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Marine Drugs

Marine Drugs is the leading, peer-reviewed, open access journal on the research, development, and production of biologically and therapeutically active compounds from the sea. Marine Drugs is published monthly online by MDPI. Australia New Zealand Marine Biotechnology Society (ANZMBS) is affiliated with Marine Drugs and its members receive a discount on article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, PubAg, MarinLit, AGRIS, and other databases.
Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmacology, Toxicology and Pharmaceutics (miscellaneous))
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 13.7 days after submission; acceptance to publication is undertaken in 1.9 days (median values for papers published in this journal in the second half of 2024).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

Impact Factor: 5.4 (2024); 5-Year Impact Factor: 5.6 (2024)

Imprint Information Journal Flyer Open Access ISSN: 1660-3397

Latest Articles

21 pages, 3190 KiB

Open AccessArticle

A Comparative Study of the Phytochemical Composition, Antioxidant Properties, and In Vitro Anti-Diabetic Efficacy of Different Extracts of Caulerpa prolifera

by Safae Ouahabi, Nour Elhouda Daoudi, Mohamed Chebaibi, Ibrahim Mssillou, Ilyesse Rahhou, Mohamed Bnouham, Belkheir Hammouti, Marie-Laure Fauconnier, Alicia Ayerdi Gotor, Larbi Rhazi and Mohammed Ramdani

Mar. Drugs 2025, 23(7), 259; https://doi.org/10.3390/md23070259 (registering DOI) - 21 Jun 2025

The Moroccan coastline has been the focus of attention for researchers studying the national algal flora, with the aim of preserving these invaluable natural resources. Since the year 2000, these resources have stimulated great interest in the creation of new drugs, as well [...] Read more.

The Moroccan coastline has been the focus of attention for researchers studying the national algal flora, with the aim of preserving these invaluable natural resources. Since the year 2000, these resources have stimulated great interest in the creation of new drugs, as well as their integration into food supplements and foods. Therefore, this study aims to explore the phytochemistry of a series of extracts derived from Caulerpa prolifera. To ensure better extraction of the various metabolites present, two extraction methods, namely maceration and the Soxhlet method, were employed using solvents of varying polarity (hexane, ethyl acetate, methanol, and water). The chemical composition of the extracts was analyzed using GC-MS for fatty acids and HPLC-DAD for phenolic compounds. Antioxidant activity was evaluated using DPPH and β-carotene bleaching assays, while antidiabetic potential was assessed by in vitro inhibition of α-amylase and α-glucosidase. In addition, Molecular docking models were employed to assess the interaction between the bioactive molecules and the human pancreatic α-amylase and α-glucosidase enzymes. Vanillin, p-coumaric acid, sinapic acid, 7,3′,4′-flavon-3-ol, and kaempferol were the most abundant phenolic compounds. Anti-diabetic and antioxidant effects were highly significant. Full article

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

33 pages, 2417 KiB

Open AccessReview

Targeting Ferroptosis in Tumors: Novel Marine-Derived Compounds as Regulators of Lipid Peroxidation and GPX4 Signaling

by Yimao Wu, Xiaoyan Chen, Zichang Chen and Yunqi Ma

Mar. Drugs 2025, 23(6), 258; https://doi.org/10.3390/md23060258 - 19 Jun 2025

This article reviews the mechanisms by which marine natural products regulate ferroptosis and their potential applications in tumor therapy. Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation, characterized primarily by the accumulation of lipid peroxides and the failure [...] Read more.

This article reviews the mechanisms by which marine natural products regulate ferroptosis and their potential applications in tumor therapy. Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation, characterized primarily by the accumulation of lipid peroxides and the failure of antioxidant defense systems. Due to their unique chemical structural diversity, marine natural products demonstrate significant advantages in regulating the ferroptosis pathway. Studies showed that marine compounds target key molecules such as glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase 4 (ACSL4(a)) ACSL4(1) to modulate lipid peroxidation and iron metabolism, inducing ferroptosis in tumor cells and reshaping the tumor microenvironment (TME). In addition, marine compounds can enhance anti-tumor effects by activating immune responses. Although marine compounds hold great potential in regulating ferroptosis, their clinical translation faces challenges such as low bioavailability and tumor type dependency. Future research needs to integrate multi-omics techniques to further analyze the mechanisms of marine compounds and develop precision therapeutic strategies based on marine compounds to overcome the bottlenecks in ferroptosis therapy. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 4th Edition)

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12 pages, 2201 KiB

Open AccessArticle

Searching for Paralytic Toxin, Tetrodotoxin, in Swedish Bivalve Shellfish

by Aida Zuberovic Muratovic, Shyamraj Dharavath, Jonas Bergquist, Malin Persson, Elin Renborg, Heidi Pekar and Mirjam Klijnstra

Mar. Drugs 2025, 23(6), 257; https://doi.org/10.3390/md23060257 - 19 Jun 2025

Tetrodotoxin (TTX), earlier known as a tropical paralytic neurotoxin from pufferfish poisoning, has increasingly been occurring in edible marine species, including filter-feeding bivalves, from relatively cold marine waters of some European countries. The defined conditions that promote the production of TTX, its origin [...] Read more.

