Marine Drugs

19 pages, 2858 KiB

Open AccessArticle

Comparative Evaluation of Dynamic Maceration and Ultrasonic Assisted Extraction of Fucoidan from Four Arctic Brown Algae on Its Antioxidant and Anticancer Properties

by Ekaterina D. Obluchinskaya, Olga N. Pozharitskaya, Irina M. Lapina, Anna A. Kulminskaya, Elena V. Zhurishkina and Alexander N. Shikov

Mar. Drugs 2025, 23(6), 230; https://doi.org/10.3390/md23060230 - 28 May 2025

Abstract

The technology of fucoidan extraction significantly affects its properties. This study aimed to evaluate the impact of dynamic maceration (DM) and ultrasound-assisted extraction (UAE) on the antioxidant and anticancer properties of fucoidan from Arctic brown algae. Fucus vesiculosus (Fv), Fucus serratus (Fs), Fucus [...] Read more.

The technology of fucoidan extraction significantly affects its properties. This study aimed to evaluate the impact of dynamic maceration (DM) and ultrasound-assisted extraction (UAE) on the antioxidant and anticancer properties of fucoidan from Arctic brown algae. Fucus vesiculosus (Fv), Fucus serratus (Fs), Fucus distichus (Fd), and Ascophyllum nodosum (An) were collected from the Barents Sea. The average yield of fucoidan and uronic acid was higher (by 43.2% and 22.0%, respectively) after UAE, while phlorotannin content decreased by 53.7% compared with DM. The fucose level for all algae increased after UAE, while the molecular weight of fucoidans was lower. The highest antioxidant activity was noted for the fucoidan from An and Fv, which were obtained by DM and can be associated with the high concentrations of phlorotannins. The treatment of HeLa G-63 cells with all studied fucoidans for 48 h increased concentration-dependently the number of dead cells. The most promising were Fv and Fs fucoidans with high phlorotannins, low sulfates, and uronic acid extracted by DM. The co-administration of paclitaxel and fucoidan caused cell cycle arrest in the G2/M phase. The calculated for the first time combinatory effect showed that the simultaneous use of paclitaxel and fucoidan exposure leads to a synergistic interaction. Our results support the rationality of fucoidan use in complex chemotherapy to improve survival, quality of life and immunity in patients with cervical carcinoma. Full article

(This article belongs to the Special Issue The Extraction and Application of Functional Components in Algae)

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19 pages, 996 KiB

Open AccessReview

Chemical Defenses in Medusozoa

by Oliver J. Lincoln, Jonathan D. R. Houghton, Muhammad Zakariya, Chiara Lauritano and Isabella D’Ambra

Mar. Drugs 2025, 23(6), 229; https://doi.org/10.3390/md23060229 - 28 May 2025

Abstract

Cnidarian defensive strategies are commonly associated with the toxins they synthesize. Because toxins have negative, sometimes lethal, effects on humans, research has focused on them for medical and biotechnological applications. However, Cnidaria possess a variety of defensive systems complementing toxins. In recent decades, [...] Read more.

Cnidarian defensive strategies are commonly associated with the toxins they synthesize. Because toxins have negative, sometimes lethal, effects on humans, research has focused on them for medical and biotechnological applications. However, Cnidaria possess a variety of defensive systems complementing toxins. In recent decades, ecological and biotechnological studies have shed light on these systems, particularly in Anthozoa, while the knowledge of defensive systems different from toxins has remained limited in Medusozoa (Cubozoa, Hydrozoa, Scyphozoa and Staurozoa). In this review, we collected the scattered information available in the literature and organized it into four main topics: UV-light protection compounds, antioxidants, antimicrobial peptides, and endosymbionts. Within the topics, we found the largest amount of data refers to antimicrobial activities, which suggests this line of research as a potential exploitation of this group of organisms often appearing in large aggregates. We also found that some Medusozoa have been studied in detail as model organisms, although the close phylogenetic relationship among classes suggests that some defensive strategies may be common to other members of different classes. Indeed, an integrated understanding of defensive systems has the potential to inform not only ecological and evolutionary frameworks, but also biotechnological applications—from the identification of novel antioxidants or antimicrobial agents to the valorization of Medusozoan biomass. Full article

(This article belongs to the Section Marine Chemoecology for Drug Discovery)

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20 pages, 2851 KiB

Open AccessArticle

Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy

by Ting Sun, Huimin Lv, Huarong Shao, Xiuhua Zhang, Anqi Wang, Wei Zhang, Fei Liu and Peixue Ling

Mar. Drugs 2025, 23(6), 228; https://doi.org/10.3390/md23060228 - 27 May 2025

Abstract

Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. [...] Read more.

Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal–lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development. Full article

(This article belongs to the Section Marine Pharmacology)

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30 pages, 37101 KiB

Open AccessReview

Harnessing Thalassochemicals: Marine Saponins as Bioactive Agents in Nutraceuticals and Food Technologies

by Vicente Domínguez-Arca, Thomas Hellweg and Luis T. Antelo

Mar. Drugs 2025, 23(6), 227; https://doi.org/10.3390/md23060227 - 26 May 2025

Abstract

The expanding field of nutraceuticals and functional food science is increasingly turning to marine-derived bioactive compounds, particularly saponins, for their diverse pharmacological properties. These so-called thalassochemicals display distinctive structural features—such as sulfated glycosidic moieties and amphiphilic backbones—that underpin potent antitumor, hypolipidemic, antioxidant, and [...] Read more.

