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Marine Drugs
Volume 23
Issue 6
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Mar. Drugs, Volume 23, Issue 6 (June 2025) – 37 articles

Cover Story (view full-size image): Polyketides are a diverse class of secondary metabolites with significant pharmacological relevance. Within this group, dinoflagellate polyketides, especially those produced by Amphidinium spp., stand out due to their unique chemical scaffolds and potent biological activities, including anticancer, antimicrobial, and antifungal effects. These features make them promising candidates for drug discovery and development. The growing interest in these compounds has driven research efforts toward understanding their biosynthetic pathways and developing novel strategies to enhance their production. This review outlines the current knowledge on Amphidinium-derived polyketides (APKs), covering their discovery, biosynthetic pathways, structural diversity, bioactivities, and emerging biotechnological approaches for their exploitation. View this paper
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32 pages, 2417 KB  
Review
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
Cited by 4 | Viewed by 2421
Abstract
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 KB  
Article
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
Viewed by 1045
Abstract
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 2025)
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28 pages, 1593 KB  
Review
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
Cited by 1 | Viewed by 3003
Abstract
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 KB  
Review
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
Viewed by 1618
Abstract
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 KB  
Article
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
Cited by 1 | Viewed by 847
Abstract
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 KB  
Systematic 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
Viewed by 3074
Abstract
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 KB  
Article
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
Cited by 1 | Viewed by 2755
Abstract
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 KB  
Article
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
Viewed by 995
Abstract
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 KB  
Article
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
Cited by 1 | Viewed by 1285
Abstract
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 KB  
Article
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
Viewed by 1004
Abstract
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 KB  
Article
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
Cited by 2 | Viewed by 1160
Abstract
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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19 pages, 2929 KB  
Article
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
Viewed by 1543
Abstract
(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 KB  
Article
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
Viewed by 979
Abstract
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 KB  
Article
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
Viewed by 1526
Abstract
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 KB  
Article
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
Viewed by 877
Abstract
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 KB  
Editorial
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
Cited by 2 | Viewed by 1509
Abstract
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 KB  
Article
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
Cited by 6 | Viewed by 2354
Abstract
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 KB  
Article
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
Viewed by 1089
Abstract
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 KB  
Editorial
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
Viewed by 1086
Abstract
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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20 pages, 1095 KB  
Article
Sustainable Extraction of Prospective Cosmetic Ingredients from Colombian Marine Macroalgae Using Natural Deep Eutectic Solvents
by Verónica María Tamayo-Rincón, Jhonny Colorado-Ríos, Didier Johan Alvarez-Bustamante, Vanessa Urrea-Victoria, Diana Margarita Márquez-Fernández, Constain H. Salamanca, Stefano Dall’Acqua, Leonardo Castellanos-Hernandez and Alejandro Martínez-Martínez
Mar. Drugs 2025, 23(6), 239; https://doi.org/10.3390/md23060239 - 30 May 2025
Cited by 2 | Viewed by 1258
Abstract
This study presents the results obtained from extracting and quantifying cosmetically valuable metabolites such as phenolic compounds and mycosporine-like amino acids (MAAs) from 12 samples of marine macroalgae collected in the Colombian Caribbean Sea. Natural deep eutectic solvents (NADESs) were prepared, physicochemically tested [...] Read more.
This study presents the results obtained from extracting and quantifying cosmetically valuable metabolites such as phenolic compounds and mycosporine-like amino acids (MAAs) from 12 samples of marine macroalgae collected in the Colombian Caribbean Sea. Natural deep eutectic solvents (NADESs) were prepared, physicochemically tested (viscosity, surface tension, pH, and conductivity), and then compared with water as the reference solvent to quantify phenolic compounds using the Folin–Ciocalteau test. With a simple extraction assay with water and ultrasound followed by ultraviolet spectral scanning the presence of MAAs was easily determined in several of the analysed samples, and then they were identified by HPLC-DAD. Hydrochloric acid solution at 5% extracted a higher content of phenolic compounds than NADES and water. The NADES that showed the highest phenolic compound extraction yield was a mixture of betaine, glucose, and water with 1:1:5 molar ratio. Sargassum cf. ramifolium and Sargassum fluitans showed the highest contents of phenolic compounds extracted with NADES, with 29.2 and 21.9 mg GAE/g DW, respectively. The results show that NADESs are an interesting alternative for the more efficient extraction of cosmetically valuable compounds such as phenolic compounds and mycosporine-type amino acids from marine macroalgae. Full article
(This article belongs to the Special Issue Nutritional Content, Biologically Active Compounds, and Correlated Health Impacts of Seaweed as a Resource for Nutraceutical, Cosmetic, and Pharmaceutical Applications)
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15 pages, 3835 KB  
Article
New Bioactive Polyketides from the Mangrove-Derived Fungus Daldinia eschscholzii HJX1P2
by Miao Yu, Yikang Qiu, Shiji Chen, Jueying Shi, Xiu Gong, Jiayi Feng, Fangru Lin, Weinv Zeng, Wenyuan Kang, Caijuan Zheng and Guolei Huang
Mar. Drugs 2025, 23(6), 238; https://doi.org/10.3390/md23060238 - 30 May 2025
Viewed by 929
Abstract
Three new naphthalene–chroman dimer derivatives, daldinaphchromes A–C (1–3), two new chroman derivatives, daldichromes A (5) and B (6), along with five known compounds (4, 7–10) were isolated from the mangrove-derived [...] Read more.
