Marine Drugs

26 pages, 2533 KB

Open AccessArticle

A Sulfated Polysaccharide from Red Seaweed Gracilaria caudata Exhibits Antioxidant and Antiadipogenic Activities In Vitro

by Maxsuell Lucas Mendes Marques, Leandro Silva Costa, Mariana Santana Santos Pereira Costa and Hugo Alexandre Oliveira Rocha

Mar. Drugs 2026, 24(1), 15; https://doi.org/10.3390/md24010015 (registering DOI) - 26 Dec 2025

Abstract

This study investigated the antioxidant and antiadipogenic activities of sulfated polysaccharide (SPs) from the red seaweed Gracilaria caudata. First, sulfated polysaccharide-rich extracts (SPREs) from fifteen tropical seaweeds were screened to evaluate both their chemical composition and antioxidant potential. Among all samples, G. [...] Read more.

This study investigated the antioxidant and antiadipogenic activities of sulfated polysaccharide (SPs) from the red seaweed Gracilaria caudata. First, sulfated polysaccharide-rich extracts (SPREs) from fifteen tropical seaweeds were screened to evaluate both their chemical composition and antioxidant potential. Among all samples, G. caudata exhibited the highest total antioxidant capacity, which justified its selection for detailed characterization. Sequential acetone precipitation produced three SPs (F1.5, F2.0, and F3.0), differing in sulfate content, monosaccharide composition, and molecular weight. In vitro assays revealed that F1.5 had the highest total antioxidant capacity and strong iron-chelating activity, while F2.0 exhibited the most effective hydroxyl radical scavenger. Importantly, F1.5 was the only SP that was non-cytotoxic to non-tumor cell lines. In 3T3-L1 preadipocytes, F1.5 attenuated H₂O₂-induced oxidative stress by reducing ROS and MDA levels and restoring GSH and SOD activity, achieving effects comparable to those of quercetin. Moreover, F1.5 inhibited adipogenic differentiation in a dose-dependent manner, as evidenced by decreased Oil Red O staining and reduced glycerol release. Collectively, these findings indicate that F1.5 exerts both antioxidant and antiadipogenic activities, highlighting G. caudata as a promising natural source of bioactive polysaccharides with potential nutraceutical applications. Nonetheless, further studies are required to elucidate the molecular mechanisms underlying these effects, validate the efficacy in vivo, and assess bioavailability and safety before clinical translation can be considered. Full article

(This article belongs to the Special Issue Marine Glycobiology)

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11 pages, 2823 KB

Open AccessArticle

Identification and Characterization of Holin-like Protein ORF70 from Cyanophage MaMV-DC

by Lihui Meng, Yi Wu, Jiahao Xu, Jiarui Zhang, Zhiyong Zhang and Chen Wang

Mar. Drugs 2026, 24(1), 14; https://doi.org/10.3390/md24010014 - 26 Dec 2025

Abstract

In this study, we characterized the holin-like protein ORF70 from the cyanophage MaMV-DC, offering valuable insights into its role in phage-mediated host cell lysis. ORF70 shares key features with class III holins, such as a hydrophobic transmembrane domain and membrane-associated localization, which are [...] Read more.

In this study, we characterized the holin-like protein ORF70 from the cyanophage MaMV-DC, offering valuable insights into its role in phage-mediated host cell lysis. ORF70 shares key features with class III holins, such as a hydrophobic transmembrane domain and membrane-associated localization, which are crucial for its bacteriolytic activity. Subcellular localization studies suggested its association with the membrane, supporting its classification as a holin-like protein. Overexpression of ORF70 in E. coli resulted in significant growth inhibition, increased β-galactosidase leakage, and visual confirmation of cell death through live/dead staining. Additionally, ORF70’s sensitivity to the energy toxin 2,4-dinitrophenol (DNP) further indicated its holin-like activity by promoting membrane depolarization. Transmission electron microscopy and Gram staining revealed characteristic morphological changes in E. coli cells, including membrane disruption, consistent with damage caused by holins. These results suggest that ORF70 acts as a holin-like protein that disrupts the host membrane, leading to bacterial cell death. Our study provides evidence supporting the holin-like activity of ORF70 from cyanophage MaMV-DC. This research significantly enhances our understanding of phage-host interactions and opens new avenues for developing phage-based therapies, offering promising alternatives to traditional antibiotics amidst the growing challenge of antibiotic resistance. Full article

(This article belongs to the Special Issue Marine Biotoxins, 4th Edition)

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18 pages, 2001 KB

Open AccessArticle

Fine-Tuning Side Chain Substitutions: Impacts on the Lipophilicity–Solubility–Permeability Interplay in Macrocyclic Peptides

by Yangping Deng, Hengwei Bian, Hongbo Li, Yingjun Cui, Sizheng Li, Jing Li, Li Chen, Xuemei Zhang, Zhuo Shen, Fengyue Li, Yue Chen and Haohao Fu

Mar. Drugs 2026, 24(1), 13; https://doi.org/10.3390/md24010013 - 25 Dec 2025

Abstract

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed [...] Read more.

