Marine Drugs

26 pages, 1786 KiB

Open AccessReview

Saxitoxin: A Comprehensive Review of Its History, Structure, Toxicology, Biosynthesis, Detection, and Preventive Implications

by Huiyun Deng, Xinrui Shang, Hu Zhu, Ning Huang, Lianghua Wang and Mingjuan Sun

Mar. Drugs 2025, 23(7), 277; https://doi.org/10.3390/md23070277 - 2 Jul 2025

Abstract

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting [...] Read more.

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting nerve impulse transmission and leading to systemic physiological dysfunctions in the nervous, respiratory, cardiovascular, and digestive systems. Severe exposure can lead to paralysis, respiratory failure, and mortality. STX primarily enters the human body through the consumption of contaminated shellfish, posing a significant public health risk as the causative agent of paralytic shellfish poisoning (PSP). Beyond its acute toxicity, STX exerts cascading impacts on food safety, marine ecosystem integrity, and economic stability, particularly in regions affected by harmful algal blooms (HABs). Moreover, the complex molecular structure of STX—tricyclic skeleton and biguanide group—and its diverse analogs (more than 50 derivatives) have made it the focus of research on natural toxins. In this review, we traced the discovery history, chemical structure, molecular biosynthesis, biological enrichment mechanisms, and toxicological actions of STX. Moreover, we highlighted recent advancements in the potential for detection and treatment strategies of STX. By integrating multidisciplinary insights, this review aims to provide a holistic understanding of STX and to guide future research directions for its prevention, management, and potential applications. Full article

(This article belongs to the Special Issue Marine Biotoxins 3.0)

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20 pages, 1923 KiB

Open AccessArticle

Anthelmintic Potential of Agelasine Alkaloids from the Australian Marine Sponge Agelas axifera

by Kanchana Wijesekera, Aya C. Taki, Joseph J. Byrne, Darren C. Holland, Ian D. Jenkins, Merrick G. Ekins, Anthony R. Carroll, Robin B. Gasser and Rohan A. Davis

Mar. Drugs 2025, 23(7), 276; https://doi.org/10.3390/md23070276 - 1 Jul 2025

Abstract

A recent high-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract from the Australian marine sponge Agelas axifera with in vitro activity against an economically important parasitic nematode, Haemonchus contortus (barber’s pole worm). The bioassay-guided fractionation of the CH [...] Read more.

A recent high-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract from the Australian marine sponge Agelas axifera with in vitro activity against an economically important parasitic nematode, Haemonchus contortus (barber’s pole worm). The bioassay-guided fractionation of the CH₂Cl₂/MeOH extract from A. axifera led to the purification of a new diterpene alkaloid, agelasine Z (1), together with two known compounds agelasine B (2) and oxoagelasine B (3). Brominated compounds (–)-mukanadin C (4) and 4-bromopyrrole-2-carboxylic acid (5) were also isolated from neighbouring UV-active fractions. All compounds, together with agelasine D (6) from NatureBank’s pure compound library, were tested for in vitro anthelmintic activity against exsheathed third-stage (xL3s) and fourth-stage larvae (L4s) of H. contortus and young adult Caenorhabditis elegans. Compounds 1, 2 and 6 induced an abnormal “skinny” phenotype, while compounds 2 and 6 also reduced the motility of H. contortus L4s by 50.5% and 51.8% at 100 µM, respectively. The minimal activity of agelasines against C. elegans young adults suggests a possible species-specific mechanism warranting further investigation. For the first time, the unexpected lability of agelasine H-8′ was explored using kinetic studies, revealing rapid deuterium exchange in MeOH-d₄ at room temperature. Full article

(This article belongs to the Section Structural Studies on Marine Natural Products)

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16 pages, 1113 KiB

Open AccessArticle

Isolation and Characterization of Secondary Metabolites from Hydractinia-Associated Fungus, Penicillium brevicompactum MSW10-1, and Their Inhibitory Effects on Hepatic Lipogenesis

by Hyeon-Jeong Hwang, Hyeokjin Lim, Jae Sik Yu, Eun Seo Jang, Youngsang Nam, Yeo Jin Lee, Eun La Kim, Seonghwan Hwang and Seoung Rak Lee

Mar. Drugs 2025, 23(7), 275; https://doi.org/10.3390/md23070275 - 30 Jun 2025

Abstract

Marine organism-associated microbes are an important source of structurally diverse and biologically active secondary metabolites exhibiting antimicrobial, anticancer, and anti-inflammatory activities. In this study, we investigated Penicillium brevicompactum MSW10-1, isolated from Hydractinia echinata, a marine invertebrate adapted to extreme intertidal and subtidal [...] Read more.