Three new naphthalene–chroman dimer derivatives, daldinaphchromes A–C (1–3), two new chroman derivatives, daldichromes A (5) and B (6), along with five known compounds (4, 7–10) were isolated from the mangrove-derived fungus Daldinia eschscholzii HJX1P2. Their structures and stereochemistries were elucidated through detailed NMR and MS analyses, calculated electronic circular dichroism, and comparison with previously reported data. Compound 1 demonstrated inhibitory effects on nitric oxide (NO) production in LPS-induced RAW 264.7 cells, with an IC50 value of 62.9 µM, and more effectively suppressed the expression of interleukin (IL)-6 than dexamethasone. A further mechanistic study suggested that 1 could prohibit the expression of iNOS in RAW 264.7 cells, and the molecular docking study suggested a possible interaction between 1 and the iNOS protein. Compounds 7 and 8 exhibited moderate to potent DPPH radical scavenging activity, with IC50 values of 117.4 and 46.2 µM, respectively, compared with the positive control ascorbic acid (IC50 = 45.6 µM). Compounds 4 and 10 showed ABTS+ radical scavenging activity, with IC50 values of 66.6 and 33.2 µM, respectively, which were equal to or lower than that of the positive control vitamin C (IC50 = 59.7 µM). Compounds 1–3, 7, and 9 showed antibacterial activity against three Staphylococcus aureus strains, with MIC values of 74.4–390.6 μM. Full article
(This article belongs to the Special Issue Advances in Secondary Metabolites from Mangrove Holobiont)
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9 pages, 2313 KB  
Communication
The Conopeptide αD-FrXXA, an Inhibitor of Voltage-Gated Potassium Channels
by Luis Martínez-Hernández, Estuardo López-Vera, Ximena C. Rodriguez-Ruiz and Mónica A. Ortíz-Arellano
Mar. Drugs 2025, 23(6), 237; https://doi.org/10.3390/md23060237 - 30 May 2025
Viewed by 758
Abstract
The conopeptide αD-FrXXA was previously isolated by our team from the venom of the vermivorous snail Conus fergusoni. This toxin is composed of two chains of 47 amino acids and inhibits neuronal and muscular subtypes of nAChR. In this study, we explored [...] Read more.
The conopeptide αD-FrXXA was previously isolated by our team from the venom of the vermivorous snail Conus fergusoni. This toxin is composed of two chains of 47 amino acids and inhibits neuronal and muscular subtypes of nAChR. In this study, we explored its effects on voltage-gated potassium channels heterologously expressed in Xenopus laevis oocytes using the two-electrode voltage-clamp technique (TEVC). At a concentration of 15 μM, αD-FrXXA was able to inhibit by 50% or more the currents of four subtypes of the Kv1 subfamily and slightly inhibit (<20%) two subtypes of the EAG subfamily. The conopeptide αD-FrXXA inhibits in a concentration-dependent manner the subtypes Kv1.3 (IC50 0.38 ± 0.06 μM) and Kv1.6 (IC50 0.52 ± 0.14 μM). The results reported here are noteworthy because this α-conopeptide behaves similarly to the α/κJ-PlXIVA conopeptide that inhibits nAChR and Kv channels. Full article
(This article belongs to the Special Issue Conotoxins: Detection, Classification and Potential Therapeutic Benefits)
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21 pages, 5296 KB  
Article
Exploring the Inhibitory Effects of Fucosylated Chondroitin Sulfate (FCS) Oligosaccharide Isolated from Stichopus horrens and the Derivatives on P-Selectin
by Caiyi Li, Huifang Sun, Xi Gu, Wen Long, Guangyu Zhu, Xiaolu Wu, Yu Wang, Pengfei Li, Le Sha, Jiali Zhang, Wenwu Sun, Na Gao, Zhili Zuo and Jinhua Zhao
Mar. Drugs 2025, 23(6), 236; https://doi.org/10.3390/md23060236 - 30 May 2025
Viewed by 995
Abstract
Unique fucosylated chondroitin sulfate (FCS) extracted from the sea cucumber Stichopus horrens was subjected to deacetylation and deaminative depolymerization to generate oligosaccharide fragments containing anTal-diol, which were further purified to obtain the trisaccharide ShFCS-3. Subsequently, the coupling of ShFCS-3 and 4-azidoaniline was achieved [...] Read more.