Tetrodotoxin (TTX), earlier known as a tropical paralytic neurotoxin from pufferfish poisoning, has increasingly been occurring in edible marine species, including filter-feeding bivalves, from relatively cold marine waters of some European countries. The defined conditions that promote the production of TTX, its origin or the processes of its accumulation in seafood are still not clarified. Recent studies in temperate waters show, however, that the accumulation of quantifiable levels of TTX in bivalves appears to be influenced by seawater temperature (>15 °C), which indicates a seasonal occurrence at these latitudes. Uncertainties still remain regarding how seawater temperature interacts with other climate and environmental factors or organisms in the marine ecosystem to result in detectable levels of TTX in shellfish. Knowledge of the occurrence and distribution of TTX in the marine environment where the edible bivalves grow is important for maintaining seafood safety, as the toxin is heat-stable and remains potent even after cooking. Therefore, in this study, 264 bivalve samples collected in 2019 and 2021 from 17 sites along the Swedish west coast were analyzed with LC-MS/MS to search for TTX. The study explores the hypothesis of TTX presence in Swedish marine waters, outlines the sample screening strategy and objectives, and reports no evidence of TTX presence in Swedish bivalve shellfish (≥7.8 µg/kg) based on the analyzed samples and the time periods in which the studied samples were collected. Full article

(This article belongs to the Special Issue Cyanobacterial Toxins 2024)

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28 pages, 1593 KiB

Open AccessReview

A Review on Marine Microbial Docosahexaenoic Acid Production Through Circular Economy, Fermentation Engineering, and Antioxidant Technology

by Fengwei Yin, Xiaolong Sun, Xi Luo, Weilong Zheng, Longfei Yin, Yingying Zhang and Yongqian Fu

Mar. Drugs 2025, 23(6), 256; https://doi.org/10.3390/md23060256 - 16 Jun 2025

Marine microbial-derived docosahexaenoic acid (DHA) has garnered significant attention as a sustainable and health-promoting alternative to fish oil-derived DHA. However, its industrial production from marine heterotrophic microorganisms faces challenges related to high costs and suboptimal oil quality, which hinder its broader application. This [...] Read more.

Marine microbial-derived docosahexaenoic acid (DHA) has garnered significant attention as a sustainable and health-promoting alternative to fish oil-derived DHA. However, its industrial production from marine heterotrophic microorganisms faces challenges related to high costs and suboptimal oil quality, which hinder its broader application. This review focuses on recent strategies aimed at achieving low-cost and high-quality marine microbial DHA production, emphasizing heterotrophic systems that dominate commercial supply. Key aspects include: Fermentation optimization using waste-derived feedstocks and bioprocess engineering to enhance DHA yields; Critical refining techniques—including degumming, neutralization, decolorization, and deodorization—are analyzed for improving DHA oil purity and quality, with emphasis on process optimization to adapt to the unique biochemical properties of microbial-derived oils. Additionally, strategies for oxidative stabilization, such as antioxidant protection, are discussed to extend the shelf life and preserve the nutritional value of marine microbial DHA oil. By integrating techno-economic and biochemical perspectives, this work outlines a holistic framework to guide the industrial optimization of marine microbial-sourced DHA oil production, addressing cost and quality challenges to facilitate its large-scale application as functional foods and nutraceuticals, thereby reducing reliance on marine resources and advancing sustainable omega-3 production. Full article

(This article belongs to the Special Issue Fatty Acids from Marine Organisms, 2nd Edition)

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27 pages, 3604 KiB

Open AccessReview

Bioactive Polyketides from Amphidinium spp.: An In-Depth Review of Biosynthesis, Applications, and Current Research Trends

by Noemi Russo, Giulia Quaini, Marcello Ziaco, Daniela Castiglia, Alessandra Ruggiero, Vincenzo D’Amelia, Concetta Di Napoli, Sergio Esposito, Angelo Fontana, Genoveffa Nuzzo and Simone Landi

Mar. Drugs 2025, 23(6), 255; https://doi.org/10.3390/md23060255 - 16 Jun 2025

Polyketides (PKs) are a widespread class of secondary metabolites with recognised pharmacological properties. These molecules are abundantly produced in the marine environment, especially by dinoflagellate-photosynthetic organisms able to produce several PKs, including neurotoxins, cytotoxins, and immunomodulating agents. The biosynthesis of these compounds is [...] Read more.