Marine organism-associated microbes are an important source of structurally diverse and biologically active secondary metabolites exhibiting antimicrobial, anticancer, and anti-inflammatory activities. In this study, we investigated Penicillium brevicompactum MSW10-1, isolated from Hydractinia echinata, a marine invertebrate adapted to extreme intertidal and subtidal environments with variable temperature, salinity, and oxygen conditions. Through a combination of LC/MS-guided chemical analysis and chromatographic purification, eight secondary metabolites were isolated, including brevicolactones A (1) and B (2). The absolute chemical structures of 1 and 2 were determined based on NMR spectroscopic experiments, HR-ESIMS data, and quantum chemical ECD calculations. The isolated compounds (1–8) were evaluated for their ability to inhibit hepatic lipogenesis, a key process in lipid metabolism that is dysregulated in metabolic-dysfunction-associated steatotic liver disease. Furthermore, the inhibitory effects of the isolated compounds on lipid accumulation were further evaluated in primary mouse hepatocytes, using Oil Red O staining. These findings suggested that the isolated compounds may serve as promising candidates for the treatment of metabolic liver diseases associated with lipid dysregulation. Full article

(This article belongs to the Special Issue Bioactive Compounds from Extreme Marine Ecosystems)

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39 pages, 2135 KiB

Open AccessReview

Neuroprotective Mechanisms of Red Algae-Derived Bioactive Compounds in Alzheimer’s Disease: An Overview of Novel Insights

by Tianzi Wang, Wenling Shi, Zijun Mao, Wei Xie and Guoqing Wan

Mar. Drugs 2025, 23(7), 274; https://doi.org/10.3390/md23070274 - 30 Jun 2025

Abstract

Alzheimer’s disease (AD) is characterized by β-amyloid plaques, neurofibrillary tangles, neuroinflammation, and oxidative stress—pathological features that pose significant challenges for the development of therapeutic interventions. Given these challenges, this review comprehensively evaluates the neuroprotective mechanisms of bioactive compounds derived from red algae, [...] Read more.

Alzheimer’s disease (AD) is characterized by β-amyloid plaques, neurofibrillary tangles, neuroinflammation, and oxidative stress—pathological features that pose significant challenges for the development of therapeutic interventions. Given these challenges, this review comprehensively evaluates the neuroprotective mechanisms of bioactive compounds derived from red algae, including polysaccharides and phycobiliproteins, which are considered a promising source of natural therapeutics for AD. Red algal constituents exhibit neuroprotective activities through multiple mechanisms. Sulfated polysaccharides (e.g., carrageenan, porphyran) suppress NF-κB-mediated neuroinflammation, modulate mitochondrial function, and enhance brain-derived neurotrophic factor (BDNF) expression. Phycobiliproteins (phycoerythrin, phycocyanin) and peptides derived from their degradation scavenge reactive oxygen species (ROS) and activate antioxidant pathways (e.g., Nrf2/HO-1), thus mitigating oxidative damage. Carotenoids (lutein, zeaxanthin) improve cognitive function through the inhibition of acetylcholinesterase and pro-inflammatory cytokines (TNF-α, IL-1β), while phenolic compounds (bromophenols, diphlorethol) provide protection by targeting multiple pathways involved in dopaminergic system modulation and Nrf2 pathway activation. Emerging extraction technologies—including microwave- and enzyme-assisted methods—have been shown to optimize the yield and maintain the bioactivity of these compounds. However, the precise identification of molecular targets and the standardization of extraction techniques remain critical research priorities. Overall, red algae-derived compounds hold significant potential for multi-mechanism AD interventions, providing novel insights for the development of therapeutic strategies with low toxicity. Full article

(This article belongs to the Special Issue Marine-Derived Bioactive Compounds for Neuroprotection)