The expanding field of nutraceuticals and functional food science is increasingly turning to marine-derived bioactive compounds, particularly saponins, for their diverse pharmacological properties. These so-called thalassochemicals display distinctive structural features—such as sulfated glycosidic moieties and amphiphilic backbones—that underpin potent antitumor, hypolipidemic, antioxidant, and antimicrobial activities. In contrast to their terrestrial analogs, marine saponins remain underexplored, and their complexity poses analytical and functional challenges. This review provides a critical and integrative synthesis of recent advances in the structural elucidation, biological function, and technological application of marine saponins. Special emphasis is placed on the unresolved limitations in their isolation, characterization, and structural validation, including coelution of isomers, adduct formation in MS spectra, and lack of orthogonal techniques such as NMR or FTIR. We illustrate these limitations through original MS/MS data and propose experimental workflows to improve compound purity and identification fidelity. In addition to discussing known structure–activity relationships (SARs) and mechanisms of action, we extend the scope by integrating recent developments in computational modeling, including machine learning, molecular descriptors, and quantitative structure–activity relationship (QSAR) models. These tools offer new avenues for predicting saponin bioactivity, despite current limitations in available high-quality datasets. Furthermore, we include a classification and comparison of steroidal and triterpenoid saponins from marine versus terrestrial sources, complemented by detailed chemical schematics. We also address the impact of processing techniques, delivery systems, and bioavailability enhancements using encapsulation and nanocarriers. Finally, this review contextualizes these findings within the regulatory and sustainability frameworks that shape the future of saponin commercialization. By bridging analytical chemistry, computational biology, and food technology, this work establishes a roadmap for the targeted development of marine saponins as next-generation nutraceuticals and functional food ingredients. Full article

(This article belongs to the Special Issue Marine Nutraceuticals and Functional Foods: 2nd Edition)

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21 pages, 1370 KiB

Open AccessArticle

Potential of Marine Bacterial Metalloprotease A69 in the Preparation of Antarctic Krill Peptides with Multi-Bioactivities

by Rui Liu, Wen-Jie Cao, Wen-Xiao Zhao, Xiao-Jie Yuan, Yu-Zhong Zhang, Qi-Long Qin, Xiao-Yan Song, Xi-Ying Zhang, Jian Li, Xiu-Lan Chen and Yu-Qiang Zhang

Mar. Drugs 2025, 23(6), 226; https://doi.org/10.3390/md23060226 - 24 May 2025

Abstract

Antarctic krill (Euphausia superba) is a nutrient-rich marine resource. Although several terrestrial proteases have been used to prepare Antarctic krill peptides (AKPs), there has been no report on the preparation of AKPs using a marine protease. Here, marine bacterial protease A69 [...] Read more.

Antarctic krill (Euphausia superba) is a nutrient-rich marine resource. Although several terrestrial proteases have been used to prepare Antarctic krill peptides (AKPs), there has been no report on the preparation of AKPs using a marine protease. Here, marine bacterial protease A69 was used to prepare AKPs with multi-bioactivities. Through optimizing hydrolysis parameters, we established a process for AKPs preparation by hydrolyzing Antarctic krill powder with A69. In the prepared AKPs, peptides less than 3000 Da and 1000 Da accounted for 99.23% and 88.37%, respectively. The scavenging ratios of the AKPs to ABTS⁺, DPPH· and ·OH reached 93.23 ± 0.09%, 99.90 ± 0.15%, and 93.90 ± 0.47%, respectively. The AKPs also had high angiotensin-converting enzyme (ACE)-inhibitory activity, with an IC₅₀ of 0.22 ± 0.04 mg/mL. At 40 mg/mL, the AKPs inhibited α-glucosidase and dipeptidyl peptidase IV (DPP-IV) activities by 7.18% and 13.62%, respectively, and displayed antibacterial activity to Escherichia coli. Moreover, 14 antioxidant peptides, 24 ACE-inhibitory peptides, 2 α-glucosidase-inhibitory peptides, and 10 DPP-Ⅳ-inhibitory peptides were identified from the AKPs. These results demonstrate that the prepared AKPs contain diverse bioactive peptides and have multi-bioactivities. This study indicates that marine bacterial protease A69 has promising application potential in preparing AKPs with multi-bioactivities. Full article

(This article belongs to the Special Issue Marine Proteins and Enzymes: Bioactivities and Medicinal Applications)

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24 pages, 3323 KiB

Open AccessArticle

Aphanizomenon flos-aquae: A Biorefinery for Health and Energy—Unleashing Phycocyanin’s Power and Biogas Potential

by Pilar Águila-Carricondo, Raquel García-García, Juan Pablo de la Roche, Pedro Luis Galán, Luis Fernando Bautista, Juan J. Espada and Gemma Vicente

Mar. Drugs 2025, 23(6), 225; https://doi.org/10.3390/md23060225 - 24 May 2025

Abstract

This study presents a biorefinery approach for Aphanizomenon flos-aquae, demonstrating its potential as a dual source for phycocyanin and biogas. The antioxidant capacity of the extract was evaluated using the ABTS^•+ assay, while flow cytometry determined its cytotoxic effects on breast [...] Read more.