Polyketides (PKs) are a widespread class of secondary metabolites with recognised pharmacological properties. These molecules are abundantly produced in the marine environment, especially by dinoflagellate-photosynthetic organisms able to produce several PKs, including neurotoxins, cytotoxins, and immunomodulating agents. The biosynthesis of these compounds is driven by a conserved enzymatic process involving polyketide synthase complexes. Different genera of dinoflagellates produce PKs. Among them, dinoflagellates of the genus Amphidinium are of particular interest due to its ability to produce the following two major families of PKs: amphidinolides and amphidinols. These compounds display remarkable biological activities, including anticancer, antimicrobial, and antifungal effects, making them attractive targets for pharmaceutical research and development. However, the natural yield of Amphidinium-derived polyketides (APKs) is generally low, limiting their potential for sustainable molecular farming. This challenge has prompted interest in developing biotechnological strategies to enhance their production. This review aims to define the current state of studies about APKs, starting from their initial discoveries to the recent understanding of their biosynthetic pathways. Additionally, it summarizes the structures of compounds discovered, highlights their biotechnological potential, and discusses novel trends in their production. Full article

(This article belongs to the Special Issue Bioactive Metabolites Produced by Marine Cyanobacteria and Other Microalgae)

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16 pages, 1568 KiB

Open AccessArticle

Exploring the Catalytic Mechanisms of a Newly Identified Salt-Activated Alginate Lyase from Pseudoalteromonas carrageenovora ASY5

by Xiaoyan Zhuang, Chao Jiao, Zewang Guo, Qiong Xiao, Jun Chen, Fuquan Chen, Qiuming Yang, Yi Ru, Huifen Weng, Siyuan Wang, Anfeng Xiao and Yonghui Zhang

Mar. Drugs 2025, 23(6), 254; https://doi.org/10.3390/md23060254 - 15 Jun 2025

Alginate lyases are critical enzymes in hydrolyzing alginate into alginate oligosaccharides (AOS), which are bioactive compounds known for their antioxidant properties and ability to lower serum glucose and lipid concentrations. However, elucidating catalytic mechanisms and discovering enzymes with enhanced catalytic efficiency remain long-term [...] Read more.

Alginate lyases are critical enzymes in hydrolyzing alginate into alginate oligosaccharides (AOS), which are bioactive compounds known for their antioxidant properties and ability to lower serum glucose and lipid concentrations. However, elucidating catalytic mechanisms and discovering enzymes with enhanced catalytic efficiency remain long-term challenges. Here, we report AlgL2491, a novel bifunctional and cold-adapted alginate lyase from Pseudoalteromonas carrageenovora ASY5, belonging to the polysaccharide lyase family 18. This enzyme uniquely cleaves both polyguluronic (polyG) and polymannuronic (polyM), predominantly releasing disaccharides, trisaccharides, and tetrasaccharides after 12 h of hydrolysis. The enzyme achieves peak catalytic efficiency at 35 °C and pH 7.5, with activity increasing 5.5-fold in 0.5 M of NaCl. Molecular dynamics simulations demonstrate that salt ions enhance structural stability by minimizing conformational fluctuations and strengthening interdomain interactions, providing mechanistic insights into its salt-activated behavior. The alginate oligosaccharides (AOS) exhibit excellent free radical-scavenging activities of 86.79 ± 0.31%, 83.42 ± 0.18%, and 71.28 ± 2.27% toward hydroxyl, ABTS, and DPPH radicals, with IC50 values of 8.8, 6.74, and 9.71 mg/mL, respectively. These findings not only reveal the salt-activation mechanism of AlgL2491 and highlight the potential value of its hydrolysate in antioxidant activity but also provide a sustainable industrial solution in industrial-scale AOS production directly from marine biomass, eliminating the need for energy-intensive desalination of alginate, which may inform future biocatalyst design for marine polysaccharide valorization. Full article

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

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21 pages, 2676 KiB

Open AccessSystematic Review

Prickly Defenders: A Review of Venomous Sea Urchins (Echinoidea)

by Sina Ehlert-Flaskämper, Cherie A. Motti and Richard J. Harris

Mar. Drugs 2025, 23(6), 253; https://doi.org/10.3390/md23060253 - 13 Jun 2025

Sea urchins, Echinoidea, are widely known for their defensive spines and pedicellariae, with some species having co-evolved venom in conjunction with those appendages. Despite this, their venomous arsenal remains poorly understood. Research has predominately focused on pedicellariae venom, while the spines have been [...] Read more.

Sea urchins, Echinoidea, are widely known for their defensive spines and pedicellariae, with some species having co-evolved venom in conjunction with those appendages. Despite this, their venomous arsenal remains poorly understood. Research has predominately focused on pedicellariae venom, while the spines have been largely neglected within studies. This review consolidates current knowledge of the venom systems (spines and pedicellariae) of sea urchins, focusing on the morphology, known venom components, and their functional effects. While early studies have established the bioactivity of crude extracts and fractions, along with the partial characterisation of some toxins, most of these studies are outdated and were conducted with very basic methodologies. Modern venomics presents an opportunity to meet this challenge, enabling development of a comprehensive database on venomous urchins and their toxins. This advancement will facilitate research into targeted early treatments and therapies for victims of sea urchin stings, ultimately improving health outcomes and enhancing our scientific understanding of venom toxins and their broader implications for human health and bioinnovation. Full article