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26 pages, 8641 KiB

Open AccessArticle

The Invertebrate-Derived Antimicrobial Peptide Cm-p5 Induces Cell Death and ROS Production in Melanoma Cells

by Ernesto M. Martell-Huguet, Daniel Alpízar-Pedraza, Armando Rodriguez, Marc Zumwinkel, Mark Grieshober, Fidel Morales-Vicente, Ann-Kathrin Kissmann, Markus Krämer, Steffen Stenger, Octavio L. Franco, Ludger Ständker, Anselmo J. Otero-Gonzalez and Frank Rosenau

Mar. Drugs 2025, 23(7), 273; https://doi.org/10.3390/md23070273 - 29 Jun 2025

Abstract

Nowadays, healthcare systems face two global challenges: the rise of multidrug-resistant pathogens and the growing incidence of cancer. Due to their broad spectrum of activities, antimicrobial peptides emerged as potential alternatives against both threats. Our group previously described the antifungal activity of the [...] Read more.

Nowadays, healthcare systems face two global challenges: the rise of multidrug-resistant pathogens and the growing incidence of cancer. Due to their broad spectrum of activities, antimicrobial peptides emerged as potential alternatives against both threats. Our group previously described the antifungal activity of the α-helical peptide Cm-p5, a derivative of the natural peptide Cm-p1, isolated from the coastal mollusk Cenchritis muricatus; however, its anti-cancer properties remained unexplored. Analyses through calorimetry and molecular dynamics simulations suggest the relevance of phosphatidylserine for the attachment of Cm-p5 to cancer cell membranes. Cm-p5 exhibited cytotoxic activity in a dose-dependent manner against A375 melanoma cells, without toxicity against non-malignant cells or hemolytic activity. DAPI/PI and DiSC3(5) staining confirmed permeabilization, disruption, and depolarization of A375 cytoplasmic membranes by Cm-p5. Furthermore, Annexin V-FITC/PI assay revealed the induction of cellular death in melanoma cells, which can result from the cumulative membrane damage and oxidative stress due to the overproduction of reactive oxygen species (ROS). Moreover, after the treatment, the proliferation of A375 cells was dampened for several days, suggesting that Cm-p5 might inhibit the recurrence of melanomas. These findings highlight the multifunctional nature of Cm-p5 and its potential for treating malignant melanoma. Full article

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

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19 pages, 1591 KiB

Open AccessArticle

Sequential Extraction of Bioactive Saponins from Cucumaria frondosa Viscera: Supercritical CO₂–Ethanol Synergy for Enhanced Yields and Antioxidant Performance

by Jianan Lin, Guangling Jiao and Azadeh Kermanshahi-pour

Mar. Drugs 2025, 23(7), 272; https://doi.org/10.3390/md23070272 - 28 Jun 2025

Abstract

This study investigates the sequential extraction of lipids and saponins from C. frondosa viscera. Lipids were extracted using supercritical carbon dioxide (scCO₂) in the presence of ethanol (EtOH) as a co-solvent. Subsequently, the lipid-extracted viscera underwent three saponin extraction approaches, scCO [...] Read more.

This study investigates the sequential extraction of lipids and saponins from C. frondosa viscera. Lipids were extracted using supercritical carbon dioxide (scCO₂) in the presence of ethanol (EtOH) as a co-solvent. Subsequently, the lipid-extracted viscera underwent three saponin extraction approaches, scCO₂-scCO₂, scCO₂-EtOH, and scCO₂-hot water, resulting in saponin-rich extracts. Process parameter investigation for saponin extraction from scCO₂-defatted viscera revealed minimal effects of temperature, pressure, extraction time, static extraction, and EtOH concentration on saponin yields, allowing for milder operational conditions (35 °C, 20 MPa, 30 min dynamic extraction, 75% EtOH at 0.5 mL/min) to achieve energy-efficient recovery. Continuous EtOH feeding predominates the scCO₂ extraction of saponins. The sequential scCO₂ extraction of lipid and saponins yielded saponins at 9.13 mg OAE/g, while scCO₂ extraction of lipid followed by a 24 h 70% EtOH extraction of saponins achieved 16.26 mg OAE/g, closely matching the optimized ultrasonic-assisted extraction of saponins (17.31 mg OAE/g) from hexane-defatted samples. Antioxidant activities of saponin-rich extracts obtained in the sequential scCO₂-EtOH extraction (17.12 ± 4.20% DPPH scavenging) and the sequential scCO₂-scCO₂ extraction (16.14 ± 1.98%) were comparable to BHT (20.39 ± 0.68%), surpassing that of hexane-defatted ultrasonic extracts (8.11 ± 1.16%). The optimized scCO₂-EtOH method offers a sustainable alternative, eliminating toxic solvents while maintaining high saponin yields and bioactivity. Full article

