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11 pages, 1776 KiB

Open AccessArticle

Comparative Assessment of APTT Reagents for Evaluating Anticoagulant Sensitivity of Fucosylated Glycosaminoglycans (FGs) Derived from Sea Cucumbers

by Huifang Sun, Shasha Yang, Pengfei Li, Xiaolei Shang, Pin Wang, Jiali Zhang, Lin Yuan, Ronghua Yin, Na Gao and Jinhua Zhao

Mar. Drugs 2023, 21(11), 568; https://doi.org/10.3390/md21110568 - 29 Oct 2023

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Abstract

Fucosylated glycosaminoglycans (FGs) derived from sea cucumbers exhibit potent intrinsic Xase (iXase) inhibition, anticoagulation, and antithrombosis. Plasma activated partial thromboplastin time (APTT), a widely used screening test worldwide, is crucial for evaluating anticoagulant efficacy. However, the applicability of these commercially available APTT reagents [...] Read more.

Fucosylated glycosaminoglycans (FGs) derived from sea cucumbers exhibit potent intrinsic Xase (iXase) inhibition, anticoagulation, and antithrombosis. Plasma activated partial thromboplastin time (APTT), a widely used screening test worldwide, is crucial for evaluating anticoagulant efficacy. However, the applicability of these commercially available APTT reagents for assessing anticoagulation of FGs remains unreported. In this study, we investigated the disparity between ellagic acid and colloidal silica APTT reagents in evaluating anticoagulation of dHG-5 and dHLFG-4, two depolymerized FGs, and elucidated the underlying rationale. The results demonstrated that dHG-5 and dHLFG-4 exhibited heightened sensitivity to the ellagic acid APTT reagent both in vitro and in vivo, and did not significantly affect the activation of APTT reagents for plasma. In addition, both ellagic acid and colloidal silica APTT reagents inhibited the anti-iXase of dHG-5 and dHLFG-4, and the inhibition of the ellagic acid APTT reagent was less pronounced compared to the colloidal silica APTT reagent. These findings suggest that the reduced impact of the ellagic acid APTT reagent on the anti-iXase activity of dHG-5 and dHLFG-4 is responsible for the increased sensitivity in plasma APTT analysis. This study offers valuable insights into the characteristics of two APTT reagents applied for assessing the anticoagulant activity of FG-related compounds. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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16 pages, 7687 KiB

Open AccessArticle

Holothurin A Inhibits RUNX1-Enhanced EMT in Metastasis Prostate Cancer via the Akt/JNK and P38 MAPK Signaling Pathway

by Sirorat Janta, Kanta Pranweerapaiboon, Pornpun Vivithanaporn, Anuchit Plubrukarn, Arthit Chairoungdua, Prachayaporn Prasertsuksri, Somjai Apisawetakan and Kulathida Chaithirayanon

Mar. Drugs 2023, 21(6), 345; https://doi.org/10.3390/md21060345 - 03 Jun 2023

Cited by 4 | Viewed by 1438

Abstract

Due to the challenge of prostate cancer (PCa) management, there has been a surge in efforts to identify more safe and effective compounds that can modulate the epithelial–mesenchymal transition (EMT) for driving metastasis. Holothurin A (HA), a triterpenoid saponin isolated from Holothuria scabra [...] Read more.

Due to the challenge of prostate cancer (PCa) management, there has been a surge in efforts to identify more safe and effective compounds that can modulate the epithelial–mesenchymal transition (EMT) for driving metastasis. Holothurin A (HA), a triterpenoid saponin isolated from Holothuria scabra, has now been characterized for its diverse biological activities. However, the mechanisms of HA in EMT-driven metastasis of human PCa cell lines has not yet been investigated. Moreover, runt-related transcription factor 1 (RUNX1) acts as an oncogene in prostate cancer, but little is known about its role in the EMT. Thus, the purpose of this study was to determine how RUNX1 influences EMT-mediated metastasis, as well as the potential effect of HA on EMT-mediated metastasis in endogenous and exogenous RUNX1 expressions of PCa cell lines. The results demonstrated that RUNX1 overexpression could promote the EMT phenotype with increased EMT markers, consequently driving metastatic migration and invasion in PC3 cell line through the activation of Akt/MAPK signaling pathways. Intriguingly, HA treatment could antagonize the EMT program in endogenous and exogenous RUNX1-expressing PCa cell lines. A decreasing metastasis of both HA-treated cell lines was evidenced through a downregulation of MMP2 and MMP9 via the Akt/P38/JNK-MAPK signaling pathway. Overall, our approach first demonstrated that RUNX1 enhanced EMT-driven prostate cancer metastasis and that HA was capable of inhibiting the EMT and metastatic processes and should probably be considered as a candidate for metastasis PCa treatment. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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19 pages, 2346 KiB

