through the gastrointestinal tract after oral administration, the biological function of fucosylated chondroitin sulfate can be negatively affected by the gastrointestinal tract before being absorbed by the body. Gastro-resistant tablet formulations are a successful solution to avoid this degradation [133].

4.5 Sea cucumbers and coronary heart

The efficacy of sea cucumbers in overcoming heart disease is thought to be due to the DHA content in sea cucumbers. Intake of DHA–the main fatty acid in sperm, brain, and retina of the eye–high can reduce blood triglycerides that cause heart disease [99]. This has been shown by the results of studies using the fatty acid content of sea cucumber S. chloronotus, which has a relatively high DHA content of 3.69%. The results of other studies also show that the sea cucumbers H. atra, H. sabra, and B. argus can kill the bacteria S. faecalis, which causes swelling of the inner lining of the heart, and S. viridans destroy heart valves [134]. Furthermore, the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is relatively high, respectively 25.69% and 3.69% [94]. A large EPA value indicates the speed at which sea cucumbers repair damaged tissue and inhibit the formation of prostaglandins that cause high inflammation. At the same time, DHA is the main fatty acid in sperm, the brain, and the eye’s retina. High DHA intake can reduce blood triglycerides that cause heart disease. DHA deficiency causes a decrease in brain serotonin which triggers Alzheimer’s disease and depression [135]. The function of sea cucumbers as anti-clotting and blood-clotting is due to the presence of glycosaminoglycan compounds. At a five micrograms/ml concentration, glycosaminoglycans can cure ischemic brain stroke and heart disease. It performs by inhibiting blood clotting activity through inhibiting fibrin monomers and increasing plasmin activity. Plasmin is an enzyme that decomposes blood plasma proteins that lowers blood viscosity [134]. It happens when the wound so that the blood coagulates. The results of other studies show the efficacy of sea cucumbers in overcoming heart disease, which is thought to be due to the content of DHA in sea cucumbers. Intake of high DHA–the main fatty acid in sperm, brain, and retina of the eye–can reduce blood triglycerides that cause heart disease. This study showed that the sea cucumber S. chloronotus has a relatively high DHA fatty acid content of 3.69% [106].

4.6 Sea cucumber as antimicrobial

Sea cucumbers can be an essential source of antimicrobial compounds, depending on the species, tissue, and solvent used to extract the resulting compounds [136]. Two sea cucumber organs isolated with ethyl acetate and methanol showed antimicrobial activity [137]. In another study, methanol extract from the body wall of sea cucumbers showed the best antimicrobial activity [138]. The different antimicrobial activities of sea cucumbers are caused by different living environments and unique chemical substances such as peptides [139], triterpene glycosides [140], and lectins [98].

The results showed that the sea cucumbers H. atra, H. sabra, and B. argus had an antibacterial effect. In contrast, the three members of the Holothuriidae family were also found in Indonesian waters [141]. The study was conducted using S. faecalis, which causes inflammation of the inner lining of the heart; S. viridans destroys heart valves; S. pneumoniae causes pneumonia and acute sinusitis; Staphylococcus aureus causes meningitis, and Proteus mirabilis which infects wounds [97]. The results showed that the growth of these bacteria was proven to be inhibited after being given sea cucumber extract [89].

Compounds contained in sea cucumbers that act as antifungals: alkaloids, saponins, and triterpenes. The mechanism of saponins proves the ability of saponins as antifungal in reducing the surface tension of the sterol membrane of the Candida albicans cell wall so that its permeability increases. Saponins are a class of compounds that can inhibit or kill microbes by interacting with sterol membranes [84, 85, 86]. The main effect of saponins on bacteria is the release of proteins and enzymes from the cell. Saponins are produced as a chemical self-defense mechanism for sea cucumbers in nature. Apart from being suspected as self-defense from predators, it is also believed to have biological effects, including antifungal, cytotoxic against tumor cells, hemolysis, immune activity, and anticancer [96]. Saponins identified from sea cucumbers with their fine chemical structure can be compared with bioactive components in Ganoderma, ginseng, and other herbal medicines. Saponins show a broad spectrum as hemolytic, cytostatic, and anti-cancer [69].

The presence of one or more bioactive compounds in the body of sea cucumbers also allows for greater antifungal abilities. The interaction of saponins and alkaloids is thought to have an antifungal effect, although the mechanism still requires further research. Alkaloid salts, amino acids, polyhydrosteroids, and saponins dominate the polar components found in marine invertebrates. Alkaloids are antimicrobial compounds, inhibiting esterase and DNA and ribonucleic acid (RNA) polymerase, inhibiting cell respiration. Alkaloids are powerful activators for immune cells that destroy bacteria, viruses, fungi, and cancer cells [109, 110].