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

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57 pages, 1430 KiB

Open AccessReview

A Fresh Perspective on Cyanobacterial Paralytic Shellfish Poisoning Toxins: History, Methodology, and Toxicology

by Zacharias J. Smith, Kandis M. Arlinghaus, Gregory L. Boyer and Cathleen J. Hapeman

Mar. Drugs 2025, 23(7), 271; https://doi.org/10.3390/md23070271 - 27 Jun 2025

Abstract

Paralytic shellfish poisoning toxins (PSPTs) are a class of neurotoxins most known for causing illness from consuming contaminated shellfish. These toxins are also present in freshwater systems with the concern that they contaminate drinking and recreational waters. This review provides (1) a complete [...] Read more.

Paralytic shellfish poisoning toxins (PSPTs) are a class of neurotoxins most known for causing illness from consuming contaminated shellfish. These toxins are also present in freshwater systems with the concern that they contaminate drinking and recreational waters. This review provides (1) a complete list of the 84+ known PSPTs and important chemical features; (2) a complete list of all environmental freshwater PSPT detections; (3) an outline of the certified PSPT methods and their inherent weaknesses; and (4) a discussion of PSPT toxicology, the weaknesses in existing data, and existing freshwater regulatory limits. We show ample evidence of production of freshwater PSPTs by cyanobacteria worldwide, but data and method uncertainties limit a proper risk assessment. One impediment is the poor understanding of freshwater PSPT profiles and lack of commercially available standards needed to identify and quantify freshwater PSPTs. Further constraints are the limitations of toxicological data derived from human and animal model exposures. Unassessed mouse toxicity data from 1978 allowed us to calculate and propose toxicity equivalency factors (TEF) for 11-hydroxysaxitoxin (11-OH STX; M2) and 11-OH dcSTX (dcM2). TEFs for the 11-OH STX epimers were calculated to be 0.4 and 0.6 for 11α-OH STX (M2α) and 11β-OH STX (M2β), while we estimate that TEFs for 11α-OH dcSTX (dcM2α) and 11β-OH dcSTX (dcM2β) congeners would be 0.16 and 0.23, respectively. Future needs for freshwater PSPTs include increasing the number of reference materials for environmental detection and toxicity evaluation, developing a better understanding of PSPT profiles and important environmental drivers, incorporating safety factors into exposure guidelines, and evaluating the accuracy of the established no-observed-adverse-effect level. Full article

(This article belongs to the Section Marine Toxins)

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17 pages, 905 KiB

Open AccessReview

From Sea to Relief: The Therapeutic Potential of Marine Algal Antioxidants in Pain Alleviation

by Mariola Belda-Antolí, Francisco A. Ros Bernal and Juan Vicente-Mampel

Mar. Drugs 2025, 23(7), 270; https://doi.org/10.3390/md23070270 - 27 Jun 2025

Abstract

Chronic pain affects approximately 20% of the global adult population, posing significant healthcare and economic challenges. Effective management requires addressing both biological and psychosocial factors, with emerging therapies such as antioxidants and marine algae offering promising new treatment avenues. Marine algae synthesize bioactive [...] Read more.