This study presents a biorefinery approach for Aphanizomenon flos-aquae, demonstrating its potential as a dual source for phycocyanin and biogas. The antioxidant capacity of the extract was evaluated using the ABTS^•+ assay, while flow cytometry determined its cytotoxic effects on breast cancer (HCC1806) and brain glioma (U-118 MG) cell lines, comparing pure C-phycocyanin to the non-purified extract. The non-purified extract scavenged 77% of ABTS^•+ radicals at 2.4 mg/mL, compared to 22% for pure C-phycocyanin. In U-118 MG cells, pure C-phycocyanin accounted for 55.5% of the 29.9 ± 6.1% total mortality observed with the non-purified extract at 0.75 mg/mL. HCC1806 cytotoxicity (80.9 ± 5.1% at 1 mg/mL) was attributed to synergistic effects of other extract components. The spent biomass was valorized through anaerobic digestion for biogas production, enhancing process sustainability. At a 2:1 inoculum-to-substrate ratio, the anaerobic digestion of the spent biomass yielded 447 ± 18 mL CH₄/gVS, significantly higher than the 351 ± 19 mL CH₄/gVS from the initial biomass. LCA estimated the environmental impacts of the A. flos-aquae biorefinery for phycocyanin production, targeting the cosmetic, food, and nutraceutical sectors, and highlighting the benefits of spent biomass valorization to produce biogas within a circular economy framework. This integrated approach demonstrates the potential of A. flos-aquae for the sustainable production of high-value compounds and renewable energy. Full article

(This article belongs to the Special Issue Algae-Powered Skincare: Innovations in Marine-Derived Cosmeceuticals)

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19 pages, 1738 KiB

Open AccessArticle

Exploration of Bioactive Compounds, Antioxidant and Antibacterial Properties, and Their Potential Efficacy Against HT29 Cell Lines in Dictyota bartayresiana

by Durairaj Swarna Bharathi, Andiyappan Boopathy Raja, Suganthi Nachimuthu, S. Thangavel, Karthik Kannan, Sengottaiyan Shanmugan and Vinaya Tari

Mar. Drugs 2025, 23(6), 224; https://doi.org/10.3390/md23060224 - 23 May 2025

Abstract

This study investigates the rare seaweed alga Dictyota bartayresiana lamour for biological activity. Antioxidant and antibacterial activities were examined. An MTT assay was carried out to examine cytotoxicity activity against colon cancer cells. The HPTLC analysis was performed for four different extracts, which [...] Read more.

This study investigates the rare seaweed alga Dictyota bartayresiana lamour for biological activity. Antioxidant and antibacterial activities were examined. An MTT assay was carried out to examine cytotoxicity activity against colon cancer cells. The HPTLC analysis was performed for four different extracts, which exhibited clear flavonoid band formation at 254 nm and 366 nm with varied ranges of R_f values: methanolic extract (R_f 0.87), acetone extract (R_f 0.82), and benzene (R_f 0.83). Methanolic Extract Fraction One (MEF1) has a distinct band formation at 366 nm, it is shown to have the highest inhibition (6.20 ± 0.53 mm) against Escherichia coli, and the MTT assay reveals that the aqueous extract of Dictyota bartayresiana extract has an IC₅₀ value of 300 µg/mL. It is divulged that methanolic extract shows the highest phytochemical compound level among the four extracts of Dictyota bartayresiana. A GC/MS analysis was employed to investigate the flavonoid profile of the crude seaweed extract. Although LC/MS is typically preferred for flavonoid analysis due to thermal sensitivity, GC/MS was used in this study owing to time constraints, with optimized conditions to reduce thermal degradation. The GC-MS analysis identified Quinoline and other flavonoids, suggesting potential bioactivity. The cytotoxicity activity of MEF1 shows that the development of a promising drug may be evaluated from a seaweed source. The present study provides excellent insight with the first report of the biologically active compound of Dictyota bartayresiana. Full article

(This article belongs to the Special Issue Marine Algae: Exploring Their Nutritional, Health, and Nutraceutical Potential)

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15 pages, 1725 KiB

Open AccessReview

Marine-Derived Antioxidants: A Comprehensive Review of Their Therapeutic Potential in Oxidative Stress-Associated Diseases

by Ruiqiu Zhang, Yuke Ren, Tianqi Ren, Yue Yu, Bo Li and Xiaobing Zhou

Mar. Drugs 2025, 23(6), 223; https://doi.org/10.3390/md23060223 - 22 May 2025

Abstract

Oxidative stress is a critical factor contributing to the pathogenesis of numerous diseases, including cardiovascular disorders, diabetes, and neurodegenerative conditions. In recent years, marine-derived antioxidants have emerged as promising therapeutic agents due to their unique biological activities and diverse sources. This comprehensive review [...] Read more.