Open AccessArticle

Proliferative Effect of Aqueous Extract of Sea Cucumber (Holothuria parva) Body Wall on Human Umbilical Cord Mesenchymal Stromal/Stem Cells

by Poorya Rasekh, Ali Kameli, Arezoo Khoradmehr, Neda Baghban, Gholamhossein Mohebbi, Alireza Barmak, Iraj Nabipour, Hossein Azari, Yaser Heidari, Adel Daneshi, Afshar Bargahi, Zahra Khodabandeh, Shahrokh Zare, Alireza Afshar, Reza Shirazi, Sahar Almasi-Turk and Amin Tamadon

Mar. Drugs 2023, 21(5), 267; https://doi.org/10.3390/md21050267 - 26 Apr 2023

Viewed by 1657

Abstract

Sea cucumber extracts and their bioactive compounds have the potential for stem cell proliferation induction and for their beneficial therapeutic properties. In this study, human umbilical cord mesenchymal stromal/stem cells (hUC-MSCs) were exposed to an aqueous extract of Holothuria parva body walls. Proliferative [...] Read more.

Sea cucumber extracts and their bioactive compounds have the potential for stem cell proliferation induction and for their beneficial therapeutic properties. In this study, human umbilical cord mesenchymal stromal/stem cells (hUC-MSCs) were exposed to an aqueous extract of Holothuria parva body walls. Proliferative molecules were detected using gas chromatography-mass spectrometry (GC-MS) analysis in an aqueous extract of H. parva. The aqueous extract concentrations of 5, 10, 20, 40, and 80 µg/mL and 10 and 20 ng/mL of human epidermal growth factor (EGF) as positive controls were treated on hUC-MSCs. MTT, cell count, viability, and cell cycle assays were performed. Using Western blot analysis, the effects of extracts of H. parva and EGF on cell proliferation markers were detected. Computational modeling was done to detect effective proliferative compounds in the aqueous extract of H. parva. A MTT assay showed that the 10, 20, and 40 µg/mL aqueous extract of H. parva had a proliferative effect on hUC-MSCs. The cell count, which was treated with a 20 µg/mL concentration, increased faster and higher than the control group (p < 0.05). This concentration of the extract did not have a significant effect on hUC-MSCs’ viability. The cell cycle assay of hUC-MSCs showed that the percentage of cells in the G2 stage of the extract was biologically higher than the control group. Expression of cyclin D1, cyclin D3, cyclin E, HIF-1α, and TERT was increased compared with the control group. Moreover, expression of p21 and PCNA decreased after treating hUC-MSCs with the extract. However, CDC-2/cdk-1 and ERK1/2 had almost the same expression as the control group. The expression of CDK-4 and CDK-6 decreased after treatment. Between the detected compounds, 1-methyl-4-(1-methyl phenyl)-benzene showed better affinity to CDK-4 and p21 than tetradecanoic acid. The H. parva aqueous extract showed proliferative potential on hUC-MSCs. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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17 pages, 2886 KiB

Open AccessArticle

Anti-Parkinson Effects of Holothuria leucospilota-Derived Palmitic Acid in Caenorhabditis elegans Model of Parkinson’s Disease

by Tanatcha Sanguanphun, Sukrit Promtang, Nilubon Sornkaew, Nakorn Niamnont, Prasert Sobhon and Krai Meemon