Unique fucosylated chondroitin sulfate (FCS) extracted from the sea cucumber Stichopus horrens was subjected to deacetylation and deaminative depolymerization to generate oligosaccharide fragments containing anTal-diol, which were further purified to obtain the trisaccharide ShFCS-3. Subsequently, the coupling of ShFCS-3 and 4-azidoaniline was achieved by reductive amination. After purification, the main product ShFCS-A1 and by-product ShFCS-A2 were obtained, which were identified as (N-(L-Fuc2S4S-α1,3-D-GlcA-β1,3-D-anTalA4S6S-1-)-4-azidoaniline) and (4S)-[2-(3-L-Fuc2S4S-α1)-D-GlcA-β1]-2,4,5-trihydroxy-5-sulfated-pent-2-enoic-acid) by 1D/2D NMR spectroscopy, respectively. ELISA experiments revealed that ShFCS-A1 exhibited P-selectin inhibition rates of 19.73% ± 9.60% at 1 μM, 96.28% ± 2.37% at 10 μM, and near-complete inhibition (99.92% ± 0.84%) at 100 μM. ShFCS-A2 demonstrated inhibition rates of 8.29% ± 3.00% at 1 μM, 74.02% ± 8.80% at 10 μM, and maximal inhibition approaching 100% at 100 μM. Cellular-level experiments revealed that ShFCS-A1 and ShFCS-A2 inhibited P-selectin binding to HL-60 cells by 92.72% ± 0.85% and 96.97% ± 1.16% at 100 μM, respectively. Molecular docking analysis indicated binding energies of −5.954 kcal/mol for ShFCS-A1 and −6.140 kcal/mol for ShFCS-A2 with P-selectin, confirming their potent inhibitory effects. These findings highlight the therapeutic potential of FCS oligosaccharides as pharmacophores and provide an important foundation for developing novel small-molecule P-selectin inhibitors. Full article
(This article belongs to the Special Issue Isolation, Identification and Applications of Marine Source Polysaccharides and Peptides—2nd Edition)
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21 pages, 1684 KB  
Review
Marine-Derived Astaxanthin: Molecular Mechanisms, Biomedical Applications, and Roles in Stem Cell Biology
by Aretha Rambaldi, Francesca Paris, Pasquale Marrazzo, Roberta Costa, Stefano Ratti and Francesco Alviano
Mar. Drugs 2025, 23(6), 235; https://doi.org/10.3390/md23060235 - 29 May 2025
Cited by 1 | Viewed by 1891
Abstract
Astaxanthin (ASX) is a xanthophyll carotenoid mainly derived from marine microalgae such as Haematococcus pluvialis and Chlorella zofingiensis, as well as the yeast Phaffia rhodozyma. Its chemical nature structure, rich in conjugated double bonds, carbonyl, and hydroxyl groups, confers potent antioxidant [...] Read more.