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE’s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug–membrane and drug–solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics. Full article

(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)

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23 pages, 3592 KB

Open AccessArticle

Phlorotannins from Ecklonia cava Regulate Dual Signaling Pathways, IL-17RA/Act1 and ERK1/2, to Suppress Ovarian Cancer Progression and Tumor-Associated Macrophage Activation

by Eun-Hye Kim, Hwi-Ho Lee, Jung-Hye Choi and Ji-Hye Ahn

Mar. Drugs 2026, 24(1), 12; https://doi.org/10.3390/md24010012 - 24 Dec 2025

Abstract

Background: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood. Methods: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8′-bieckol) through network [...] Read more.

Background: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood. Methods: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8′-bieckol) through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation in SKOV3 ovarian cancer cells and tumor-associated macrophages (TAMs). Results: Computational analyses revealed stable binding of phlorotannins to IL-17RA, with 7-phloroeckol and 8,8′-bieckol preferentially engaging loop-proximal regions of the receptor, while dieckol interacted with spatially distinct residues. In SKOV3 ovarian cancer cells, phlorotannins suppressed migration and invasion by approximately 40 to 60%, accompanied by reduced MMP expression linked to IL-17RA–Act1 signaling attenuation and by increased TIMP1 expression in association with transient ERK1/2 activation. In TAMs, phlorotannins attenuated pro-tumorigenic cytokine production and polarization marker expression, indicating suppression of tumor-supportive immune activity. Conclusions: Collectively, these findings demonstrate that E. cava-derived phlorotannins exert anti-metastatic effects through dual regulation of IL-17RA/Act1 and ERK1/2 signaling pathways, offering mechanistic insight into their therapeutic potential against inflammation-driven malignancies. Full article

(This article belongs to the Special Issue Marine Bioactive Compounds: Roles in Signaling Pathway Regulation and Potential Applications)

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33 pages, 3188 KB

Open AccessReview

Mediterranean Seaweed Polysaccharides: Insight into Chemical Structures, Applications, and Structure/Application Correlations

by Silvia Fanina, Angela Casillo and Maria Michela Corsaro

Mar. Drugs 2026, 24(1), 11; https://doi.org/10.3390/md24010011 - 24 Dec 2025

Abstract

Although extensive research has been conducted on algal polysaccharides worldwide, Mediterranean species remain comparatively understudied, despite the region’s rich biodiversity and the presence of several endemic taxa with promising biotechnological potential. This review provides an overview of the major polysaccharides isolated from Mediterranean [...] Read more.

Although extensive research has been conducted on algal polysaccharides worldwide, Mediterranean species remain comparatively understudied, despite the region’s rich biodiversity and the presence of several endemic taxa with promising biotechnological potential. This review provides an overview of the major polysaccharides isolated from Mediterranean macroalgae, highlighting their structural features and bioactivities, as well as potential structure-activity relationships. Furthermore, the extraction and purification strategies used to isolate these biomolecules, ranging from conventional chemical approaches to emerging green technologies, were overlooked. Overall, the growing evidence of potent biological activities, combined with advances in sustainable extraction, underscores the significant potential of Mediterranean macroalgal polysaccharides as valuable resources unlocking new opportunities for their application in pharmaceutical, cosmetic, biomedical, and biotechnology fields. Full article

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20 pages, 4387 KB

Open AccessArticle

Enzymatic Hydrolysis-Assisted Separation and Purification of High F-Value Oligopeptides from Sea Cucumbers and Their Anti-Fatigue Mechanism

by Xin Mu, Xinxin Yang, Jian Jiao, Ming Du and Zhenyu Wang

Mar. Drugs 2026, 24(1), 10; https://doi.org/10.3390/md24010010 - 23 Dec 2025

Abstract

Sea cucumber peptides have been shown to possess a number of functions, including antioxidant, anti-inflammatory, anti-tumor, and anti-fatigue effects, as well as immune regulation and promotion of collagen synthesis. Among these, high F-value oligopeptides are a promising natural active ingredient demonstrating excellent anti-fatigue [...] Read more.