Mar. Drugs 2023, 21(3), 141; https://doi.org/10.3390/md21030141 - 23 Feb 2023

Cited by 4 | Viewed by 1931

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease which is still incurable. Sea cucumber-derived compounds have been reported to be promising candidate drugs for treating age-related neurological disorders. The present study evaluated the beneficial effects of the Holothuria leucospilota (H. [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease which is still incurable. Sea cucumber-derived compounds have been reported to be promising candidate drugs for treating age-related neurological disorders. The present study evaluated the beneficial effects of the Holothuria leucospilota (H. leucospilota)-derived compound 3 isolated from ethyl acetate fraction (HLEA-P3) using Caenorhabditis elegans PD models. HLEA-P3 (1 to 50 µg/mL) restored the viability of dopaminergic neurons. Surprisingly, 5 and 25 µg/mL HLEA-P3 improved dopamine-dependent behaviors, reduced oxidative stress and prolonged lifespan of PD worms induced by neurotoxin 6-hydroxydopamine (6-OHDA). Additionally, HLEA-P3 (5 to 50 µg/mL) decreased α-synuclein aggregation. Particularly, 5 and 25 µg/mL HLEA-P3 improved locomotion, reduced lipid accumulation and extended lifespan of transgenic C. elegans strain NL5901. Gene expression analysis revealed that treatment with 5 and 25 µg/mL HLEA-P3 could upregulate the genes encoding antioxidant enzymes (gst-4, gst-10 and gcs-1) and autophagic mediators (bec-1 and atg-7) and downregulate the fatty acid desaturase gene (fat-5). These findings explained the molecular mechanism of HLEA-P3-mediated protection against PD-like pathologies. The chemical characterization elucidated that HLEA-P3 is palmitic acid. Taken together, these findings revealed the anti-Parkinson effects of H. leucospilota-derived palmitic acid in 6-OHDA induced- and α-synuclein-based models of PD which might be useful in nutritional therapy for treating PD. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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15 pages, 5143 KiB

Open AccessArticle

Branched Chondroitin Sulfate Oligosaccharides Derived from the Sea Cucumber Acaudina molpadioides Stimulate Neurite Outgrowth

by Weili Wang, Hui Mao, Sujuan Li, Longlong Zhang, Lian Yang, Ronghua Yin and Jinhua Zhao

Mar. Drugs 2022, 20(10), 653; https://doi.org/10.3390/md20100653 - 21 Oct 2022

Cited by 3 | Viewed by 1426

Abstract

Fucosylated chondroitin sulfate (FCS) from the sea cucumber Acaudina molpadioides (FCS_Am) is the first one that was reported to be branched by disaccharide GalNAc-(α1,2)-Fuc_3S4S (15%) and sulfated Fuc (85%). Here, four size-homogenous fractions, and seven oligosaccharides, were separated from its [...] Read more.

Fucosylated chondroitin sulfate (FCS) from the sea cucumber Acaudina molpadioides (FCS_Am) is the first one that was reported to be branched by disaccharide GalNAc-(α1,2)-Fuc_3S4S (15%) and sulfated Fuc (85%). Here, four size-homogenous fractions, and seven oligosaccharides, were separated from its β-eliminative depolymerized products. Detailed NMR spectroscopic and MS analyses revealed the oligomers as hexa-, hepta-, octa-, and nonasaccharide, which further confirmed the precise structure of native FCS_Am: it was composed of the CS-E-like backbone with a full content of sulfation at O-4 and O-6 of GalNAc in the disaccharide repeating unit, and the branches consisting of sulfated fucose (Fuc_4S and Fuc_2S4S) and heterodisaccharide [GalNAc-(α1,2)-Fuc_3S4S]. Pharmacologically, FCS_Am and its depolymerized derivatives, including fractions and oligosaccharides, showed potent neurite outgrowth-promoting activity in a chain length-dependent manner. A comparison of analyses among oligosaccharides revealed that the sulfate pattern of the Fuc branches, instead of the heterodisaccharide, could affect the promotion intensity. Fuc_2S4S and the saccharide length endowed the neurite outgrowth stimulation activity most. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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16 pages, 735 KiB

Open AccessArticle

In Silico Analysis of Bioactive Peptides Produced from Underutilized Sea Cucumber By-Products—A Bioinformatics Approach

by Tharindu R. L. Senadheera, Abul Hossain, Deepika Dave and Fereidoon Shahidi

Mar. Drugs 2022, 20(10), 610; https://doi.org/10.3390/md20100610 - 28 Sep 2022

Cited by 17 | Viewed by 2761

Abstract

Bioinformatic tools are widely used in predicting potent bioactive peptides from food derived materials. This study was focused on utilizing sea cucumber processing by-products for generating antioxidant and ACE inhibitory peptides by application of a range of in silico techniques. Identified peptides using [...] Read more.