(This article belongs to the Special Issue Chemical Defense in Marine Organisms, 3rd Edition)

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38 pages, 5968 KiB

Open AccessArticle

Marine Jellyfish Collagen and Other Bioactive Natural Compounds from the Sea, with Significant Potential for Wound Healing and Repair Materials

by Ana-Maria Pesterau, Antoanela Popescu, Rodica Sirbu, Emin Cadar, Florica Busuricu, Ana-Maria Laura Dragan, Carolina Pascale, Ana-Maria Ionescu, Claudia Florina Bogdan-Andreescu, Marius-Daniel Radu and Cezar Laurentiu Tomescu

Mar. Drugs 2025, 23(6), 252; https://doi.org/10.3390/md23060252 - 13 Jun 2025

Skin health must be ensured at all times in the case of wounds when the skin is subjected to traumatic actions that require multiple wound-healing measures. Wound healing is a complex, multi-phase biological process critical for restoring skin integrity after trauma. This study [...] Read more.

Skin health must be ensured at all times in the case of wounds when the skin is subjected to traumatic actions that require multiple wound-healing measures. Wound healing is a complex, multi-phase biological process critical for restoring skin integrity after trauma. This study investigates the development and evaluation of a novel composite hydrogel formulated from collagen peptides extracted from the jellyfish Rhizostoma pulmo and hydroethanolic extracts from the brown alga Cystoseira barbata, both sourced from the Romanian Black Sea coast. Throughout the work, the characteristics due to the biochemical compositions of the extracts from the brown alga C. barbata and from the jellyfish R. pulmo are highlighted as important, emphasizing the content of polysaccharides, proteins, and lipids. Total phenol content was analyzed for three extracts from natural products. The biochemical composition, antioxidant, antimicrobial, and in vitro wound-healing properties of the components and their composite (JPC-ALG) were assessed. The rheological behavior and optical microscopy studies of collagen hydrogels were prepared. The general mechanisms of wound healing with the involvement of polysaccharides and collagen peptides existing in all categories of extracts were highlighted. The study of the effects of JPC-ALG composites and individual extracts on fibroblast and keratocyte cell lines is also presented. Results demonstrated that the composite exhibited synergistic effects, enhancing fibroblast and keratinocyte migration and proliferation, key factors in wound closure. The findings support the potential application of this marine-derived bioactive composite as a promising biomaterial for wound-healing therapies. Full article

(This article belongs to the Special Issue Marine Bioactive Compounds for Skin Health)

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12 pages, 877 KiB

Open AccessArticle

New Polyketide and Butenolide Derivatives from the Mangrove Fungus Aspergillus spelaeus SCSIO 41433

by Zimin Xiao, Jiaqi Liang, Chun Yang, Jian Cai, Bin Yang, Xuefeng Zhou, Jie Yuan and Huaming Tao

Mar. Drugs 2025, 23(6), 251; https://doi.org/10.3390/md23060251 - 13 Jun 2025

Two new racemic mixtures, including a polyketide, (±)-penilactone F (1), and a butenolide, (±) phenylbutyrolactone IIa (2), were isolated from the mangrove sediment-derived strain Aspergillus spelaeus SCSIO 41433. Additionally, 20 known compounds were isolated, including four penicillin-like compounds ( [...] Read more.

Two new racemic mixtures, including a polyketide, (±)-penilactone F (1), and a butenolide, (±) phenylbutyrolactone IIa (2), were isolated from the mangrove sediment-derived strain Aspergillus spelaeus SCSIO 41433. Additionally, 20 known compounds were isolated, including four penicillin-like compounds (11–14), three alkaloids (15–17), one sesquiterpene (18), and four phenolic acids (19–22). Their structures were elucidated through NMR spectroscopy, HRESIMS, X-ray diffraction, and ECD calculations. In the PDE4 inhibitory activity and anticancer cell activity assays, compounds 2, 3, 5, 8, 9, 11–14, and 16 exhibited weak PDE4 inhibitory activity at a concentration of 10 µM, Compound 11 demonstrated potent inhibitory effects against six cancer cell lines (MDA-MB-231, MDA-MB-435, HCT116, SNB-19, PC3, and A549), with IC₅₀ values ranging from 3.4 to 23.7 µM. Full article

(This article belongs to the Special Issue Advances in Secondary Metabolites from Mangrove Holobiont)

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17 pages, 2589 KiB

Open AccessArticle

Rhamnan Sulfate from the Seaweed Monostroma nitidum May Improve Cognitive Impairment Caused by Hyperglycemia

by Takaichi Miwa, Masaya Sato, Ning Ma, Keiichi Hiramoto, Masahiro Terasawa and Koji Suzuki

Mar. Drugs 2025, 23(6), 250; https://doi.org/10.3390/md23060250 - 12 Jun 2025

Rhamnan sulfate (RS), extracted from the seaweed Monostroma nitidum, suppresses vascular endothelial inflammation and arteriosclerosis, decreases blood glucose levels, and improves blood lipid metabolism and the intestinal environment. We examined whether RS improves hyperglycemia-induced cognitive decline in a hyperglycemic mouse model pretreated [...] Read more.