Sea cucumber peptides have been shown to possess a number of functions, including antioxidant, anti-inflammatory, anti-tumor, and anti-fatigue effects, as well as immune regulation and promotion of collagen synthesis. Among these, high F-value oligopeptides are a promising natural active ingredient demonstrating excellent anti-fatigue effects. This study utilized fresh sea cucumbers as the primary raw material, employing membrane separation technology to investigate the simultaneous separation of sea cucumber polysaccharides and peptides. The process for removing aromatic amino acids during the preparation of high F-value oligopeptides from sea cucumbers was optimized, and the mechanism underlying their anti-fatigue effects was explored. A two-step enzymatic hydrolysis method using neutral protease and composite flavor protease was employed, followed by membrane separation using a 10,000 Da molecular weight ultrafiltration membrane, yielding a sea cucumber peptide yield of 45.00 ± 0.12% and a sea cucumber polysaccharide yield of 51.28 ± 0.63%. Following the removal of aromatic amino acids by means of activated carbon adsorption, the F-value of the high-F-value oligopeptides attained 23.82, with a yield of 24.56%. The experimental findings demonstrated that high-F-value oligopeptides exhibited a substantial increase in the swimming duration of mice and a notable enhancement in their grip strength. These observations signified their substantial anti-fatigue potential. Furthermore, studies have indicated that sea cucumber high-F-value oligopeptides reduce metabolites produced by exercise, enhance muscle protection, increase the activity of antioxidant enzymes in the body, and alleviate fatigue, thereby achieving an anti-fatigue effect. Full article

(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)

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20 pages, 1469 KB

Open AccessReview

Diarrhetic Shellfish Poisoning Toxins: Current Insights into Toxicity, Mechanisms, and Ecological Impacts

by Hajar Bouda, Rajae El Bourki, Abderrazzak Fattah and Nadia Takati

Mar. Drugs 2026, 24(1), 9; https://doi.org/10.3390/md24010009 - 23 Dec 2025

Abstract

Diarrheic shellfish toxins (DSTs), especially okadaic acid (OA) and its related compounds, are lipophilic marine biotoxins mainly synthesized by dinoflagellates of the genera Dinophysis and Prorocentrum. These compounds bioaccumulate in filter-feeding shellfish like mussels and clams, posing a considerable public health risk due [...] Read more.

Diarrheic shellfish toxins (DSTs), especially okadaic acid (OA) and its related compounds, are lipophilic marine biotoxins mainly synthesized by dinoflagellates of the genera Dinophysis and Prorocentrum. These compounds bioaccumulate in filter-feeding shellfish like mussels and clams, posing a considerable public health risk due to their strong gastrointestinal effects when contaminated seafood is consumed. This review offers a thorough overview of the current understanding of OA-group toxins with a focus on the molecular mechanisms of toxicity, including cytoskeletal disruption, apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction. Additionally, their ecological impacts on aquatic organisms and patterns of bioaccumulation are explored. Recent advances in detection methods and regulatory frameworks are discussed, highlighting the necessity for robust monitoring systems to safeguard seafood safety. Enhanced knowledge of the toxicity, distribution, and fate of DSP (diarrheic shellfish poisoning) is essential for improving risk assessment and managing marine biotoxins. Despite methodological advances, gaps remain regarding chronic exposure and species-specific detoxification pathways. Full article

(This article belongs to the Special Issue Marine Biotoxins, 4th Edition)

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14 pages, 1434 KB

Open AccessArticle

Oxylipin Profiling in Selected Brown and Red Algae: Detection of Heterobicyclic Oxylipins, Plasmodiophorols and Ectocarpins in Phaeophyceae

by Yana Y. Toporkova, Elena O. Smirnova, Oksana S. Belous, Tatiana M. Iljina, Natalia V. Lantsova, Svetlana S. Gorina and Alexander N. Grechkin

Mar. Drugs 2026, 24(1), 8; https://doi.org/10.3390/md24010008 - 23 Dec 2025

Abstract

GC-MS oxylipin profiling of brown and red algal thalli was performed. Brown algae (Fucus distichus and Alaria esculenta) were collected from the Barents Sea coastline nearby Teriberka, Murmansk region, Kola Peninsula, Russia, while other brown and red algae were sourced from [...] Read more.