Chronic pain affects approximately 20% of the global adult population, posing significant healthcare and economic challenges. Effective management requires addressing both biological and psychosocial factors, with emerging therapies such as antioxidants and marine algae offering promising new treatment avenues. Marine algae synthesize bioactive compounds, including polyphenols, carotenoids, and sulfated polysaccharides, which modulate oxidative stress, inflammation, and neuroimmune signaling pathways implicated in pain. Both preclinical and clinical studies support their potential application in treating inflammatory, neuropathic, muscular, and chronic pain conditions. Notable constituents include polyphenols, carotenoids (such as fucoxanthin), vitamins, minerals, and sulfated polysaccharides. These compounds modulate oxidative stress and inflammatory pathways, particularly by reducing reactive oxygen species (ROS) and downregulating cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Brown and red algae produce phlorotannins and fucoidans that alleviate pain and inflammation in preclinical models. Carotenoids like fucoxanthin demonstrate neuroprotective effects by influencing autophagy and inflammatory gene expression. Algal-derived vitamins (C and E) and minerals (magnesium, selenium, and zinc) contribute to immune regulation and pain modulation. Additionally, sulfated polysaccharides suppress microglial activation in the central nervous system (CNS). Marine algae represent a promising natural source of bioactive compounds with potential applications in pain management. Although current evidence, primarily derived from preclinical studies, indicates beneficial effects in various pain models, further research is necessary to confirm their efficacy, safety, and mechanisms in human populations. These findings advocate for the continued exploration of marine algae as complementary agents in future therapeutic strategies. Full article

(This article belongs to the Special Issue Effects of Marine Natural Products in Brain Health and Metabolic Diseases)

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34 pages, 1252 KiB

Open AccessReview

Greener Extraction Solutions for Microalgal Compounds

by Gwendoline Kopp and Chiara Lauritano

Mar. Drugs 2025, 23(7), 269; https://doi.org/10.3390/md23070269 - 27 Jun 2025

Abstract

Conventional methods for extracting bioactive compounds from microalgae rely on organic solvents that are both polluting and potentially harmful to human health. In recent years, a noticeable shift has emerged toward greener extraction alternatives that are more environmentally friendly and sustainable. This review [...] Read more.

Conventional methods for extracting bioactive compounds from microalgae rely on organic solvents that are both polluting and potentially harmful to human health. In recent years, a noticeable shift has emerged toward greener extraction alternatives that are more environmentally friendly and sustainable. This review highlights various green extraction techniques, compounds, and yields obtained from different microalgal species for a range of applications and provides a comparison between the yields of conventional and green extraction methods. Green extraction methods have shown yields that are comparable to, or even exceed, those of conventional techniques, although they are predominantly studied for the extraction of lipids and pigments. This review aims to provide an overview of the current state of green extraction applied to microalgae, and to outline future research perspectives in this emerging field. Full article

(This article belongs to the Special Issue Sustainable Approaches for the Biotechnological Development of Marine Microalgae-Derived Products)

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28 pages, 12490 KiB

Open AccessArticle

Selective Antiproliferative Effects of Marine Oils on Neuroblastoma Cells in 3D Cultures

by Luís Freiría-Martínez, Jose María Oliva-Montero, Ainhoa Rodríguez-Tébar, Ola Hermanson, Santiago P. Aubourg, Carlos Spuch and Isabel Medina

Mar. Drugs 2025, 23(7), 268; https://doi.org/10.3390/md23070268 - 26 Jun 2025

Abstract

Dietary marine lipids enriched in ω-3 polyunsaturated fatty acids (PUFAs) are spotlighted for favorable effects in neurodegenerative conditions and tumor cell proliferation. Commercial marine oils, with high EPA and DHA content, consist of non-polar lipids constituted by triacylglycerols or polar oils composed of [...] Read more.

Dietary marine lipids enriched in ω-3 polyunsaturated fatty acids (PUFAs) are spotlighted for favorable effects in neurodegenerative conditions and tumor cell proliferation. Commercial marine oils, with high EPA and DHA content, consist of non-polar lipids constituted by triacylglycerols or polar oils composed of phospholipids. Both classes have shown different activities to significantly inhibit proliferation and migration, and induce apoptosis in cancer cells. This work was aimed at testing marine oils’ associated effects on neuroblastoma (NB) and glioblastoma (GB). Commercial non-polar and polar marine oils were studied in 3D spheroid models developed with human neuroblastoma, GB, and non-nervous embryonic kidney cell lines. This study also included results provided by a new sustainable polar marine oils source: fishery side-streams. Cell viability and mitochondrial activity assessments demonstrated that both marine oils dramatically reduced NB cells’ metabolism, proliferation, and viability. Effects on GB and epithelial cells were different, including a metabolic increase. Marine oils also induce cell differentiation and selectively modulate the activity of neurons and glia, depending on the oils’ chemical form. Sustainable polar oil showed bioactive characteristics similar to commercial krill oil. We propose that marine oils rich in triacylglycerols and phospholipids with high EPA and DHA levels may be a useful tool in NB antiproliferative therapies. Full article