Oxidative stress is a critical factor contributing to the pathogenesis of numerous diseases, including cardiovascular disorders, diabetes, and neurodegenerative conditions. In recent years, marine-derived antioxidants have emerged as promising therapeutic agents due to their unique biological activities and diverse sources. This comprehensive review explores the therapeutic potential of various marine antioxidants in mitigating oxidative stress-associated diseases. Marine organisms are rich in bioactive compounds, such as polysaccharides, polyphenols, carotenoids, peptides, and vitamins, which exhibit potent antioxidant and free radical scavenging abilities. These compounds have been shown to effectively inhibit oxidative reactions, repair oxidative damage, and enhance the body’s antioxidant defense mechanisms. For instance, marine polysaccharides and their derivatives can scavenge reactive oxygen species (ROS), protect neurons from oxidative damage, and alleviate inflammation in neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases. Similarly, marine unsaturated fatty acids, such as omega-3 polyunsaturated fatty acids (PUFAs), have been found to reduce cardiovascular risks by lowering serum triglyceride levels and improving vascular endothelial function. Additionally, marine-derived superoxide dismutase (SOD) plays a crucial role in neutralizing ROS, thereby offering protection against oxidative stress in various diseases. Despite these promising findings, challenges remain in the field, including the need for improved extraction and purification technologies, more comprehensive activity evaluation systems, and further research into the safety and bioavailability of these compounds. This review provides a detailed overview of the current research status, highlighting the types, structural characteristics, antioxidant activities, and mechanisms of action of marine antioxidants. It also identifies key areas for future research and development, aiming to harness the full potential of marine-derived antioxidants in the prevention and treatment of oxidative stress-related diseases. Full article

(This article belongs to the Special Issue Marine Anti-inflammatory Agents )

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28 pages, 2231 KiB

Open AccessReview

Diversity of Bioactive Compounds in Microalgae: Key Classes and Functional Applications

by Maslin Osathanunkul, Suebsuya Thanaporn, Lefkothea Karapetsi, Georgia Maria Nteve, Emmanouil Pratsinakis, Eleni Stefanidou, Giorgos Lagiotis, Eleni Avramidou, Lydia Zorxzobokou, Georgia Tsintzou, Artemis Athanasiou, Sofia Mpelai, Constantinos Constandinidis, Panagiota Pantiora, Marián Merino, José Luis Mullor, Luka Dobrovic, Leonardo Cerasino, Tomohisa Ogawa, Meropi Tsaousi, Alexandre M. C. Rodrigues, Helena Cardoso, Rita Pires, Daniel Figueiredo, Inês F. Costa, Catarina Anjos, Nikolaos E. Labrou and Panagiotis Madesis Show full author list Hide full author list

Mar. Drugs 2025, 23(6), 222; https://doi.org/10.3390/md23060222 - 22 May 2025

Abstract

Microalgae offer a sustainable and versatile source of bioactive compounds. Their rapid growth, efficient CO₂ utilization, and adaptability make them a promising alternative to traditional production methods. Key compounds, such as proteins, polyunsaturated fatty acids (PUFAs), polyphenols, phytosterols, pigments, and mycosporine-like amino [...] Read more.

Microalgae offer a sustainable and versatile source of bioactive compounds. Their rapid growth, efficient CO₂ utilization, and adaptability make them a promising alternative to traditional production methods. Key compounds, such as proteins, polyunsaturated fatty acids (PUFAs), polyphenols, phytosterols, pigments, and mycosporine-like amino acids (MAAs), hold significant commercial value and are widely utilized in food, nutraceuticals, cosmetics, and pharmaceuticals, driving innovation across multiple industries. Their antiviral and enzyme-producing capabilities further enhance industrial and medical applications. Additionally, microalgae-based biostimulants and plant elicitor peptides (PEPs) contribute to sustainable agriculture by enhancing plant growth and resilience to environmental stressors. The GRAS status of several species facilitates market integration, but challenges in scaling and cost reduction remain. Advances in biotechnology and metabolic engineering will optimize production, driving growth in the global microalgae industry. With increasing consumer demand for natural, eco-friendly products, microalgae will play a vital role in health, food security, and environmental sustainability. Full article

(This article belongs to the Special Issue Marine Biorefinery for Bioactive Compounds Production)

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17 pages, 3104 KiB

Open AccessArticle

Codium fragile Extract Ameliorates Respiratory Function by Controlling Allergic Inflammation in Ovalbumin-Induced Bronchial Disorders in Mice

by Hyo Lim Lee, Yeong Hyeon Ju, In Young Kim, Hye Ji Choi, Yu Mi Heo, Hwa Rang Na and Ho Jin Heo

Mar. Drugs 2025, 23(5), 221; https://doi.org/10.3390/md23050221 - 21 May 2025

Abstract

This study investigated the effect of Codium fragile (WCF) water extract in reducing allergic inflammation in ovalbumin (OVA)-induced mice. Mice were sensitized to OVA + aluminum hydroxide, administered WCF for one week, and exposed to 1% aerosolized OVA. As a result, WCF intake [...] Read more.