Rhamnan sulfate (RS), extracted from the seaweed Monostroma nitidum, suppresses vascular endothelial inflammation and arteriosclerosis, decreases blood glucose levels, and improves blood lipid metabolism and the intestinal environment. We examined whether RS improves hyperglycemia-induced cognitive decline in a hyperglycemic mouse model pretreated with nicotinamide and streptozotocin and then orally administered a high-fat diet and maltodextrin (MD) for 4 months. RS was administered in an MD solution at doses of 75, 225, and 750 mg/kg of mouse body weight. Administration of RS to hyperglycemic mice significantly reduced blood glucose levels and tended to improve memory function in behavioral pharmacological tests using spontaneous locomotor activity, rotarod test, and eight-way-maze test, although the results were not significant. Brain histopathological analysis showed that RS significantly reduced atrophy of neuronal layers in each region of the hippocampus compared with untreated hyperglycemic controls. RS also significantly suppressed TNF-α expression and microglial activation in the brain. These results suggest that RS intake suppresses inflammation in the brain and alleviates the cognitive impairment associated with hyperglycemic diabetes. Full article

(This article belongs to the Special Issue Marine Anti-Inflammatory and Antioxidant Agents, 5th Edition)

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18 pages, 1214 KiB

Open AccessArticle

Microwave Pretreatment-Induced Significant Nutrient and Metabolite Changes in Sea Cucumber Apostichopus japonicus

by Dairong Song, Fang Liu, Airong Jia, Xue Liu, Tingting Cui, Hui Zhang and Miansong Zhang

Mar. Drugs 2025, 23(6), 249; https://doi.org/10.3390/md23060249 - 11 Jun 2025

The body wall of sea cucumbers is rich in nutrients and small-molecule metabolites; however, traditional hot water pretreatment often leads to nutrient loss. To optimise processing techniques, this study compared the effects of microwave pretreatment and conventional hot water pretreatment on nutrient retention [...] Read more.

The body wall of sea cucumbers is rich in nutrients and small-molecule metabolites; however, traditional hot water pretreatment often leads to nutrient loss. To optimise processing techniques, this study compared the effects of microwave pretreatment and conventional hot water pretreatment on nutrient retention and metabolite profiles. Untreated sea cucumber body wall samples served as controls. The samples were subjected to microwave pretreatment (4 W/g, 12 min) or hot water pretreatment (100 °C, 10 min). Nutrient retention rates and metabolite variations were systematically analysed. Microwave pretreatment demonstrated superior retention of protein (96%), crude fat (92%), total sugar (55%), and saponins (40%). It also promotes the accumulation of small-molecule metabolites, including spermidine, tagatose, and melatonin. Notably, the lysine and methionine retention rates were enhanced by 10-fold and 12-fold, respectively, while the vitamin A, vitamin B3, and melatonin retention increased by 2.4-fold, 2-fold, and 3-fold, significantly outperforming traditional pretreatment. These findings highlight the potential of microwave pretreatment as an efficient alternative to conventional methods for preserving the nutritional and functional components of sea cucumbers. Full article

(This article belongs to the Special Issue New Methods in Extraction and Isolation of Marine Natural Products)

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17 pages, 2393 KiB

Open AccessArticle

Evaluation of the Immunostimulatory Effect of Ulvan Polysaccharide on Human Macrophages: Use as a Potential Vaccine Adjuvant

by Valeska Guevara-Torrejón, Paola Chandía Parra, Carolina Campos-Estrada and Waleska E. Vera Quezada

Mar. Drugs 2025, 23(6), 248; https://doi.org/10.3390/md23060248 - 11 Jun 2025

The ulvans are sulfated heteropolysaccharides that can stimulate the immune response in vitro. Using a human cell model, this study aimed to characterize and evaluate the immunostimulatory properties of crude ulvans extracted from Ulva spp., collected in Algarrobo, Chile. The crude ulvans, characterized [...] Read more.