GC-MS oxylipin profiling of brown and red algal thalli was performed. Brown algae (Fucus distichus and Alaria esculenta) were collected from the Barents Sea coastline nearby Teriberka, Murmansk region, Kola Peninsula, Russia, while other brown and red algae were sourced from the Pacific coast of the Russian Far East. Triols and δ-ketols (epoxyalcohol synthase products) were found in most brown and red algae. Several Heterokontophyta and Rhodophyta species possessed α-ketols (products of allene oxide synthase) and related vic-diols. Plasmodiophorols and ectocarpins (hydroperoxide bicyclase (HPB) products) were found only in brown algae from the Ectocarpales, Fucales, and Laminariales orders, not in brown algae from the Desmarestiales or Dictyotales orders, or in any red algae. Therefore, plasmodiophorol A and other HPB products could be used as chemotaxonomic markers for the classification of the separate orders of algae within Heterokontophyta. The in vitro incubations of F. distichus thalli with linoleic and α-linolenic acid resulted in the formation of α-ketols and the hydroperoxide bicyclase product, plasmodiophorol A. Full article

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18 pages, 7767 KB

Open AccessArticle

Genome Mining and Molecular Networking-Targeted Discovery of Siderophores with Plant Growth-Promoting Activities from the Marine-Derived Streptomonospora nanhaiensis 12A09^T

by Yan Bai, Weixian Gao, Wendian Zhao, Amr A. Arishi, Zhuo Shang, Jiangchun Hu and Huaqi Pan

Mar. Drugs 2026, 24(1), 7; https://doi.org/10.3390/md24010007 - 22 Dec 2025

Abstract

Plant growth regulators (PGRs) significantly contribute to enhancing crop quality and yield. There is an urgent market demand for innovative natural PGRs. Marine natural products have the potential to serve as valuable sources of PGRs. To discover natural siderophore-type PGRs from marine natural [...] Read more.

Plant growth regulators (PGRs) significantly contribute to enhancing crop quality and yield. There is an urgent market demand for innovative natural PGRs. Marine natural products have the potential to serve as valuable sources of PGRs. To discover natural siderophore-type PGRs from marine natural products, according to a systematic pipeline for efficient lead-structure discovery from microbial natural products (SPLSD), a unique desferrioxamine-like siderophore biosynthetic gene cluster was discovered and activated by genome mining and culture regulation from a novel species, Streptomonospora nanhaiensis 12A09^T. Some potentially new desferrioxamine derivatives were further discovered by the LC-MS/MS molecular network. Three new desferrioxamine derivatives, desferrioxamines C1, C2, and G3 (1–3) and three known ones, terragine E (4) and desferrioxamines E and D2 (5–6), were selectively isolated and identified using chromatography and spectroscopy techniques from S. nanhaiensis 12A09^T. In the ferric iron-chelating assay, 4 and 5 showed moderate Fe (III)-complexing capability, compared with desferrioxamine mesylate. In the plant growth-regulatory assay, 1, 5, and 6 potently boosted the root length of Oryza sativa and Brassica campestris seedlings, equivalent to gibberellin. This study reports the first discovery of desferrioxamine derivatives exhibiting plant growth-promoting activity. These findings offer valuable lead compounds for PGRs. Full article

(This article belongs to the Special Issue Genome Mining and Discovery of Marine Bioactive Secondary Metabolites)

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15 pages, 3400 KB

Open AccessArticle

Enhanced Thermostability and Catalytic Efficiency of Alginate Lyase Alyw203 by Hydrogen Bond Network Reconstruction

by Chengcheng Jiang, Jing-Run Ye, Tian-Tian Zhu, Qin Wang, Yan Ma, Zhi-Peng Wang, Chuan-Yang Shi, Ying Wang, Shou-Fu Zhang, Tian-Hong Liu and Hai-Ying Wang

Mar. Drugs 2026, 24(1), 6; https://doi.org/10.3390/md24010006 - 22 Dec 2025

Abstract

Alginate lyases are commonly employed for producing alginate oligosaccharides (AOS), but their industrial application is often constrained by low thermal stability and catalytic efficiency. This study engineered mutants of alginate lyase Alyw203 from marine Vibrio based on B-factor values and negative ΔΔG values. [...] Read more.