Astaxanthin (ASX) is a xanthophyll carotenoid mainly derived from marine microalgae such as Haematococcus pluvialis and Chlorella zofingiensis, as well as the yeast Phaffia rhodozyma. Its chemical nature structure, rich in conjugated double bonds, carbonyl, and hydroxyl groups, confers potent antioxidant and anti-inflammatory properties. ASX modulates oxidative stress via the PI3K/Akt-Nrf2 pathway and suppresses NF-κB-mediated inflammatory responses, reducing cytokine levels such as TNF-α, IL-6, and iNOS. ASX exerts dual apoptotic effects, cytoprotective in non-transformed cells and pro-apoptotic in cancer cells through p53 activation. Sustainable extraction techniques, especially supercritical CO2, have improved its industrial applicability. Recent findings highlight ASX’s role in stem cell biology, enhancing proliferation, supporting lineage-specific differentiation, and protecting against oxidative and inflammatory damage, which is a crucial issue for regenerative medicine applications. These multifaceted molecular effects support ASX’s therapeutic potential in chronic diseases, including diabetes, cardiovascular pathologies, and cancer. This review outlines ASX’s natural sources, extraction methods, and biological mechanisms, emphasizing its application in oxidative stress- and inflammation-related conditions. Full article
(This article belongs to the Special Issue Recent Advances in Marine-Derived Pigments)
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14 pages, 1175 KB  
Article
Isolation and Identification of Cis-2,5-Diketopiperazine from a Novel Bacillus Strain and Synthesis of Its Four Stereoisomers
by Alan M. C. Obled, Refaat B. Hamed, Edward Spence, Marija K. Zacharova, Sunil V. Sharma, Yunpeng Wang, Rosemary Lynch, Helen Connaris, Adina Tatheer, Marie-Lise Bourguet-Kondracki, Gordon J. Florence and Rebecca J. M. Goss
Mar. Drugs 2025, 23(6), 234; https://doi.org/10.3390/md23060234 - 29 May 2025
Cited by 1 | Viewed by 1371
Abstract
The Bacillus horneckiae-like strain 2011SOCCUF3 was isolated from the marine sponge Spongia officinalis and its metabolome was studied for secondary metabolites with antimicrobial activity. Culturing in the presence of Diaion HP-20 resin and purifying the culture extract identified cyclo-phenylalanine-proline (cyclo-(Phe-Pro)), a 2,5-diketopiperazine [...] Read more.
The Bacillus horneckiae-like strain 2011SOCCUF3 was isolated from the marine sponge Spongia officinalis and its metabolome was studied for secondary metabolites with antimicrobial activity. Culturing in the presence of Diaion HP-20 resin and purifying the culture extract identified cyclo-phenylalanine-proline (cyclo-(Phe-Pro)), a 2,5-diketopiperazine (2,5-DKP), isolated as a major metabolite. Further, LCMS analysis of the extract showed the presence of two isomers of the molecule in the culture broth. To confirm the stereochemistry of the isomers observed in the natural extract, all four stereoisomers of cyclo-(Phe-Pro) were synthesised. NMR and LCMS studies identified the presence of both cis- and trans-cyclo-(Phe-Pro) isomers. Stability and epimerisation studies on synthetic isomers and the effect of culturing conditions suggested that the less stable cis isomer was naturally produced, which epimerised in culture broth. Full article
(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)
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28 pages, 831 KB  
Review
Cyanobacterial Peptides in Anticancer Therapy: A Comprehensive Review of Mechanisms, Clinical Advances, and Biotechnological Innovation
by Heayyean Lee, Khuld Nihan and Yale Ryan Kwon
Mar. Drugs 2025, 23(6), 233; https://doi.org/10.3390/md23060233 - 29 May 2025
Cited by 1 | Viewed by 1829
Abstract
Cyanobacteria-derived peptides represent a promising class of anticancer agents due to their structural diversity and potent bioactivity. They exert cytotoxic effects through mechanisms including microtubule disruption, histone deacetylase inhibition, and apoptosis induction. Several peptides—most notably the dolastatin-derived auristatins—have achieved clinical success as cytotoxic [...] Read more.