Bioinformatic tools are widely used in predicting potent bioactive peptides from food derived materials. This study was focused on utilizing sea cucumber processing by-products for generating antioxidant and ACE inhibitory peptides by application of a range of in silico techniques. Identified peptides using LC−MS/MS were virtually screened by PepRank technique followed by in silico proteolysis simulation with representative digestive enzymes using BIOPEP-UWM^TM data base tool. The resultant peptides after simulated digestion were evaluated for their toxicity using ToxinPred software. All digestive resistance peptides were found to be non-toxic and displayed favorable functional properties indicating their potential for use in a wide range of food applications, including hydrophobic and hydrophilic systems. Identified peptides were further assessed for their medicinal characteristics by employing SwissADME web-based application. Our findings provide an insight on potential use of undervalued sea cucumber processing discards for functional food product development and natural pharmaceutical ingredients attributed to the oral drug discovery process. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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11 pages, 1114 KiB

Open AccessArticle

The Phospholipid Molecular Species Profile of Apostichopus japonicus Tissues Modifies through Exposure to n-3 Polyunsaturated Fatty Acid-Deficient Diet

by Ekaterina V. Ermolenko, Tatyana V. Sikorskaya and Valeria P. Grigorchuk

Mar. Drugs 2022, 20(9), 578; https://doi.org/10.3390/md20090578 - 15 Sep 2022

Cited by 3 | Viewed by 1331

Abstract

The sea cucumber Apostichopus japonicus, being a target species of commercial fisheries and aquaculture, is also used as a source of biologically active compounds with high pharmacological potential. By the methods of high-performance liquid chromatography with high resolution mass spectrometry, we analyzed [...] Read more.

The sea cucumber Apostichopus japonicus, being a target species of commercial fisheries and aquaculture, is also used as a source of biologically active compounds with high pharmacological potential. By the methods of high-performance liquid chromatography with high resolution mass spectrometry, we analyzed the major structural phospholipids (PL)—glycerophosphoethanolamines (PE), glycerophosphocholines (PC), glycerophosphoserines (PS), and glycerophosphoinositols (PI)—in tissues of wild and cultured sea cucumbers. The intestines of the wild and cultured animals differed from the other tissues by an elevated content of molecular species of PE, PC, and PS with 22:6n-3 fatty acid. The respiratory trees of the studied animals contained a high level of odd-chain PI and PI with 20:4n-6. The exposure to n-3 PUFA-deficient diet resulted in substantial changes in the molecular species profile of PL of the wild and cultured animals. The cultured sea cucumbers showed a significant decrease in the 20:5n-3 content in all four studied PL classes. A replacement of 20:5n-3 by 20:4n-6 occurred in PE, PC, and PI. The decrease in the level of molecular species of PS with 20:5n-3 was compensated by an increase in the level of monounsaturated long-chain PS. The diet of cultured sea cucumbers is a crucial factor for enhancing the nutritional properties of the product obtained from them. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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12 pages, 2483 KiB

Open AccessArticle

Characterization and Expression Analysis of Regeneration-Associated Protein (Aj-Orpin) during Intestinal Regeneration in the Sea Cucumber Apostichopus japonicus

by Fang Su, Lina Sun, Xiaoni Li, Wei Cui and Hongsheng Yang

Mar. Drugs 2022, 20(9), 568; https://doi.org/10.3390/md20090568 - 06 Sep 2022

Cited by 2 | Viewed by 1699

Abstract

Apostichopus japonicus achieves intestinal regeneration in a short period after evisceration, and multiple genes are involved in this process. The transcriptome of A. japonicus was screened for regeneration-associated protein (Aj-Orpin), a gene that is specifically upregulated during intestinal regeneration. The expression and function [...] Read more.

Apostichopus japonicus achieves intestinal regeneration in a short period after evisceration, and multiple genes are involved in this process. The transcriptome of A. japonicus was screened for regeneration-associated protein (Aj-Orpin), a gene that is specifically upregulated during intestinal regeneration. The expression and function of Aj-Orpin were identified and investigated in this study. The 5′ and 3′ RACE polymerase chain reaction (PCR) was used to clone the full-length cDNA of Aj-Orpin. The open reading frame codes for a 164 amino-acid protein with an EF-hand_7 domain and overlapping signal peptides and transmembrane regions. Moreover, Aj-Orpin mRNA and protein expression during intestinal regeneration was investigated using real-time quantitative PCR and Western blot. The expression pattern of Aj-Orpin in the regenerating intestine was investigated using immunohistochemistry. The results showed that Aj-Orpin is an exocrine protein with two EF-hand-like calcium-binding domains. Expression levels were higher in the regenerating intestine than in the normal intestine, but protein expression changes lagged behind mRNA expression changes. Aj-Orpin was found to play a role in the formation of blastema and lumen. It was primarily expressed in the serosal layer and submucosa, suggesting that it might be involved in proliferation. These observations lay the foundation for understanding the role of Orpin-like in echinoderm intestinal regeneration. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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Review