Alginate lyases are commonly employed for producing alginate oligosaccharides (AOS), but their industrial application is often constrained by low thermal stability and catalytic efficiency. This study engineered mutants of alginate lyase Alyw203 from marine Vibrio based on B-factor values and negative ΔΔG values. The L172V mutant exhibited a 2.43-fold increase in half-life at 40 °C, reduced K_m (from 107 to 65 mg/mL), and enhanced k_cat/K_m (from 0.07 to 0.35 mL/mg/s), indicating improved thermal stability, substrate affinity, and catalytic efficiency. Molecular dynamics simulations revealed that these improvements originated from reconstructed hydrogen bond networks, which stabilized enzyme–substrate interactions and reduced conformational flexibility. These results demonstrate that rational design focused on strengthening hydrogen bonding can simultaneously improve both stability and activity, offering a promising strategy for industrial AOS production. Full article

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

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62 pages, 10208 KB

Open AccessFeature PaperReview

Extracting Value from Marine and Microbial Natural Product Artifacts and Chemical Reactivity

by Mark S. Butler and Robert J. Capon

Mar. Drugs 2026, 24(1), 5; https://doi.org/10.3390/md24010005 - 20 Dec 2025

Abstract

Natural products are and continue to be a remarkable resource, rich in structural diversity, and endowed with valuable chemical and biological properties that have advanced both science and society. Some natural products, especially those from marine organisms, are chemically reactive, and during extraction [...] Read more.

Natural products are and continue to be a remarkable resource, rich in structural diversity, and endowed with valuable chemical and biological properties that have advanced both science and society. Some natural products, especially those from marine organisms, are chemically reactive, and during extraction and handling can partially or totally transform into artifacts. All too often overlooked or mischaracterised as natural products, artifacts can be invaluable indicators of a uniquely evolved and primed chemical space, with enhanced chemical and biological properties highly prized for drug discovery. To demonstrate this potential, we review a wide selection of marine and microbial case studies, revealing the factors that initiate artifact formation (e.g., solvents, heat, pH, light and air oxidation) and commenting on the mechanisms behind artifact formation. We conclude with reflections on how to recognise and control artifact formation, and how to exploit knowledge of artifacts as a window into unique regions of natural product chemical space—to better inform the development of future marine bioproducts. Full article

(This article belongs to the Special Issue From Marine Natural Products to Marine Bioproducts)

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29 pages, 2351 KB

Open AccessArticle

Omega-3 Source Matters: Comparative Lipid Signatures and Quantitative Distribution of EPA/DHA Across Marine Resources

by Kolos Makay, Carola Griehl, Stephan Schilling and Claudia Grewe

Mar. Drugs 2026, 24(1), 4; https://doi.org/10.3390/md24010004 - 20 Dec 2025

Abstract

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential omega-3 polyunsaturated fatty acids (n-3 PUFAs) with well-established health benefits. They occur primarily in marine resources, while their quantitative distribution within the glycerolipidome is rarely analyzed. Therefore, we investigated major commercial sources, including 12 [...] Read more.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential omega-3 polyunsaturated fatty acids (n-3 PUFAs) with well-established health benefits. They occur primarily in marine resources, while their quantitative distribution within the glycerolipidome is rarely analyzed. Therefore, we investigated major commercial sources, including 12 microalgal species, the protist Schizochytrium sp., four fish species, and nine commercial n-3 supplements (fish, krill and Schizochytrium-derived “algal” oils) by high-performance thin-layer chromatography–gas chromatography–mass spectrometry (HPTLC–GC–MS). The class-resolved mapping of EPA and DHA revealed signature lipid profiles across all sources. In microalgae, 60–80% of EPA was localized in glycolipids, whereas in Schizochytrium and fish, >90% of DHA occurred in triacylglycerols. Krill oils exhibited phospholipid-rich profiles with ~70% of phosphatidylcholine-bound DHA. Nutritional indices also highlighted major differences: fish and fish oils showed favorable PUFA-to-saturated FA ratios (>0.45) and hypocholesterolemic-to-hypercholesterolemic ratios (>1), while Schizochytrium-based “algal” oils even surpassed these values. The microalgae Nannochloropsis granulata contained the highest EPA content in biomass form, combined with favorable nutritional indices. Beyond total n-3 content in relation to recommended daily intake values, the lipid-class distribution and nutritional indices should be considered decisive metrics for evaluating the health relevance of n-3 resources in the human diet. Full article

(This article belongs to the Special Issue Applications of Lipids from Marine Sources)

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23 pages, 4061 KB

Open AccessArticle

Ly6/uPAR Protein from Asterias rubens Starfish Stimulates Migration and Invasion of Human Epithelial and Immune Cells

by Ekaterina N. Lyukmanova, Tamara Y. Gornostaeva, Sergey V. Shabelnikov, Zakhar O. Shenkarev, Mikhail P. Kirpichnikov, Alexander S. Paramonov and Maxim L. Bychkov

Mar. Drugs 2026, 24(1), 3; https://doi.org/10.3390/md24010003 - 19 Dec 2025

Abstract

Recently, we found that Lystar5 protein from coelomic cells of A. rubens starfish interacts with nicotinic acetylcholine receptors (nAChRs) and integrin α8-like protein. We hypothesized that Lystar5 mediates detachment of coelomic cells from the matrix and their migration. Skin wound healing in humans [...] Read more.