The ulvans are sulfated heteropolysaccharides that can stimulate the immune response in vitro. Using a human cell model, this study aimed to characterize and evaluate the immunostimulatory properties of crude ulvans extracted from Ulva spp., collected in Algarrobo, Chile. The crude ulvans, characterized by spectrophotometric methods, are composed of 47.6% total sugars, 14.3% uronic acids, and 8.9% sulfates, with an average molecular weight of 40.000 kDa. The FTIR spectrum showed bands related to uronic acids, rhamnose, and sulfate groups. GCMS analysis confirmed the presence of rhamnose, xylose, glucose, and galactose, with a predominance of the disaccharides U3s and B3s. HL60 cells differentiated into macrophages were cultured with three concentrations of crude ulvans (25, 50, and 100 μg/mL), with cell viability remaining above 90% at the lower concentrations. The crude ulvan activated CD86 co-stimulatory molecules and promoted the release of IL-6, IL-10, IL-4, and nitric oxide cytokines. The results suggest that ulvan is non-toxic and can activate inflammatory pathways, making it a potential candidate for studies as a vaccine adjuvant. Full article

(This article belongs to the Special Issue Marine Polysaccharides and Oligosaccharides: Extraction and Biological Activities)

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20 pages, 2929 KiB

Open AccessArticle

A Chemoinformatics Investigation of Spectral and Quantum Chemistry Patterns for Discovering New Drug Leads from Natural Products Targeting the PD-1/PD-L1 Immune Checkpoint, with a Particular Focus on Naturally Occurring Marine Products

by Henrique Rabelo, Ayana Tsimiante, Yuri Binev and Florbela Pereira

Mar. Drugs 2025, 23(6), 247; https://doi.org/10.3390/md23060247 - 10 Jun 2025

(1) Background: Although the field of natural product (NP) drug discovery has been extensively developed, there are still several bottlenecks hindering the development of drugs from NPs. The PD-1/PD-L1 immune checkpoint axis plays a crucial role in immune response regulation. Therefore, drugs targeting [...] Read more.

(1) Background: Although the field of natural product (NP) drug discovery has been extensively developed, there are still several bottlenecks hindering the development of drugs from NPs. The PD-1/PD-L1 immune checkpoint axis plays a crucial role in immune response regulation. Therefore, drugs targeting this axis can disrupt the interaction and enable immune cells to continue setting up a response against the cancer cells. (2) Methods: We have explored the immuno-oncological activity of NPs targeting the PD-1/PD-L1 immune checkpoint by estimating the half maximal inhibitory concentration (IC₅₀) through molecular docking scores and predicting it using machine learning (ML) models. The LightGBM (Light Gradient-Boosted Machine), a tree-based ML technique, emerged as the most effective approach and was used for building the quantitative structure–activity relationship (QSAR) classification model. (3) Conclusions: The model incorporating 570 spectral descriptors from NMR SPINUS was selected for the optimization process, and this approach yielded results for the external test set with a sensitivity of 0.74, specificity of 0.81, overall predictive accuracy of 0.78, and Matthews correlation coefficient (MCC) of 0.55. The strategy used here for estimating the IC₅₀ from docking scores and predicting it through ML models appears to be a promising approach for pure compounds. Nevertheless, further optimization is indicated, particularly through the simulation of the spectra of mixtures by combining the spectra of individual compounds. Full article

(This article belongs to the Special Issue Chemoinformatics for Marine Drug Discovery)

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15 pages, 3326 KiB

Open AccessArticle

Structural and Functional Insights into a Novel Aspergillus ochraceus Polysaccharide from the Weddell Sea: Implications for Melanoma Immunotherapy In Vitro

by Jiale Hao, Kouame kra Wilfred Armel, Pengcheng Gao, Jinglei Wang, Weibin Zhang, Kexin Du, Qi Li, Huishu Gao, Guangli Yu and Guoyun Li

Mar. Drugs 2025, 23(6), 246; https://doi.org/10.3390/md23060246 - 10 Jun 2025

Immunotherapy is a transformative strategy in oncology, yet the development of novel immunomodulatory agents remains essential. This study explores the anti-tumor potential of a structurally unique polysaccharide isolated from an Aspergillus ochraceus (AOP), sourced from the Antarctic Weddell Sea. Using alkaline-assisted extraction and [...] Read more.

Immunotherapy is a transformative strategy in oncology, yet the development of novel immunomodulatory agents remains essential. This study explores the anti-tumor potential of a structurally unique polysaccharide isolated from an Aspergillus ochraceus (AOP), sourced from the Antarctic Weddell Sea. Using alkaline-assisted extraction and chromatographic purification, we obtained a homogeneous polysaccharide predominantly composed of galactose and mannose, with an average molecular weight of 39.67 kDa. The structure was characterized by an integrated nuclear magnetic resonance spectroscopy and mass spectrometry analysis, revealing that the AOP is composed of β (1→5)-linked galactofuranose units, with a minor substitution by α-D-mannopyranose residues via (1→2) glycosidic bonds at the C2 of the galactofuranose. Functional assays, including CCK8 and wound-healing tests, demonstrated that this polysaccharide, referred to as AOP, inhibited melanoma cell proliferation and migration in a dose-dependent manner. Additionally, the AOP activated RAW264.7 and bone marrow-derived macrophage (BMDM) cells without exhibiting significant cytotoxicity, leading to the release of inflammatory factors such as TNF-α, IL-1β, and IL-6. Mechanistically, the AOP was found to upregulate the expression of CD86 and IFN-γ, while downregulating genes like IL-4 and Arg1. These findings position the AOP as the first documented Antarctic fungal polysaccharide with macrophage-reprogramming capabilities against melanoma, offering novel molecular insights for marine-derived immunotherapeutics. 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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18 pages, 1844 KiB