This study investigated the effect of Codium fragile (WCF) water extract in reducing allergic inflammation in ovalbumin (OVA)-induced mice. Mice were sensitized to OVA + aluminum hydroxide, administered WCF for one week, and exposed to 1% aerosolized OVA. As a result, WCF intake reduced the OVA-induced increase in CD4⁺ T cells, CD8⁺ T cells, the T helper type 2 (Th2)/T helper type 1 (Th1) cell ratio, and inflammatory cells such as eosinophils and lymphocytes. Furthermore, WCF reduced Th2 cytokines such as interleukin (IL)-5, IL-13, and IL-33 and inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-1β in lung tissues. A histological analysis showed that WCF intake decreases OVA-induced pulmonary inflammation, bronchial wall thickness, and mucus score and increases pulmonary alveolar area. Moreover, WCF inhibited the nuclear factor κB (NF-κB) pathway, the transforming growth factor β (TGF-β)/Smad pathway, and apoptosis-related proteins in lung tissues that OVA excessively activated. The oleamide (9-octadecenamide) content, representing a physiologically active component of WCF, was analyzed and validated using a high-performance liquid chromatography-photodiode array (HPLC-PDA) system. These results demonstrate that WCF may serve as a potential preventive agent for respiratory dysfunction such as allergic asthma by suppressing NF-κB and TGF-β/Smad pathways. Full article

(This article belongs to the Special Issue Marine Anti-Inflammatory and Antioxidant Agents, 4th Edition)

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11 pages, 991 KiB

Open AccessPerspective

The Enigma of Sponge-Derived Terpenoid Isothiocyanate–Thiocyanate Pairs: A Biosynthetic Proposal

by Tadeusz F. Molinski

Mar. Drugs 2025, 23(5), 220; https://doi.org/10.3390/md23050220 - 21 May 2025

Abstract

The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R⁺ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration [...] Read more.

The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R⁺ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration of three biosynthetic motifs: terpenoid carbocation (R⁺) capture by cyanoformate, NC-COOH (itself in equilibrium with NC⁻ and CO₂); co-localized rhodanese (a dual-function enzyme) that can both convert fugitive inorganic NC⁻ to thiocyanate ion, NCS⁻, and alkyl isonitriles to alkyl isothiocyanate (R-NC → R-NCS) and adventitious capture of the NCS⁻ by R⁺. The former two scenarios explain the preponderance of isothiocyanates, R-NCS, as products of a linear reaction path—the α-addition of S⁰ to R-NC—and the third scenario explains minor, less stable thiocyanates, R-SCN, as products of the adventitious capture of liberated NCS⁻ by the penultimate R⁺ precursor. DFT calculations support this proposal and eliminate other possibilities, e.g., the isomerization of R-NCS to R-SCN. Full article

(This article belongs to the Special Issue Biosynthesis of Biologically Active Marine Natural Products 2025)

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13 pages, 1859 KiB

Open AccessArticle

The Isolation, Structural Characterization, and Biosynthetic Pathway of Unguisin from the Marine-Derived Fungus Aspergillus candidus

by Wenjiao Diao, Wei Zhang, Xiaoxi Zhang, Siyu Du, Caijuan Zheng, Xuenian Huang and Xuefeng Lu

Mar. Drugs 2025, 23(5), 219; https://doi.org/10.3390/md23050219 - 21 May 2025

Abstract

Unguisins, a class of structurally complex cyclic peptides featuring a γ-aminobutyric acid residue embedded in the skeleton, exhibit diverse biological activities. Here, a new unguisin K, along with three known congeners, was isolated from the marine-derived fungus Aspergillus candidus MEFC1001. The biosynthetic [...] Read more.

Unguisins, a class of structurally complex cyclic peptides featuring a γ-aminobutyric acid residue embedded in the skeleton, exhibit diverse biological activities. Here, a new unguisin K, along with three known congeners, was isolated from the marine-derived fungus Aspergillus candidus MEFC1001. The biosynthetic pathway was elucidated through gene disruption coupled with in vitro enzymatic characterization. The ugs biosynthetic gene cluster (BGC) containing ugsA and ugsB, in conjunction with an extra-clustered gene ugsC, collaborates to synthesize these unguisins. The alanine racemase (AR) UgsC catalyzes the isomerization of Ala and provides d-Ala as the starter unit for the non-ribosomal peptide synthetase (NRPS). The unique localization of ugsC outside the ugs BGC is different from previously reported unguisin-producing systems where AR genes reside within BGCs. The methyltransferase UgsB mediates a key pre-modification step by methylating phenylpyruvic acid to yield β-methylphenylpyruvate, which is subsequently incorporated as β-methylphenylalanine during NRPS assembly. This represents the first experimental evidence of the β-carbon methylation of Phe residue occurring at the precursor level rather than through post-assembly modification. The NRPS UgsA recruits a variety of amino acids for assembly and cyclization to form mature unguisins. Additionally, genome mining utilizing UgsA as a query identified homologous NRPSs in diverse fungal species, highlighting the potential for unguisin production in fungi. This study enriches the biosynthetic diversity of cyclic peptides and provides guidance for exploring unguisin-like natural products derived from fungi. Full article

(This article belongs to the Special Issue Biosynthesis of Biologically Active Marine Natural Products 2025)

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31 pages, 3605 KiB

Open AccessArticle

Bioactivity Assessment and Untargeted Metabolomics of the Mediterranean Sea Pen Pennatula phosphorea

by Silvia Scarpato, Daniel Venturi, Fortunato Palma Esposito, Maria Cristina Mangano, Gianluca Sarà, Francesco Margiotta, Ester Pagano, Maria Miraglia, Enrico Sangiovanni, Mercedes Garcia-Gil, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Mario Dell’Agli, Angelo A. Izzo, Paola Nieri, Donatella de Pascale and Gerardo Della Sala

Mar. Drugs 2025, 23(5), 218; https://doi.org/10.3390/md23050218 - 21 May 2025

Abstract

Octocorals have proven to be a prolific source of bioactive natural products, exhibiting a wide spectrum of pharmacological activities. Among octocorals, Pennatulaceans, commonly known as sea pens, are among the most dominant soft coral species living in benthic communities. Nonetheless, reports on bioactivity [...] Read more.