Recently, we found that Lystar5 protein from coelomic cells of A. rubens starfish interacts with nicotinic acetylcholine receptors (nAChRs) and integrin α8-like protein. We hypothesized that Lystar5 mediates detachment of coelomic cells from the matrix and their migration. Skin wound healing in humans is based on keratinocytes migration and is regulated by nAChRs and integrins. Here, we revealed that Lystar5 stimulates migration of human skin HaCaT keratinocytes and peripheral blood monocytes. Using ELISA, we found that Lystar5 binds to the membrane fraction of coelomic cells with its loops I and II, which form an active site of Lystar5 and resemble its pro-migratory activity. In keratinocytes and monocytes, Lystar5 and the peptides mimicking its loops I and II bound with α3, α4, and β2 nAChR and α5, αV, and β1 integrin subunits, which form molecular complexes. In keratinocytes, Lystar5 and its mimetics promoted short-term E/N cadherin switch and upregulated expression of α5 and αV integrins, EGFR, and ICAM-1. In keratinocytes and monocytes, Lystar5 and its mimetics upregulated E-selectin secretion. The ability of Lystar5 and its mimetics to stimulate skin keratinocyte migration and immune cell infiltration may be considered promising for the development of new wound-healing agents. Full article

(This article belongs to the Special Issue Marine Bioactives for Functional Cosmetics with Health-Promoting Properties)

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21 pages, 2385 KB

Open AccessArticle

Exploring the Microbial Reservoir of Geodia cydonium (Linnaeus, 1767): Insights into Site-Specific Diversity and Biotechnological Potential

by Roberta Esposito, Roberta Trani, Marco Bertolino, Michele Sonnessa, Gaia Laurenzi, Valerio Zupo, Caterina Longo and Maria Costantini

Mar. Drugs 2026, 24(1), 2; https://doi.org/10.3390/md24010002 - 19 Dec 2025

Abstract

Marine sponges are recognized as reservoirs of diverse microorganisms that produce bioactive natural compounds. In this study, we conducted a metataxonomic analysis of Geodia cydonium specimens collected from four sites in Italy: Secca delle Fumose (Gulf of Naples, Tyrrhenian Sea), Mar Piccolo of [...] Read more.

Marine sponges are recognized as reservoirs of diverse microorganisms that produce bioactive natural compounds. In this study, we conducted a metataxonomic analysis of Geodia cydonium specimens collected from four sites in Italy: Secca delle Fumose (Gulf of Naples, Tyrrhenian Sea), Mar Piccolo of Taranto and an Integrated Multi-Trophic Aquaculture (IMTA) system in Mar Grande of Taranto (both located in the Ionian Sea), and Polignano a Mare (Adriatic Sea). Our results revealed a highly diverse microbial community within the sponges, encompassing 24 bacterial phyla. Among these, Chloroflexota was the most abundant phylum, accounting for an average of 30.2% of the total community across all samples. In addition, the majority of the microbiota was composed of Actinomycetota, Proteobacteria, Acidobacteriota, Poribacteriota, Gemmatimonadota, and Dadabacteria. The sponge sample from Polignano a Mare exhibited the richest and most diverse bacterial community. This observation was supported by phylogenetic analysis, which identified seven bacterial genera, Albidovulum, Filomicrobium, Microtrix, Gaiellales, D90 (Gammaproteobacteria class), and Blastopirellula, exclusive to this site. Several of these taxa are known for their potential biotechnological applications, underlining the significance of site-specific microbial diversity in G. cydonium. Full article

(This article belongs to the Special Issue Marine Omics for Drug Discovery and Development, 2nd Edition)

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15 pages, 1976 KB

Open AccessReview

CRISPR-Cas Technology Turns Chlamydomonas reinhardtii into a Flagship for Algal Biotechnology

by Amina Antonacci, Annalisa Masi, Vincenzo Vedi, Sara Colella, Federica Musella, Gabriella Fiorentino and Viviana Scognamiglio

Mar. Drugs 2026, 24(1), 1; https://doi.org/10.3390/md24010001 - 19 Dec 2025

Abstract

Microalgae represent some of the most promising eukaryotic platforms in biotechnology due to their rapid growth, simple cultivation requirements, reliance on sunlight as a primary energy source, and ability to synthesize high-value bioactive compounds. These characteristics have made microalgae attractive candidates in various [...] Read more.