Cyanobacteria-derived peptides represent a promising class of anticancer agents due to their structural diversity and potent bioactivity. They exert cytotoxic effects through mechanisms including microtubule disruption, histone deacetylase inhibition, and apoptosis induction. Several peptides—most notably the dolastatin-derived auristatins—have achieved clinical success as cytotoxic payloads in antibody–drug conjugates (ADCs). However, challenges such as limited tumor selectivity, systemic toxicity, and production scalability remain barriers to broader application. Recent advances in targeted delivery technologies, combination therapy strategies, synthetic biology, and genome mining offer promising solutions. Emerging data from preclinical and clinical studies highlight their therapeutic potential, particularly in treatment-resistant cancers. In this review, we (i) summarize key cyanobacterial peptides and their molecular mechanisms of action, (ii) examine progress toward clinical translation, and (iii) explore biotechnological approaches enabling sustainable production and structural diversification. We also discuss future directions for enhancing specificity and the therapeutic index to fully exploit the potential of these marine-derived peptides in oncology. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 4th Edition)
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19 pages, 15212 KB  
Article
The Alkaloid Caulerpin Exhibits Potent and Selective Anti-Inflammatory Activity Through Interaction with the Glucocorticoid Receptor
by Jônatas Sousa Pires dos Santos, Dahara Keyse Carvalho Silva, Vanessa da Silva Oliveira, Sergio Santos Silva Junior, Edivaldo dos Santos Rodrigues, Claudia Valeria Campos de Souza, Sabrina Teixeira Martinez, Osvaldo Andrade Santos-Filho, Cássio Santana Meira and Milena Botelho Pereira Soares
Mar. Drugs 2025, 23(6), 232; https://doi.org/10.3390/md23060232 - 29 May 2025
Cited by 3 | Viewed by 1310
Abstract
Inflammation plays a central role in various pathological conditions, necessitating the search for safer and more effective anti-inflammatory agents. This study investigates the anti-inflammatory activity of caulerpin, a bisindolic alkaloid isolated from Caulerpa racemosa. In vitro assays demonstrated that caulerpin significantly reduced [...] Read more.
Inflammation plays a central role in various pathological conditions, necessitating the search for safer and more effective anti-inflammatory agents. This study investigates the anti-inflammatory activity of caulerpin, a bisindolic alkaloid isolated from Caulerpa racemosa. In vitro assays demonstrated that caulerpin significantly reduced nitric oxide, TNF-α, IL-6, and IL-12 levels in macrophages stimulated with LPS + IFN-γ, without affecting cell viability. In silico toxicity predictions using Protox 3.0 reinforce a favorable safety profile of caulerpin. Molecular docking and molecular dynamics simulations revealed its high-affinity binding to the glucocorticoid receptor ligand-binding domain (GR-LBD), suggesting a mechanism of action similar to dexamethasone. The involvement of the glucocorticoid receptor was confirmed by the partial reversal of caulerpin’s effects upon RU486 treatment. In vivo, caulerpin exhibited a favorable safety profile, with no signs of acute toxicity at an oral dose of 100 mg/kg. Moreover, in a mouse model of endotoxic shock, caulerpin administration significantly improved survival rates in a dose-dependent manner, providing complete protection at 4 mg/kg. These findings highlight caulerpin as a promising candidate for the development of novel anti-inflammatory therapies. Further studies are warranted to explore its pharmacokinetics, optimize its structure, and evaluate its efficacy in chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Immunomodulatory Activities of Marine Products)
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20 pages, 3148 KB  
Review
Advances in Jellyfish Sting Mechanisms and Treatment Strategies
by Bingbing Li, Yueyue Li, Zhiwen Qiu, Chuantao Zhang, Yue Li, Wei Li and Jishun Yang
Mar. Drugs 2025, 23(6), 231; https://doi.org/10.3390/md23060231 - 28 May 2025
Viewed by 4618
Abstract
Jellyfish stings, as one of the most prevalent forms of marine injury, have increasingly become a subject of concern. Despite their simple morphology and structure, jellyfish possess a complex venom composition that can inflict varying degrees of damage on multiple human physiological systems. [...] Read more.
Jellyfish stings, as one of the most prevalent forms of marine injury, have increasingly become a subject of concern. Despite their simple morphology and structure, jellyfish possess a complex venom composition that can inflict varying degrees of damage on multiple human physiological systems. Consequently, the clinical symptoms associated with jellyfish stings are highly intricate. Although antivenoms have been developed for certain jellyfish species (e.g., C. fleckeri), specific antivenoms targeting the mechanisms of most jellyfish venoms remain understudied. To effectively prevent, treat, and cure jellyfish stings, we adhere to the principle of knowing their nature and their reasons. It is essential to investigate the emission mechanism of jellyfish nematocysts and the composition of their venom. Understanding these factors is crucial for the development of targeted treatment strategies. This review delves into the venom emission mechanism of jellyfish stinging cells, the symptoms resulting from jellyfish stings, and the comprehensive treatment strategies post-sting. It offers a scientific reference for comprehending jellyfish stings and establishes a theoretical foundation for subsequent research endeavors. Full article
(This article belongs to the Section Marine Toxins)
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19 pages, 2858 KB  
Article
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
Cited by 7 | Viewed by 1796
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 KB  
Review
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
Viewed by 1199
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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