Octocorals have proven to be a prolific source of bioactive natural products, exhibiting a wide spectrum of pharmacological activities. Among octocorals, Pennatulaceans, commonly known as sea pens, are among the most dominant soft coral species living in benthic communities. Nonetheless, reports on bioactivity and chemical investigations of this genus are scarce. This prompted us to shed light on the pharmacological potential of the extracts of the sea pen Pennatula phosphorea, Linneus 1758, and gain an overview of its metabolome. Crude octocoral extracts, obtained with a modified Kupchan extraction protocol, were assessed for their bioactivity potential, revealing the hexanic extract to exert anti-inflammatory effects and interesting protective properties in an in vitro model of sarcopenia and in auditory HEI-OC1 cisplatin-treated cells, while the chloroformic extract was active in reducing A375 melanoma cell viability in a concentration-dependent manner. An untargeted metabolomic analysis unveiled that P. phosphorea collects a wide array of glycerophospholipids and phosphosphingolipids belonging to the ceramide phosphoinositol class, which were exclusive or more abundant in the hexanic extract. Their proven anti-inflammatory and cytoprotective effects could demonstrate the activity shown by the P. phosphorea hexanic extract. In addition, a group of prostaglandins, eluted mainly in the chloroformic extract, were putatively annotated. Since prostanoids from marine origin have been demonstrated to exert cytotoxic and anti-proliferative properties against various cancer cell lines, the presence of PGs in the P. phosphorea chloroform extract could justify its anti-melanoma activity. This is the first report on the presence of glycerophospholipids, phosphosphingolipids, and prostaglandins, along with the identification of novel congeners, in sea pens. Full article

(This article belongs to the Section Marine Biotechnology Related to Drug Discovery or Production)

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17 pages, 4015 KiB

Open AccessArticle

Paralytic Shellfish Toxins in Coastal Waters of Changdao Island (China): Toxin Profiles, Potential Producers, and Environmental Conditions

by Guanchao Zheng, Yuxiang Deng, Haiyan Wu, Xiaokang Li, Ling Cheng, Chengxu Yuan, Minlu Liu and Zhijun Tan

Mar. Drugs 2025, 23(5), 217; https://doi.org/10.3390/md23050217 - 21 May 2025

Abstract

In recent decades, there have been frequent occurrences of paralytic shellfish toxin (PST) contamination in the Yellow and Bohai Seas, China. The waters around Changdao Island, situated at the convergence of these two seas, have suffered harmful algal blooms of Alexandrium spp., indicating [...] Read more.

In recent decades, there have been frequent occurrences of paralytic shellfish toxin (PST) contamination in the Yellow and Bohai Seas, China. The waters around Changdao Island, situated at the convergence of these two seas, have suffered harmful algal blooms of Alexandrium spp., indicating a potential risk of PST contamination in shellfish. However, a systematic investigation and assessment of PSTs in this area is still lacking. The presence of PSTs in plankton concentrates and shellfish in coastal areas of Changdao Island was monitored from April to October 2022, using liquid chromatography–tandem mass spectrometry. The potential toxin-producing microalgae were analyzed, as were the environmental conditions associated with their occurrence. The highest levels of PSTs in plankton concentrates and shellfish were both observed in September, reaching levels of 105.8 ng STXeq./L and 114.7 μg STXeq./kg, respectively. The main analogues were C1, C2, and GTX1–4. High-throughput analysis of the plankton concentrates identified eight species of Alexandrium, which are potential producers of PSTs. Sediment samples also revealed the presence of permanent cysts of Alexandrium. This research represents a significant advance in our understanding of the distribution and hypothetical sources of PSTs in the coastal waters of Changdao Island. Full article

(This article belongs to the Special Issue Emerging Toxins Accumulation in Shellfish)

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14 pages, 1806 KiB

Open AccessArticle

Chartarlactams U-X: Novel Phenylspirodrimanes from a Marine Derived Fungus Stachybotrys sp. SZU-W23 with Anti-Inflammatory Activity Mediated by the NF-κB/ROS Signaling Pathways

by Yanhua Wu, Lanyi Lu, Peng Zhang and Liyan Wang

Mar. Drugs 2025, 23(5), 216; https://doi.org/10.3390/md23050216 - 20 May 2025

Abstract

In this investigation, the anti-inflammatory potential of phenylspirodrimanes (PSDs) produced by the marine-derived fungal strain Stachybotrys sp. SZU-W23 was systematically explored. A total of 15 PSDs were successfully isolated. Among them, four novel compounds, designated as chartarlactams U-X, were precisely characterized using NMR, [...] Read more.