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

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19 pages, 3862 KiB

Open AccessArticle

Characterization of Novel ACE-Inhibitory Peptides from Nemopilema nomurai Jellyfish Venom Hydrolysate: In Vitro and In Silico Approaches

by Ramachandran Loganathan Mohan Prakash, Deva Asirvatham Ravi, Du Hyeon Hwang, Changkeun Kang and Euikyung Kim

Mar. Drugs 2025, 23(7), 267; https://doi.org/10.3390/md23070267 - 26 Jun 2025

Abstract

The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. [...] Read more.

The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. In this study, we conducted a detailed biochemical and computational characterization of these peptides. The IC₅₀ values were determined to be 23.81 µM for IVGRPLANG and 5.68 µM for IGDEPRHQYL. Kinetic analysis using Lineweaver–Burk plots revealed that both peptides act as competitive ACE inhibitors, with calculated inhibition constants (K_i) of 51.38 µM and 5.45 µM, respectively. To assess the structural stability of the ACE–peptide complexes, molecular dynamics simulations were performed. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses provided insights into complex stability, while interaction fraction analysis elucidated key bond types and residue–ligand contacts involved in binding. Furthermore, a network pharmacology approach was employed to predict therapeutic targets within the renin–angiotensin–aldosterone system (RAAS). Eleven target proteins were identified: IVGRPLANG was associated with REN, ACE, CTSB, CTSS, and AGTR2; IGDEPRHQYL was linked to REN, AGT, AGTR1, AGTR2, KNG1, and BDKR2. Molecular docking analyses using HADDOCK software (version 2.4) were conducted for all targets to evaluate binding affinities, providing further insight into the peptides’ therapeutic potential. Full article

(This article belongs to the Special Issue Jellyfish-Derived Compounds)

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21 pages, 6129 KiB

Open AccessArticle

Diversity and Novelty of Venom Peptides in Vermivorous Cone Snails, Subgenus Rhizoconus (Gastropoda: Mollusca)

by Christine Marie C. Florece, Quentin Kaas, Neda Barghi and Arturo O. Lluisma

Mar. Drugs 2025, 23(7), 266; https://doi.org/10.3390/md23070266 - 26 Jun 2025

Abstract

A large majority of cone snails (a species in the genus Conus) are vermivorous (worm-hunting), but the diversity and bioactivity of their venom peptides remain largely unexplored. In this study, we report the first venom gland transcriptomes from two species in the [...] Read more.

A large majority of cone snails (a species in the genus Conus) are vermivorous (worm-hunting), but the diversity and bioactivity of their venom peptides remain largely unexplored. In this study, we report the first venom gland transcriptomes from two species in the Rhizoconus clade, Conus capitaneus and Conus mustelinus, and a new Conus miles transcriptome from a specimen collected in the Philippines. From the set of assembled sequences, a total of 225 C. capitaneus, 121 C. miles, and 168 C. mustelinus putative peptide toxin transcripts were identified, which were assigned to 27 canonical gene superfamilies in C. capitaneus and 24 in C. miles and in C. mustelinus. Most of these venom peptides are novel, and some exhibit new cysteine patterns. Clustering also revealed 12 putative novel gene superfamilies, highlighting the diversity of uncharacterized venom peptides in this group. The O1-, M-, O2-, and con-ikot-ikot superfamilies were the most abundant, while gene superfamilies such as D and G2 were highly expressed. Several hormone-like conopeptides were also identified in this study, revealing the vast diversity of conopeptides from the Rhizoconus species. Full article

(This article belongs to the Section Marine Toxins)