Open AccessArticle

Pseudopterosin A-D Modulates Dendritic Cell Activation in Skin Sensitization

by Johanna Maria Hölken, Katja Friedrich, Russel Kerr and Nicole Elisabeth Teusch

Mar. Drugs 2025, 23(6), 245; https://doi.org/10.3390/md23060245 - 10 Jun 2025

This study investigates the anti-inflammatory effects of the marine diterpene glycosides pseudopterosin A-D (PsA-D) in mitigating nickel sulfate (NiSO₄)-induced skin sensitization. In dermal dendritic cell (DDC) surrogates, PsA-D pre-treatment significantly reduced NiSO₄-induced upregulation of key activation surface markers, cluster [...] Read more.

This study investigates the anti-inflammatory effects of the marine diterpene glycosides pseudopterosin A-D (PsA-D) in mitigating nickel sulfate (NiSO₄)-induced skin sensitization. In dermal dendritic cell (DDC) surrogates, PsA-D pre-treatment significantly reduced NiSO₄-induced upregulation of key activation surface markers, cluster of differentiation (CD)54 (~1.2-fold), and CD86 (~1.6-fold). Additionally, PsA-D inhibited the NiSO₄-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by suppressing inhibitor of kappa B alpha (IκBα) degradation. Furthermore, PsA-D suppressed inflammatory responses by inhibiting the NiSO₄-induced secretion of pro-inflammatory cytokines, including interleukin (IL)-8 (~6.8-fold), IL-6 (~2.2-fold), and IL-1β (~5.3-fold). In a full-thickness human skin model incorporating DDC surrogates, topical application of PsA-D effectively attenuated NiSO₄-induced mRNA expression of IL-8 (~2.1-fold), IL-6 (~2.6-fold), and IL-1β (~2.2-fold), along with the key inflammatory mediators cyclooxygenase-2 (COX-2) (~3.5-fold) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) (~2.1-fold). Overall, PsA-D demonstrated comparable efficacy to dexamethasone, a benchmark corticosteroid, providing a promising therapeutic alternative to corticosteroids for the treatment of skin sensitization and allergic contact dermatitis. However, to maximize PsA-D’s therapeutic potential, future studies on optimizing the bioavailability and formulation of PsA-D are required. Full article

(This article belongs to the Special Issue Marine Natural Products with Immunomodulatory Activity)

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15 pages, 823 KiB

Open AccessArticle

Research on the Influence of Orthogonal Design Optimized Elicitor Combinations on Fucoxanthin Accumulation in Phaeodactylum tricornutum and Its Expression Regulation

by Han Yang, Yifu Gong, Boyue Liu, Yuru Chen, Huan Qin, Heyu Wang and Hao Liu

Mar. Drugs 2025, 23(6), 244; https://doi.org/10.3390/md23060244 - 9 Jun 2025

Fucoxanthin, a carotenoid with notable pharmaceutical potential, has attracted significant attention due to its efficient accumulation in marine microalgae and the importance of optimizing its induction conditions. In this study, Phaeodactylum tricornutum was employed as a model organism to screen optimal conditions for [...] Read more.

Fucoxanthin, a carotenoid with notable pharmaceutical potential, has attracted significant attention due to its efficient accumulation in marine microalgae and the importance of optimizing its induction conditions. In this study, Phaeodactylum tricornutum was employed as a model organism to screen optimal conditions for fucoxanthin accumulation using a three-factor, four-level orthogonal design. Furthermore, the underlying mechanisms related to photosynthetic physiology and gene regulation were explored. The results revealed that both glycine (Gly) and light intensity significantly enhanced fucoxanthin content (p < 0.05). The optimal condition (Combination C: 0.50 g L⁻¹ Gly, 36 μmol photons·m⁻²·s⁻¹, 12 h light/12 h dark) yielded a fucoxanthin content of 0.87 μg g⁻¹, representing a 35% increase compared to the control. Meanwhile, Combination p (0.50 g L⁻¹ Gly, 36 μmol photons·m⁻²·s⁻¹, 24 h light/0 h dark) significantly improved cell density (5.11 × 10⁶ cells mL⁻¹; +18%) and fucoxanthin yield (4.10 μg L⁻¹; +47%). Analysis of photosynthetic parameters demonstrated that the non-photochemical quenching coefficient (NPQ) was suppressed. Gene expression profiling showed that Combination C upregulated photosynthetic genes (psbA, rbcL, rbcS) by up to 2.36-fold, while Combination P notably upregulated fcpb (7.59-fold), crtiso, and pds. Principal component analysis identified that rbcS and pds are key regulatory genes. These findings demonstrate that Gly, light intensity, and photoperiod synergistically regulate the expression of genes involved in photosynthesis and carotenoid biosynthesis, thereby promoting fucoxanthin accumulation. This work provides valuable insights and a theoretical basis for optimizing fucoxanthin production in support of marine drug development. Full article