Microalgae represent some of the most promising eukaryotic platforms in biotechnology due to their rapid growth, simple cultivation requirements, reliance on sunlight as a primary energy source, and ability to synthesize high-value bioactive compounds. These characteristics have made microalgae attractive candidates in various fields, including biofuel production, carbon capture, and pharmaceutical development. However, several technical limitations have limited their large-scale use as sustainable biofactories. A paradigm shift is currently occurring thanks to the genetic manipulation of microalgae, driven by CRISPR-Cas technology. Significant progress has been made in the model species Chlamydomonas reinhardtii, particularly in the targeted and efficient insertion of foreign DNA. Despite this progress, key challenges remain, and further optimization of CRISPR-Cas methodologies is needed to fully unleash the genetic potential of this organism. This review provides an overview of the convergence of CRISPR-Cas technologies in microalgae research, highlighting their impact on genetic studies, metabolic engineering, and industrial applications. It summarizes recent advances in microalgal genome editing through CRISPR systems, outlines current technical challenges, and highlights future directions for improving the implementation of this innovative technology in microalgal biotechnology. Full article

(This article belongs to the Special Issue Algal Cultivation for Obtaining High-Value Products, 2nd Edition)

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21 pages, 13312 KB

Open AccessFeature PaperArticle

Precision-Engineered Dermatan Sulfate-Mimetic Glycopolymers for Multi-Targeted SARS-CoV-2 Inhibition

by Lihao Wang, Lei Gao, Chendong Yang, Mengfei Yin, Jiqin Sun, Luyao Yang, Chanjuan Liu, Simon F. R. Hinkley, Guangli Yu and Chao Cai

Mar. Drugs 2025, 23(12), 486; https://doi.org/10.3390/md23120486 - 18 Dec 2025

Abstract

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose major global health challenges despite extensive vaccination efforts. Variant escape, waning immunity, and reduced vaccine efficacy in immunocompromised populations underscore the urgent need for complementary antiviral therapeutics. Here, we report the design, synthesis, [...] Read more.

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose major global health challenges despite extensive vaccination efforts. Variant escape, waning immunity, and reduced vaccine efficacy in immunocompromised populations underscore the urgent need for complementary antiviral therapeutics. Here, we report the design, synthesis, and biological evaluation of precision-engineered dermatan sulfate (DS)-mimetic glycopolymers as multi-targeted inhibitors of SARS-CoV-2. Guided by molecular docking and virtual screening, sulfation at the C2 and C4 positions of iduronic acid was identified as critical for binding to the viral spike protein and inhibiting host and viral enzymes, including heparanase (HPSE) and main protease (M^pro). Chemically synthesized DS disaccharides were covalently grafted onto polymer scaffolds via a post-modification strategy, yielding glycopolymers with well-defined assembly that form uniform nanoparticles under physiological conditions. Surface plasmon resonance and pseudovirus assays revealed strong binding to the viral spike protein (K_D ≈ 177 nM), potent viral neutralization, and minimal cytotoxicity. Cellular uptake studies further demonstrated efficient internalization of nanoparticles and intracellular inhibition of HPSE and M^pro. These results establish a modular, non-anticoagulant, and glycosaminoglycan-mimetic platform for the development of broad-spectrum antiviral agents to complement vaccination and enhance preparedness against emerging coronavirus variants. Full article

(This article belongs to the Special Issue Synthetic Studies of Marine Bioactive Natural Products and Analogs to Develop Novel Drug Leads)

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28 pages, 849 KB

Open AccessReview

Astaxanthin from Haematococcus pluvialis and Chromochloris zofingiensis: Biosynthetic Pathways, Engineering Strategies, and Industrial Prospects

by Shufang Yang, Xue Lu, Jia Wang, Ye Liu, Man Nie, Jin Liu and Han Sun

Mar. Drugs 2025, 23(12), 485; https://doi.org/10.3390/md23120485 - 18 Dec 2025

Abstract

Astaxanthin, a high-value keto-carotenoid with potent antioxidant and health-promoting properties, has gained global attention as a sustainable nutraceutical and biotechnological product. The green microalgae Haematococcus pluvialis and Chromochloris zofingiensis represent two promising natural producers, yet they differ markedly in physiology, productivity, and industrial [...] Read more.

