Thromboembolic diseases pose a serious risk to human health worldwide. Fucosylated chondroitin sulfate (FCS) is reported to have good anticoagulant activity with a low bleeding risk. Molecular weight plays a significant role in the anticoagulant activity of FCS, and FCS smaller than octasaccharide in size has no anticoagulant activity. Therefore, identifying the best candidate for developing novel anticoagulant FCS drugs is crucial. Herein, native FCS was isolated from sea cucumber Cucumaria frondosa (FCScf) and depolymerized into a series of lower molecular weights (FCScfs). A comprehensive assessment of the in vitro anticoagulant activity and in vivo bleeding risk of FCScfs with different molecule weights demonstrated that 10 kDa FCScf (FCScf-10 K) had a greater intrinsic anticoagulant activity than low molecular weight heparin (LMWH) without any bleeding risk. Using molecular modeling combined with experimental validation, we revealed that FCScf-10 K can specifically inhibit the formation of the Xase complex by binding the negatively charged sulfate group of FCScf-10 K to the positively charged side chain of arginine residues on the specific surface of factor IXa. Thus, these data demonstrate that the intermediate molecular weight FCScf-10 K is a promising candidate for the development of novel anticoagulant drugs.

Acute lung injury (ALI) represents a life-threatening condition with high morbidity and mortality despite modern mechanical ventilators and multiple pharmacological strategies. Therefore, there is a need to develop efficacious interventions with minimal side effects. The anti-inflammatory activities of sea cucumber (Cucumaria frondosa) and wild blueberry (Vaccinium angustifolium) extracts have been reported recently. However, their anti-inflammatory activities and the mechanism of action against ALI are not fully elucidated. Thus, the present study aims to understand the mechanism of the anti-inflammatory activity of sea cucumber and wild blueberry extracts in the context of ALI. Experimental ALI was induced via intranasal lipopolysaccharide (LPS) instillation in C57BL/6 mice and the anti-inflammatory properties were determined by cytokine analysis, histological examination, western blot, and qRT-PCR. The results showed that oral supplementation of sea cucumber extracts repressed nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby downregulating the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) in the lung tissue and in the plasma. Wild blueberry extracts also suppressed the expression of IL-4. Furthermore, the combination of sea cucumber and wild blueberry extracts restrained MAPK signaling pathways by prominent attenuation of phosphorylation of NF-κB, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) while the levels of pro-inflammatory cytokines were significantly suppressed. Moreover, there was a significant and synergistic reduction in varying degrees of ALI lesions such as distorted parenchyma, increased alveoli thickness, lymphocyte and neutrophil infiltrations, fibrin deposition, pulmonary emphysema, pneumonia, intra-alveolar hemorrhage, and edema. The anti-inflammatory effect of the combination of sea cucumber and wild blueberry extracts is associated with suppressing MAPK and NF-κB signaling pathways, thereby significantly reducing cytokine storm in LPS-induced experimental ALI.

Frondosides are the major saponins (triterpene glycosides) of the North Atlantic sea cucumber (Cucumaria frondosa). Frondosides possess amphiphilic characteristics due to the presence of various hydrophilic sugar moieties and hydrophobic genin (sapogenin). Saponins are abundant in holothurians, including in sea cucumbers that are widely distributed across the northern part of the Atlantic Ocean. Over 300 triterpene glycosides have been isolated, identified, and categorized from many species of sea cucumbers. Furthermore, specific saponins from sea cucumbers are broadly classified on the basis of the fron-dosides that have been widely studied. Recent studies have shown that frondoside-containing extracts from C. frondosa exhibit anticancer, anti-obesity, anti-hyperuricemic, anticoagulant, antioxidant, antimicrobial, antiangiogenic, antithrombotic, anti-inflammatory, antitumor, and immunomodulatory activities. However, the exact mechanism(s) of action of biological activities of frondosides is not clearly understood. The function of some frondosides as chemical defense molecules need to be understood. Therefore, this review discusses the different frondosides of C. frondosa and their potential therapeutic activities in relation to the postulated mechanism(s) of action. In addition, recent advances in emerging extraction techniques of frondosides and other saponins and future perspectives are discussed.

Sea cucumber processing discards, which include mainly internal organs, represent up to 50% of the sea cucumber biomass, and are a rich source of bioactive compounds, including phenolics. This work aimed to extract free, esterified, and insoluble-bound phenolics from the internal organs of the Atlantic sea cucumber (C. frondosa) using high-pressure processing (HPP) pre-treatment. The sea cucumber internal organs were subjected to HPP (6000 bar for 10 min), followed by the extraction and characterization of phenolics. Samples were evaluated for their total contents of phenolics and flavonoids, as well as several in vitro methods of antioxidant activities, namely, free radical scavenging and metal chelation activities. Moreover, anti-tyrosinase and antiglycation properties, as well as inhibitory activities against LDL cholesterol oxidation and DNA damage, were examined. The results demonstrated that HPP pre-treatment had a significant effect on the extraction of phenolics, antioxidant properties, and other bioactivities. The phenolics in sea cucumber internal organs existed mainly in the free form, followed by the insoluble-bound and esterified fractions. Additionally, UHPLC-QTOF-MS/MS analysis identified and quantified 23 phenolic compounds from HPP-treated samples, mostly phenolic acids and flavonoids. Hence, this investigation provides fundamental information that helps to design the full utilization of the Atlantic sea cucumber species and the production of a multitude of value-added products.