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

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5 pages, 148 KiB

Open AccessEditorial

Marine Natural Products as Anticancer Agents 3.0

by Celso Alves and Marc Diederich

Mar. Drugs 2025, 23(6), 243; https://doi.org/10.3390/md23060243 - 5 Jun 2025

Cancer represents a major global health challenge[...] Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

21 pages, 2879 KiB

Open AccessArticle

Undaria pinnatifida Fucoidan Enhances Gut Microbiome, Butyrate Production, and Exerts Anti-Inflammatory Effects in an In Vitro Short-Term SHIME^® Coupled to a Caco-2/THP-1 Co-Culture Model

by Barbara C. Wimmer, Corinna Dwan, Jelle De Medts, Cindy Duysburgh, Chloë Rotsaert and Massimo Marzorati

Mar. Drugs 2025, 23(6), 242; https://doi.org/10.3390/md23060242 - 4 Jun 2025

Fucoidans have demonstrated a wide range of bioactivities including immune modulation and benefits in gut health. To gain a deeper understanding on the effects of fucoidan from Undaria pinnatifida (UPF) on the colonic microbiome, the short-term Simulator of the Human Intestinal Microbial Ecosystem [...] Read more.

Fucoidans have demonstrated a wide range of bioactivities including immune modulation and benefits in gut health. To gain a deeper understanding on the effects of fucoidan from Undaria pinnatifida (UPF) on the colonic microbiome, the short-term Simulator of the Human Intestinal Microbial Ecosystem^®, a validated in vitro gut model, was applied. Following a three-week intervention period on adult faecal samples from three healthy donors, microbial community activity of the colonic microbiota was assessed by quantifying short-chain fatty acids while composition was analysed utilising 16S-targeted Illumina sequencing. Metagenomic data were used to describe changes in community structure. To assess the secretion of cytokines, co-culture experiments using Caco-2 and THP1-Blue™ cells were performed. UPF supplementation over a three-week period had a profound butyrogenic effect while also enriching colonic microbial diversity, consistently stimulating saccharolytic genera, and reducing genera linked with potentially negative health effects in both regions of the colon. Mild immune modulatory effects of UPF were also observed. Colonic fermentation of UPF showed anti-inflammatory properties by inducing the secretion of the anti-inflammatory cytokines IL-6 and IL-10 in two out of three donors in the proximal and distal colon. In conclusion, UPF supplementation may provide significant gut health benefits. Full article

(This article belongs to the Special Issue Research on Marine Compounds and Inflammation)

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12 pages, 1750 KiB

Open AccessArticle

Catechol Siderophores from a Mangrove-Derived Bacteria Serratia marcescens F2-2 and Their Cytotoxic Activity

by Gang Zhang, Xunming Wang, Xingwang Zhang, Lin Ye, Longyang Ke, Shimin Fan, Xuan Hong, Guoqiang Li, Bingye Yang and Lianzhong Luo

Mar. Drugs 2025, 23(6), 241; https://doi.org/10.3390/md23060241 - 30 May 2025

Serratia marcescens is a common Gram-negative and facultative anaerobic bacillus that produces serratiochelins with several bioactivities. In this study, four catechol siderphores (1–4), including two new ones named serratiochelins E (1) and F (2), were [...] Read more.

Serratia marcescens is a common Gram-negative and facultative anaerobic bacillus that produces serratiochelins with several bioactivities. In this study, four catechol siderphores (1–4), including two new ones named serratiochelins E (1) and F (2), were obtained from the fermentation of a mangrove-derived bacterium, S. marcescens F2-2. The structures were elucidated with various spectroscopic methods such as NMR and HR-ESI-MS. Absolute and geometric configurations of the new compounds were established by employing quantum NMR calculations in conjunction with DP4+ probability analysis, ECD calculations, and the advanced Marfey’s method. The bioactivity test showed that serratiochelin B (3) displayed weak but selective cytotoxicity against HepG2 cancer cells with an IC₅₀ of 50.6 μmol/L and could trigger apoptosis through both Bcl-2/Bax/caspase-3 and Fas/FasL/caspase-8 signaling pathways. These findings deepen the understanding of siderophores of S. marcescens and provide a lead for research on anti-liver cancer drugs. Full article

(This article belongs to the Special Issue Advances in Secondary Metabolites from Mangrove Holobiont)

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5 pages, 269 KiB

Open AccessEditorial

Exploring Marine-Derived Antioxidant and Anti-Inflammatory Agents: Findings from Recent Studies

by Marzia Vasarri and Donatella Degl’Innocenti

Mar. Drugs 2025, 23(6), 240; https://doi.org/10.3390/md23060240 - 30 May 2025

The Special Issue “Marine Anti-Inflammatory and Antioxidant Agents, 4th Edition” of Marine Drugs underscores the immense therapeutic potential embedded within our planet’s vast marine environments [...] Full article

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

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