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23 pages, 15688 KiB

Open AccessReview

A Bibliometric and In Silico-Based Analysis of Anti-Lung Cancer Compounds from Sea Cucumber

by Afshin Zare, Safoura Izanloo, Sajed Khaledi, Mussin Nadiar Maratovich, Asset Askerovich Kaliyev, Nurgul Abdullayevna Abenova, Farhad Rahmanifar, Mahdi Mahdipour, Shabnam Bakhshalizadeh, Reza Shirazi, Nader Tanideh and Amin Tamadon

Mar. Drugs 2023, 21(5), 283; https://doi.org/10.3390/md21050283 - 28 Apr 2023

Viewed by 1651

Abstract

Lung cancer is one of the most lethal malignancies in the world. However, current curative approaches for treating this type of cancer have some weaknesses. Therefore, scientists are attempting to discover new anti-lung cancer agents. Sea cucumber is a marine-derived source for discovering [...] Read more.

Lung cancer is one of the most lethal malignancies in the world. However, current curative approaches for treating this type of cancer have some weaknesses. Therefore, scientists are attempting to discover new anti-lung cancer agents. Sea cucumber is a marine-derived source for discovering biologically active compounds with anti-lung cancer properties. To explore the anti-lung cancer properties of sea cucumber, we analyzed surveys using VOSviewer software and identified the most frequently used keywords. We then searched the Google Scholar database for compounds with anti-lung cancer properties within that keyword family. Finally, we used AutoDock 4 to identify the compounds with the highest affinity for apoptotic receptors in lung cancer cells. The results showed that triterpene glucosides were the most frequently identified compounds in studies examining the anti-cancer properties of sea cucumbers. Intercedenside C, Scabraside A, and Scabraside B were the three triterpene glycosides with the highest affinity for apoptotic receptors in lung cancer cells. To the best of our knowledge, this is the first time that anti-lung cancer properties of sea cucumber-derived compounds have been examined in in silico conditions. Ultimately, these three components displayed anti-lung cancer properties in in silico conditions and may be used for the manufacture of anti-lung cancer agents in the near future. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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20 pages, 4263 KiB

Open AccessReview

Saponins of North Atlantic Sea Cucumber: Chemistry, Health Benefits, and Future Prospectives

by Oladapo F. Fagbohun, Jitcy S. Joseph, Olumayowa V. Oriyomi and H. P. Vasantha Rupasinghe

Mar. Drugs 2023, 21(5), 262; https://doi.org/10.3390/md21050262 - 23 Apr 2023

Cited by 2 | Viewed by 2616

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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22 pages, 2374 KiB

Open AccessReview

Antioxidant Potential of Sea Cucumbers and Their Beneficial Effects on Human Health

by Abul Hossain, Deepika Dave and Fereidoon Shahidi

Mar. Drugs 2022, 20(8), 521; https://doi.org/10.3390/md20080521 - 15 Aug 2022

Cited by 28 | Viewed by 4683

Abstract

Sea cucumbers are considered a luxury food item and used locally in traditional medication due to their impressive nutritional profile and curative effects. Sea cucumbers contain a wide range of bioactive compounds, namely phenolics, polysaccharides, proteins (collagen and peptides), carotenoids, and saponins, demonstrating [...] Read more.

Sea cucumbers are considered a luxury food item and used locally in traditional medication due to their impressive nutritional profile and curative effects. Sea cucumbers contain a wide range of bioactive compounds, namely phenolics, polysaccharides, proteins (collagen and peptides), carotenoids, and saponins, demonstrating strong antioxidant and other activities. In particular, phenolic compounds, mainly phenolic acids and flavonoids, are abundant in this marine invertebrate and exhibit antioxidant activity. Protein hydrolysates and peptides obtained from sea cucumbers exhibit antioxidant potential, mainly dependent on the amino acid compositions and sequences as well as molecular weight, displayed for those of ≤20 kDa. Moreover, the antioxidant activity of sea cucumber polysaccharides, including fucosylated chondroitin sulfate and fucan, is a combination of numerous factors and is mostly associated with molecular weight, degree of sulfation, and type of major sugars. However, the activity of these bioactive compounds typically depends on the sea cucumber species, harvesting location, food habit, body part, and processing methods employed. This review summarizes the antioxidant activity of bioactive compounds obtained from sea cucumbers and their by-products for the first time. The mechanism of actions, chemical structures, and factors affecting the antioxidant activity are also discussed, along with the associated health benefits. Full article

(This article belongs to the Special Issue Bioactive Compounds from Sea Cucumbers)

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