In this investigation, the anti-inflammatory potential of phenylspirodrimanes (PSDs) produced by the marine-derived fungal strain Stachybotrys sp. SZU-W23 was systematically explored. A total of 15 PSDs were successfully isolated. Among them, four novel compounds, designated as chartarlactams U-X, were precisely characterized using NMR, HRESIMS, and ECD analyses. Specifically, compound 10 exhibited the most potent inhibitory effect on nitric oxide production in LPS-stimulated RAW 264.7 macrophages within the 0.3–30 μM concentration range, with an IC₅₀ value of 12.4 μM. Additionally, MTT assays revealed no detectable cytotoxicity at these concentrations. Mechanistic studies revealed that compound 10 effectively suppressed ROS generation, likely inactivating the NF-κB signaling pathway and consequently downregulating pro-inflammatory mediators, including iNOS, IL-6, and IL-1β. Full article

(This article belongs to the Special Issue Structural Diversity in Marine Natural Products)

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17 pages, 3430 KiB

Open AccessArticle

Reeler Domain-Containing Proteins Involved in the Antibacterial Immunity of Shrimp Litopenaeus vannamei

by Jianying Qi, Guoqing Dai, Huiling Xing, Zhibin Fu, Sheng Ke and Lili Shi

Mar. Drugs 2025, 23(5), 215; https://doi.org/10.3390/md23050215 - 20 May 2025

Abstract

Like other invertebrates, Litopenaeus vannamei lacks adaptive immunity and relies mainly on innate immunity for defense against foreign pathogens. In this study, three distinct Reeler domain-containing molecules were discovered in L. vannamei, designated as LvReeler1, LvReeler2, and LvReeler3. Analysis [...] Read more.

Like other invertebrates, Litopenaeus vannamei lacks adaptive immunity and relies mainly on innate immunity for defense against foreign pathogens. In this study, three distinct Reeler domain-containing molecules were discovered in L. vannamei, designated as LvReeler1, LvReeler2, and LvReeler3. Analysis of tissue-specific expression patterns indicated that LvReeler1 showed predominant expression in the stomach, whereas LvReeler2 and LvReeler3 demonstrated peak transcriptional activity within gill tissues. The expression of these molecules was induced by Vibrio parahaemolyticus. In vivo interference with LvReelers expressions via dsRNA significantly increased the mortality rate of L. vannamei, while also leading to a marked increase in the bacterial load of V. parahaemolyticus in the gills. Additionally, recombinant proteins of LvReeler1 (rLvReeler1), LvReeler2 (rLvReeler2), and LvReeler3 (rLvReeler3) were successfully expressed in Escherichia coli. Antibacterial assays demonstrated that rLvReelers inhibited the growth of V. parahaemolyticus, Vibrio alginolyticus, and Vibrio harveyi, with rLvReeler3 exhibiting the strongest inhibitory activity. Scanning electron microscopy (SEM) observations revealed that rLvReeler3 caused bacterial aggregates to disintegrate after binding to V. parahaemolyticus and V. alginolyticus. In conclusion, LvReelers play an active role in the antimicrobial immune response of L. vannamei. Full article

(This article belongs to the Special Issue Sustainable Valorization of Seafood By-Products through Recovery of Valuable Bioactive Compounds 2nd Edition)

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24 pages, 7095 KiB

Open AccessArticle

Targeting YY1-DR5 Axis by Pyripyropene O as a Novel Therapeutic Strategy Against Prostate Cancer: Molecular Mechanisms and In Vivo Zebrafish Validation

by Wenxuan Fang, Ying Chen, Mingyi Nie, Xuefeng Zhou, Yonghong Liu, Huaming Tao, Bin Yang and Xueni Wang

Mar. Drugs 2025, 23(5), 214; https://doi.org/10.3390/md23050214 - 19 May 2025

Abstract

Background: Induction of apoptosis is an important strategy for the treatment of prostate cancer. DR5 is a member of the death receptor superfamily and targeting DR5 is an effective way to induce apoptosis. Pyripyropene O is a natural compound isolated from the marine [...] Read more.

Background: Induction of apoptosis is an important strategy for the treatment of prostate cancer. DR5 is a member of the death receptor superfamily and targeting DR5 is an effective way to induce apoptosis. Pyripyropene O is a natural compound isolated from the marine fungus Aspergillus fumigatus SCSIO 41220. We found it has anti-prostate cancer potential by inducing apoptosis; Methods: The effects of pyripyropene O on the viability, proliferation, cell cycle, apoptosis and migration of prostate cancer cells were investigated by MTT assay, plate clone formation assay, 3D cell sphere assay, flow cytometry and real-time cell analysis. Transmission electron microscopy was used to observe the changes in the internal structure of prostate cancer cells after treatment with pyripyropene O. After determining the mode of cell death, the mechanism of action of pyripyropene O on prostate cancer was further investigated using apoptotic protein microarray, western blot, qPCR, molecular docking, cellular immunofluorescence staining and cellular thermal shift assay. After explaining the mechanism of action of pyriproxyfen O, the in vivo absorption, distribution, metabolism, excretion and potential toxicity of pyriproxyfen O were investigated using ADMETLab 2.0 software. Finally, a zebrafish xenograft tumour model was developed to evaluate the anti-prostate cancer effects of pyriproxyfen O in vivo; Results: The experimental results at the cellular level showed that pyripyropene O inhibited the survival, proliferation and migration of prostate cancer cells, and also showed that pyripyropene O blocked the prostate cancer cell cycle at the G2/M phase and induced apoptosis. At the molecular level, pyripyropene O binds to the transcription factor YY1, promotes YY1 nuclear translocation, regulates the transcription level of DR5, a target gene of YY1, and upregulates the expression of DR5 mRNA and protein. The in vivo results showed that pyripyropene O effectively inhibited the development of prostate cancer in zebrafish; Conclusions: Pyripyropene O has a clear anti-prostate cancer effect at both cellular and animal levels, inhibiting the survival and proliferation of prostate cancer cells by binding to the transcription factor YY1 to activate the expression of DR5 to promote apoptosis, thus exerting an inhibitory effect on prostate cancer. Full article