Natural antifungal compounds from sea cucumbers are a source of new antifungal drugs that can be developed because of their great potential [89]. The high level of diversity and the uniqueness of new compounds found in marine organisms is the influence of the high biodiversity of marine organisms [142]. The effects of the marine environment, such as salinity, low light intensity, currents, and strong competition, encourage marine organisms to produce secondary metabolites whose chemical structures are relatively different from organisms on land [95]. There is a tendency for the largest source of bioactive substances to come from marine organisms in the tropics, particularly the Indo-Pacific. Saponins from the sea contained in Holothuria sp. sea cucumbers have greater hemolytic activity when compared to saponins derived from land, namely from plants [16].

4.7 Sea cucumbers and osteoporosis

Sea cucumbers can also function to strengthen bones and joints. The content of chondroitin sulfate prevents the loss of joints that cause inflammation. The compound repairs and rebuilds cartilage, forming joints eroded by accidents, collisions, and being overweight without any side effects [132]. That is why the governments of Australia and New Zealand allow the use of sea cucumbers as a cure for arthritis rather than chemical drugs. The results showed that sea cucumbers contain 86% protein, easily broken down by the pepsin enzyme of that amount, about 80% is in the form of collagen. It acts as a tissue binder in the growth of bones and joints. Calcium supplements alone are insufficient for bone growth because bones comprise calcium phosphate and collagen as fillers. Without collagen, bones become brittle and break easily. Conversely, without calcium, the bones will be supple like rubber. In addition to maintaining bones and joints, collagen, and keratin, are responsible for skin elasticity [122].

The body’s collagen content decreases with aging due to a lack of protein intake and skin wrinkles. The aging process must be balanced with the provision of nutrients. The goal is to increase the ability to block tumor cell infection and decrease antioxidant capacity [84, 85, 86]. Reduced antioxidants increase the amount of oxygen free radicals that cause damage to body tissues. Sea cucumbers have natural killer cells against foreign cells and tumors, increasing superoxide dismutase [116, 125]. Superoxide dismutase, an antioxidant that reduces skin-damaging free radicals, protects against DNA damage and protein denaturation [114].

4.8 Sea cucumber as antidiabetic

Diabetes is caused by a dysfunctional interaction between insulin resistance and insulin secretion, which results in hyperglycemia and causes damage to various organs in the human body [143]. Because α-glucosidase plays an essential role in diabetes, inhibition of α-glucosidase can be an effective method for treating diabetes [143]. A study found that sea cucumber fatty acids provide anti-hyperglycemic activity by inhibiting α-glucosidase activity [144].

Fucoidan isolated from sea cucumber A. molpadioides was able to reduce serum resistin, leptin, and tumor necrosis factor alpha (TNF-α), and increase liver glycogen [100]. Fucosylated chondroitin sulfate can improve insulin sensitivity and glucose metabolism through the regulation of critical genes for phosphorylation, such as p85-PI3K, Ser473-PKB, and Thr308-PKB in the PI3K/PKB pathway [145, 146]. EPA rich anti-diabetic activity phosphatidylcholine derived from sea cucumbers was reported by reducing blood glucose levels and increasing serum insulin and glycogen levels by regulating the PI3K/PKB pathway [147]. Several studies have shown that saponins in sea cucumbers have the potential to treat diabetes by increasing serum insulin and glycogen levels [148]. Apart from saponins, several polypeptides in sea cucumbers also exhibit anti-hyperglycemic activity [142].

4.9 Sea cucumber as antiobesity

In general, bioactive compounds treat obesity through the following mechanisms: (1) controlling appetite, (2) inhibiting fat absorption, (3) stimulating energy, (4) suppressing the growth of adipose tissue, and (5) increasing the mobilization of body fat [95]. Anti-obesity activity has been reported for various sea cucumber compounds by reducing metabolic syndrome. Fucoidan compound isolated from sea cucumber Acaudina molpadioides significantly lowered the fat content in vitro [149].

Fucosylated chondroitin sulfate obtained from sea cucumber A. molpadioides can inhibit the growth of adipose (fat) tissue [150, 151]. Anti-obesity mechanism of fucoidan and fucosylated chondroitin sulfate is similar, activating the Wnt /β- catenin pathway negatively affecting adipocyte differentiation, downregulating the expression of SREBP-1c, C/EBPα, and PPARγ; and suppresses the two primary enzymes fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT) in the growth of adipose tissue.

4.10 Sea cucumbers and cell regeneration

Sea cucumbers can cure various diseases, especially their ability to regenerate cells, which is why they are used to cure various diseases [117]. Besides being able to regenerate cells, sea cucumbers are also rich in nutritional content. Most active compounds are in the form of antioxidants and are very good for repairing human body cells. The results showed that sea cucumbers contained 86% protein, whereas the pepsin enzyme easily hydrolyzed the protein of that amount; about 80% is in the form of collagen, which acts as a tissue binder in the growth of bones and skin [152]. Calcium supplements alone are insufficient for bone growth because bones comprise calcium phosphate and collagen as fillers. Bones become brittle and break like glass without collagen. Conversely, without calcium, the bones will be supple like rubber [15].