Astaxanthin, a high-value keto-carotenoid with potent antioxidant and health-promoting properties, has gained global attention as a sustainable nutraceutical and biotechnological product. The green microalgae Haematococcus pluvialis and Chromochloris zofingiensis represent two promising natural producers, yet they differ markedly in physiology, productivity, and industrial scalability. This review provides a focused comparative analysis of these two species, emphasizing their quantitative performance differences. H. pluvialis can accumulate astaxanthin up to ~3–5% of dry biomass but typically reaches biomass densities of only 5–10 g L⁻¹, whereas C. zofingiensis achieves ultrahigh biomass concentrations of 100–220 g L⁻¹ under heterotrophic fed-batch fermentation, although its astaxanthin content is much lower (~0.1–0.5% DW). While H. pluvialis remains the benchmark for natural astaxanthin due to its exceptionally high cellular content, its thick cell wall, slow growth, and strict phototrophic requirements impose major cost and operational barriers. In contrast, C. zofingiensis exhibits rapid and flexible growth under heterotrophic, mixotrophic, or phototrophic conditions and can achieve ultrahigh biomass in fermentation, though its ketocarotenoid flux and astaxanthin accumulation remain comparatively limited. Meanwhile, a rapidly growing patent landscape demonstrates global technological competition, with major portfolios emerging in China, the United States, and Europe, spanning chemical synthesis, microbial fermentation, algal metabolic engineering, and high-density cultivation methods. These patents reveal clear innovation trends—ranging from solvent-free green synthesis routes to engineered microalgae and yeast chassis for enhanced astaxanthin production—which increasingly shape industrial development strategies. By synthesizing recent advances in metabolic engineering, two-stage cultivation, and green extraction technologies, this review identifies key knowledge gaps and outlines a practical roadmap for developing next-generation astaxanthin biorefineries, with an emphasis on scalable production and future integration into broader biorefinery frameworks. The findings aim to guide future research and provide actionable insights for scaling sustainable, cost-effective production of natural astaxanthin. Full article

(This article belongs to the Special Issue Fermentation Processes for Obtaining Marine Bioactive Products)

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19 pages, 3502 KB

Open AccessArticle

Oyster Peptides Prepared by Lactobacillus casei Fermentation Enhance Immune Activity in RAW264.7 Cells via Activation of the MAPK Pathway

by Lingyue Zhong, Yirui Wu, Xuefang Guan, Mei Xu, Juqing Huang, Yafeng Zheng and Qi Wang

Mar. Drugs 2025, 23(12), 484; https://doi.org/10.3390/md23120484 - 18 Dec 2025

Abstract

Oyster peptides (OPs) have gained increasing attention for their excellent biological activities, especially immunomodulatory effects. In this study, oyster proteins were fermented using Lactobacillus casei to prepare bioactive peptides, and the effects of fermentation parameters (time, temperature, and inoculum amount) on the degree [...] Read more.

Oyster peptides (OPs) have gained increasing attention for their excellent biological activities, especially immunomodulatory effects. In this study, oyster proteins were fermented using Lactobacillus casei to prepare bioactive peptides, and the effects of fermentation parameters (time, temperature, and inoculum amount) on the degree of hydrolysis (DH) were optimized. The optimal fermentation conditions were determined as 30 h, 35 °C, and 5% inoculum amount, resulting in a DH of 28.24%. Structural characterization showed that OPs were mainly composed of low-molecular-weight peptides (<1000 Da) with high hydrophobic amino acid content, and they exhibited good stability during in vitro gastrointestinal digestion. In vitro immunological evaluation using RAW264.7 macrophages demonstrated that OPs significantly enhanced phagocytic activity and nitric oxide (NO) production, and upregulated the mRNA expression levels of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. Mechanistically, OPs exerted immunostimulatory effects by specifically activating the extracellular signal-regulated kinase (ERK) pathway within the mitogen-activated protein kinase (MAPK) signaling cascade, without significant alterations in the phosphorylation levels of p38 and c-Jun N-terminal kinase (JNK). These findings highlight the potential of Lactobacillus casei-fermented oyster peptides as natural immunomodulatory ingredients for functional food development. Full article

(This article belongs to the Section Marine-Derived Ingredients for Drugs, Cosmeceuticals and Nutraceuticals)

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3 pages, 133 KB

Open AccessEditorial

Marine-Derived Terpenes: Chemistry, Synthesis and Their Therapeutic Potential

by Jinmei Xia

Mar. Drugs 2025, 23(12), 483; https://doi.org/10.3390/md23120483 - 17 Dec 2025

Abstract

The past five years have marked a significant evolution in terpenoid natural product research, with direct implications for marine drug discovery [...] Full article

(This article belongs to the Special Issue Marine-Derived Terpenes: Chemistry, Synthesis and Their Therapeutic Potential)

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