BACKGROUND: Based on the consumers\' attention issues of sea cucumbers, we aimed to complete comprehensive information of commercial Canadian sea cucumbers (CCSC), which sprang up extensively in Chinese food market.
RESULTS: CCSC were identified as Cucumaria frondosa and characterized based on the characteristics, nutritional compositions, and heavy metals. The abdomen and five internal tendons of Cucumaria frondosa were special orange. The average of soaking degree and water content, which consumers paid great attention to, was 2.8 ± 0.3 and 0.46 ± 0.09%, respectively. Proteins (56.4 ± 9.1%) and polysaccharides (12.2 ± 14.7%) were the principal nutrient component. In addition, there was a variety of free amino acids, in which arginine (70.1 ± 50.0 mg/100 g), glutamate (42.6 ± 23.9 mg/100 g), and alanine (32.2 ± 21.0 mg/100 g) were the main components. Phosphorus (P, 0.26 ± 0.05%), magnesium (Mg, 0.19 ± 0.07%), and kalium (K, 0.17 ± 0.08%) were the major mineral elements. Amount of heavy metal was within the safety limitation (5.5 ± 1.4 mg/kg). Furthermore, the active ingredients were positively correlated with size.
CONCLUSIONS: The overall findings enriched the information of Cucumaria frondosa for consumers and suggested that the quality of Cucumaria frondosa was varied following commercial classification and size.

Osteosarcoma (OS) has been demonstrated to be difficult to cure due to its potently malignant metastasis. Therefore, new therapeutic approaches blocking the metastatic potential of OS are urgently required to improve the outcomes for OS patients. In the present study, the anti‑metastatic capacity of sea cucumber (Cucumaria frondosa) fucoidan (Cf‑Fuc) was evaluated on osteosarcoma cells by cell adhesion assay, Transwell assay and U2OS cell migration assay. The underlying mechanism on the dynamic remodeling of the cytoskeleton was also explored. The present data indicated that Cf‑Fuc could block the U2OS osteosarcoma cell adhesion to fibronectin and significantly inhibit U2OS cell migration. Cf‑Fuc greatly impaired the migration capacity of U2OS cells, and the migrated distance and velocity of Cf‑Fuc‑treated cells were markedly reduced. Also, Cf‑Fuc could impair the dynamic remodeling of the cytoskeleton possibly by suppressing the phosphorylation of focal adhesion kinase and paxillin, as well as the activation of the Rac1/PAK1/LIMK1/cofilin signaling axis. Collectively, the present findings provide a novel therapeutic potential of C. frondosa fucoidan for osteosarcoma metastasis.

Sea cucumber (Cucumaria frondosa) is the most abundant and widely distributed species in the cold waters of North Atlantic Ocean. C. frondosa contains a wide range of bioactive compounds, mainly collagen, cerebrosides, glycosaminoglycan, chondroitin sulfate, saponins, phenols, and mucopolysaccharides, which demonstrate unique biological and pharmacological properties. In particular, the body wall of this marine invertebrate is the major edible part and contains most of the active constituents, mainly polysaccharides and collagen, which exhibit numerous biological activities, including anticancer, anti-hypertensive, anti-angiogenic, anti-inflammatory, antidiabetic, anti-coagulation, antimicrobial, antioxidation, and anti- osteoclastogenic properties. In particular, triterpene glycosides (frondoside A and other) are the most researched group of compounds due to their potential anticancer activity. This review summarizes the latest information on C. frondosa, mainly geographical distribution, landings specific to Canadian coastlines, processing, commercial products, trade market, bioactive compounds, and potential health benefits in the context of functional foods and nutraceuticals.

Sulfated fucan chondroitin sulfate-dominated polysaccharide fraction from low-edible-value sea cucumber may be a good alternative to high-edible-value sea cucumber-derived polysaccharide for application in hypoglycemic functional foods. To evaluate the potential effect of low-edible-value sea cucumber-derived polysaccharide fraction on type 2 diabetes (T2DM), two sulfated fucan/fucosylated chondroitin sulfate-dominated polysaccharide fractions screening from 10 global commercial low-edible-value sea cucumber species were investigated to identify their anti-diabetics efficacies using a high-fat diet and streptozotocin-induced T2DM rat model. Sulfated fucan-dominated polysaccharide fraction from Thelenota ananas and fucosylated chondroitin sulfate-dominated polysaccharide fraction from Cucumaria frondosa ameliorated hyperglycemia, restored hypertriglyceridemia and hypercholesterolemia, decreased inflammatory status and oxidative stress, protected against liver injury, as well as improved insulin resistance and promoted accumulation of hepatic glycogen by activating IRS/PI3K/AKT signaling and regulating GSK-3β gene expression in T2DM rats. The current findings provide an available strategy for the commercialization of sea cucumber polysaccharide based-hypoglycemic functional food.

Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were given 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage) and were compared with a control group and the DSS group. Disease activity index (DAI) and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO) concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT-PCR. The tissue content of leukotriene B4 (LTB4) was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2), and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α) both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4) induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity.

A fucosylated chondroitin sulfate (FCS) CF was isolated from the sea cucumber Cucumaria frondosa and purified by anion-exchange chromatography. Chemical and NMR spectroscopic methods were applied for the structural characterization of this biopolymer. The backbone of CF was found to consist of chondroitin sulfate A and E fragments together with rather uncommon disaccharide repeating units →3)-β-d-GalNAc4S6S-(1→4)-β-d-GlcA3S-(1→ and →3)-β-d-GalNAc4S-(1→4)-β-d-GlcA3S-(1→. Three types of branches were found in molecules of CF. Two of them were identified as α-l-Fuc p3S4S and α-l-Fuc p2S4S attached to O-3 of Glc pA residues, while the third one was per-O-sulfated α-l-Fuc p linked to O-6 of Gal pNAc residue. The ratio of these branches was 5:2:1. According to these data, CF has more complicated structure than the corresponding FCS, isolated from the same holothurian species and described previously (Liu et al., 2016). The presence of new structural features both in the backbone and in branches of CF gives an additional example of structural variability within holothurian FCS.