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21 pages, 601 KiB

Open AccessArticle

Cladolosides of Groups S and T: Triterpene Glycosides from the Sea Cucumber Cladolabes schmeltzii with Unique Sulfation; Human Breast Cancer Cytotoxicity and QSAR

by Alexandra S. Silchenko, Elena A. Zelepuga, Ekaterina A. Chingizova, Ekaterina S. Menchinskaya, Kseniya M. Tabakmakher, Anatoly I. Kalinovsky, Sergey A. Avilov, Roman S. Popov, Pavel S. Dmitrenok and Vladimir I. Kalinin

Mar. Drugs 2025, 23(7), 265; https://doi.org/10.3390/md23070265 - 25 Jun 2025

Abstract

Four new minor monosulfated triterpene penta- and hexaosides, cladolosides S (1), S₁ (2), T (3), and T₁ (4), were isolated from the Vietnamese sea cucumber Cladolabes schmeltzii (Sclerodactylidae, Dendrochirotida). The structures of the [...] Read more.

Four new minor monosulfated triterpene penta- and hexaosides, cladolosides S (1), S₁ (2), T (3), and T₁ (4), were isolated from the Vietnamese sea cucumber Cladolabes schmeltzii (Sclerodactylidae, Dendrochirotida). The structures of the compounds were established based on extensive analysis of 1D and 2D NMR spectra as well as HR-ESI-MS data. Cladodosides S (1), S₁ (2) and T (3), T₁ (4) are two pairs of dehydrogenated/hydrogenated compounds that share identical carbohydrate chains. The oligosaccharide chain of cladolosides of the group S is new for the sea cucumber glycosides due to the presence of xylose residue attached to C-4 Xyl1 in combination with a sulfate group at C-6 MeGlc4. The oligosaccharide moiety of cladolosides of the group T is unique because of the position of the sulfate group at C-3 of the terminal sugar residue instead of the 3-O-Me group. This suggests that the enzymatic processes of sulfation and O-methylation that occur during the biosynthesis of glycosides can compete with each other. This can presumably occur due to the high level of expression or activity of the enzymes that biosynthesize glycosides. The mosaicism of glycoside biosynthesis (time shifting or dropping out of some biosynthetic stages) may indicate a lack of compartmentalization inside the cells of organism producers, leading to a certain degree of randomness in enzymatic reactions; however, this also offers the advantage of providing chemical diversity of the glycosides. Analysis of the hemolytic activity of a series of 26 glycosides from C. schmeltzii revealed some patterns of structure–activity relationships: the presence or absence of 3-O-methyl groups has no significant impact, hexaosides, which are the final products of biosynthesis and predominant compounds of the glycosidic fraction of C. schmeltzii, are more active than their precursors, pentaosides, and the minor tetraosides, cladolosides of the group A, are weak membranolytics and therefore are not synthesized in large quantities. Two glycosides from C. schmeltzii, cladolosides D (18) and H₁ (26), display selectivity of cytotoxic action toward triple-negative breast cancer cells MDA-MB-231, while remaining non-toxic in relation to normal mammary cells MCF-10A. Quantitative structure–activity relationships (QSAR) were calculated based on the correlational analysis of the physicochemical properties and structural features of the glycosides and their hemolytic and cytotoxic activities against healthy MCF-10A cells and cancer MCF-7 and MDA-MB-231 cell lines. QSAR highlighted the complexity of the relationships as the cumulative effect of many minor contributions from individual descriptors can have a significant impact. Furthermore, many structural elements were found to have different effects on the activity of the glycosides against different cell lines. The opposing effects were especially pronounced in relation to hormone-dependent breast cancer cells MCF-7 and triple-negative MDA-MB-231 cells. Full article

(This article belongs to the Special Issue Novel Biomaterials and Active Compounds from Sea Cucumbers)

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15 pages, 3858 KiB

Open AccessArticle

Lipotrichaibol A and Trichoderpeptides A–D: Five New Peptaibiotics from a Sponge-Derived Trichoderma sp. GXIMD 01001

by Weichan Yang, Zhenzhou Tang, Xiaowei Luo, Yuman Gan, Meng Bai, Houwen Lin, Chenghai Gao, Ling Chai and Xiao Lin

Mar. Drugs 2025, 23(7), 264; https://doi.org/10.3390/md23070264 - 24 Jun 2025

Abstract

Five previously undescribed peptaibiotics, including one 7-mer lipopeptaibol named lipotrichaibol A (1), and four 11-mer peptaibiotics named trichoderpeptides A-D (2–5) were isolated from the rice culture medium of the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures [...] Read more.