(This article belongs to the Special Issue Marine Microorganisms Bioprospecting)

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23 pages, 6051 KiB

Open AccessArticle

Identification, Expression Profiling, Microbial Binding, and Agglutination Analyses of Two Cathepsin B Genes in Black Rockfish (Sebastes schlegelii)

by Xinghua Zhuang, Xingchun Li, Wenpeng Li, Xuan Xu, Fengjun Lin, Yiying Liu, Chonghui Chen, Xiaoxu Zhang, Pei Zhang, Chao Li and Qiang Fu

Mar. Drugs 2025, 23(5), 213; https://doi.org/10.3390/md23050213 - 18 May 2025

Abstract

As a lysosomal cysteine protease of the papain subfamily, cathepsin B (CTSB) is characterized by its innate immune functions and hydrolytic activity. However, the functions of CTSB in the immune responses of teleosts remain to be clarified. In this study, two CTSB genes [...] Read more.

As a lysosomal cysteine protease of the papain subfamily, cathepsin B (CTSB) is characterized by its innate immune functions and hydrolytic activity. However, the functions of CTSB in the immune responses of teleosts remain to be clarified. In this study, two CTSB genes in S. schlegelii, SsCTSBa and SsCTSBb, were identified. Both SsCTSBa and SsCTSBb are composed of a 993 bp ORF encoding 330 amino acids. It was found in a phylogeny analysis that both genes form monophyletic clades with their orthologous counterparts of Honeycomb rockfish (Sebastes umbrosus). A synteny analysis indicated that the CTSB homologues were comparatively conserved during vertebrate evolution. Additionally, quantitative real-time PCR revealed the ubiquitous mRNA expression of SsCTSBa and SsCTSBb in all of the examined tissues, and substantially differential expression patterns could be observed following Aeromonas salmonicida infection. A subcellular localization analysis demonstrated that the distribution of SsCTSBa and SsCTSBb was mainly in the cytoplasm. Moreover, rSsCTSBa and rSsCTSBb showed strong binding to Poly(I:C) and exhibited diverse agglutination effects on different bacteria. Overall, these findings suggest that the CTSB genes in black rockfish might show essential functions in the host defense of teleosts against bacterial infections, providing valuable insights for further investigations into the immune mechanism of teleost CTSB. Full article

(This article belongs to the Section Marine Biotechnology Related to Drug Discovery or Production)

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15 pages, 3422 KiB

Open AccessArticle

Dihydrogeodin from Fennellia flavipes Modulates Platelet Aggregation via Downregulation of Calcium Signaling, αIIbβ₃ Integrins, MAPK, and PI3K/Akt Pathways

by Abdul Wahab Akram, Dae-Cheol Choi, Hyung-Kyu Chae, Sung Dae Kim, Dongmi Kwak, Bong-Sik Yun and Man Hee Rhee

Mar. Drugs 2025, 23(5), 212; https://doi.org/10.3390/md23050212 - 17 May 2025

Abstract

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, frequently arising from platelet hyperactivation and subsequent thrombus formation. Although conventional antiplatelet therapies are available, challenges, such as drug resistance and bleeding complications, require the development of novel agents. In this study, [...] Read more.

Cardiovascular disease remains a leading cause of morbidity and mortality worldwide, frequently arising from platelet hyperactivation and subsequent thrombus formation. Although conventional antiplatelet therapies are available, challenges, such as drug resistance and bleeding complications, require the development of novel agents. In this study, dihydrogeodin (DHG) was isolated from Fennellia flavipes and evaluated using platelets derived from Sprague–Dawley rats. Platelet aggregation induced by collagen, adenosine diphosphate, or thrombin was assessed by light transmission aggregometry; DHG significantly reduced aggregation in a dose-dependent manner. Further assays demonstrated that DHG suppressed intracellular calcium mobilization, adenosine triphosphate release, and integrin αIIbβ₃-dependent fibrinogen binding, thereby impairing clot retraction. Western blot analysis revealed that DHG reduced the phosphorylation of mitogen-activated protein kinases (ERK, JNK, p38) and PI3K/Akt, indicating inhibition across multiple platelet-signaling pathways. Additionally, SwissADME-assisted pharmacokinetics predicted favorable properties without violations of the Lipinski (Pfizer) filter, Muegge (Bayer) filter, Ghose filter, Veber filter, and Egan filter, and network pharmacology revealed inhibition of calcium and MAPK pathways. These results highlight the potential of DHG as a novel antiplatelet agent with broad-spectrum activity and promising drug-like characteristics. Further studies are warranted to assess its therapeutic window, safety profile, and potential for synergistic use with existing antiplatelet drugs. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products, 2nd Edition)

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