Another ingredient is glycosaminoglycans (GAGs). In the form of chondroitin sulfate, it restores joint ailments and rebuilds cartilage. GAGs can also relieve joint pain caused by sitting too long. It works by stimulating the body to secrete synovial fluid to lubricate joints. GAGs provide a slime effect on cell walls [152]. Therefore, sea cucumbers function as anti-thrombogenic to prevent clotting through blood dilution. The results of other studies showed that 11 amino acids in sea cucumbers: myristic, palmitate, palmitoleic, stearic, oleic, linoleic, arachidic, eicosapentaenoic, behenate, trust, and docosahexaenoic. These fatty acids are thought to accelerate the healing of external and internal wounds [15].

5. Sea cucumber based nutraceutical products

When a functional food aids in the prevention and treatment of disease and disorder, it is called a nutraceutical [153]; in developing nutraceuticals made from sea cucumbers, several factors need to be considered, such as organoleptic properties, bioaccessibility, bioavailability, and products that are personally designed. Organoleptic properties are an essential factor in the development of sea cucumber-based nutraceuticals, where the sensory properties of the product need to meet consumer preferences [154]. Bioaccessibility and bioavailability are two other essential factors in developing sea cucumber-based nutraceuticals. Bioaccessibility is the amount of ingested nutrients available for absorption in the gut after digestion. In contrast, bioavailability is the fraction of ingested nutrients available for use in normal physiological functions or stored in the body [155]. The bioactive compounds in sea cucumbers vary significantly in their bioaccessibility and bioavailability. Appropriate processing technologies, such as micro-encapsulation and gastro-resistant tablets, can enhance these properties [133, 155]. Table 4 shows various nutraceutical products on the market. Personalized Nutrition is another significant trend in the development of sea cucumber-based nutraceuticals. Personalized Nutrition studies the interaction between diet and genetic variants to optimize health or prevent/treat disease [156]. Products derived from sea cucumbers need to diversify their functions to meet different needs, considering the various bioactive contained and physiological functions of sea cucumbers.

Table 4: Nutraceutical products based on sea cucumbers^*

Brand	Material Feature	Product Benefits	Form	Price
Dabc Oak Land	Dried sea cucumbers (Atlantic Black)	Reproductive enhancement, as well as joint relief properties	Dried	$39.99 -$158.99/Depend on weight
	Dried Alaska Red Sea Cucumber	Reproductive enhancement, as well as joint relief properties	Dried	$99.99 -$259.99/Depend on weight
	South American Sea Cucumber	Reproductive enhancement, as well as joint relief properties	Dried	$8.85 / Ounce
Xlseafood	Dried sea cucumbers	Increasing white blood cells boosts immunity, improves joints, and is the leading choice for whitening.	Dried	$13.75 / Ounce
Woho	Dried red sea cucumbers	joint health	Dried	$11.50 / Ounce
Swanson	Natural	Joint health & Mobility Support - Supports Cartilage Protection & Connective Tissue Health	Capsule	$0.13 / Count
Deep blue health	Natural	Immunity body, joint health	Capsule	$70.00– $0.78 / Count
Ultrahealth	Natural	General health tonic	Capsule	$39 / Bottle
Nova Sea Atlantic	Natural	Anti-aging, Antioxidant	Capsule	$1.00 / Count
Clean Nutraceuticals	Natural	Gluten Free	Capsule	$0.50 / Count
Arctic Star	Natural	Help reduce stiffness and joint pain, improve blood flow, support immunity, support healthy teeth, bones, and muscles, support calcium absorption and cardiovascular function.	Capsule	$0.50 / Count
Dabc Oak Land	Natural	Antioxidant, Hydrating	Capsule	$79.99/Count
Chi’s Enterprise	Natural	Dietary Supplement, Immune Health, help block Angiogenesis	Capsule	$1.87 / Count
TerraVita	Natural	Nutritional Support	Capsule	$0.62 / Count
Hawaii pharms	Organic, Gluten Free, Genetically Modified Organism (GMO) Free, Natural	Anti-tumor	Liquid	$11.48 / Fl Oz
Beaugreen	Paraben Free	Fine Lines Treatment (Firming solution, IMPROVING skin elasticity, Promoting activation of metabolism)	Gell	$0.29 / Count
Hwajin cosmetics	Natural	Moisturizing and anti-wrinkle	Sheet/ mask pack	Secure transaction
Bêche	Natural	Natural Nutritional Support, Antioxidants, Source of Amino Acid, and Immune System Support	Powder	$1.67 / Count

^*) The information was obtained from available products on www.amazon.com; keywords: sea cucumber, sea cucumber extract, and sea cucumber product

6. Conclusion

Sea cucumbers contain many bioactive compounds, including triterpene glycosides, fucoidans, fucosylated chondroitin sulfates, fucan sulfates, and phenols. Various physiological activities of these compounds are known, such as antioxidant, anticancer, anti-inflammatory, antithrombotic, antimicrobial, anti-diabetic, and anti-obesity. This functional property provides an excellent opportunity to develop high-value nutraceuticals made from sea cucumbers, where the main factors for producing and developing nutraceuticals based on sea cucumbers are organoleptic, bioaccessibility, and bioavailability.

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