Five previously undescribed peptaibiotics, including one 7-mer lipopeptaibol named lipotrichaibol A (1), and four 11-mer peptaibiotics named trichoderpeptides A-D (2–5) were isolated from the rice culture medium of the sponge-derived fungus Trichoderma sp. GXIMD 01001. Their structures and absolute configurations were unambiguously established by extensive spectroscopic data analysis and advanced Marfey’s method. All isolated compounds were evaluated via CCK8 bioassays to investigate their antiproliferative activity. Only compound 1 exerted potent cytotoxicity against HT-29 and DLD-1 cells with IC₅₀ values at 10.3 ± 1.9 and 12.31 ± 1.5 μM, respectively. In further in vitro bioassay, compound 1 exhibited significant inhibition in colony formation assay, induced apoptosis and blocked the cell cycle in the G0/G1 phase. The mechanism may be related to the regulation of the Erk1/2 signaling pathway. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi, 3rd Edition)

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17 pages, 1156 KiB

Open AccessArticle

An Integrated Biorefinery Process to Revalorize Marine Biomass from the Microalga Nannochloropsis gaditana Using Pressurized Green Solvents

by Cristina Blanco-Llamero, Paz García-García and Francisco Javier Señoráns

Mar. Drugs 2025, 23(7), 263; https://doi.org/10.3390/md23070263 - 23 Jun 2025

Abstract

Biorefinery is gaining attention as a promising approach to valorize natural resources and promote a circular bioeconomy. This study aimed to recover high-value molecules, such as xanthophylls and polar lipids with nutraceutical applications, through enzymatic pretreatment and sequential pressurized liquid extraction (PLEseq), by [...] Read more.

Biorefinery is gaining attention as a promising approach to valorize natural resources and promote a circular bioeconomy. This study aimed to recover high-value molecules, such as xanthophylls and polar lipids with nutraceutical applications, through enzymatic pretreatment and sequential pressurized liquid extraction (PLEseq), by reusing the residual biomass of Nannochloropsis gaditana after each processing step. Remarkably, pure glycolipids (102.95 ± 1.10 mg g⁻¹ dry weight) were obtained immediately after enzymatic pretreatment, facilitating their easy recovery. Furthermore, two alternative sequential extraction processes were successfully developed, using ethanol and water as green solvents at varying temperatures and in different orders. The most effective PLEseq conditions yielded up to 48 mg mL⁻¹ of carbohydrates using water at 50 °C, and up to 44 mg mL⁻¹ of proteins via subcritical water extraction at 100 °C, prior to conventional lipid extraction with ethanol to produce various concentrated extracts. In the inverted PLEseq process—starting with ethanol extraction followed by successive water washes—isolated and purified fractions of lutein and astaxanthin were obtained, contributing to the complete depletion of the residual biomass. Overall, the development of an integrated and sequential biorefinery protocol that enables the extraction of multiple high-value compounds holds significant potential for application in the food industry. Full article

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

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18 pages, 2254 KiB

Open AccessArticle

Didemnosides A and B: Antiproliferative Nucleosides from the Red Sea Marine Tunicate Didemnum Species

by Lamiaa A. Shaala, Diaa T. A. Youssef, Hadeel Almagthali, Ameen M. Almohammadi, Wafaa T. Arab, Torki Alzughaibi, Noor M. Bataweel and Reham S. Ibrahim

Mar. Drugs 2025, 23(7), 262; https://doi.org/10.3390/md23070262 - 23 Jun 2025

Abstract

Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides [...] Read more.

Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides A and B (1 and 2) and 1,1′,3,3′-bisuracil (3), together with thymidine (4), 2′-deoxyuridine (5), homarine (6), and acetamide (7). Planar structures of the compounds were explained through analyses of their 1D (¹H and ¹³C) and 2D (¹H–¹H COSY, HSQC, and HMBC) NMR spectra and high-resolution mass spectral determinations. Compound 1 exhibited the highest growth inhibition toward the MCF-7 cancer cell line with IC₅₀ values of 0.597 μM, while other compounds were inactive (≥50 μM) against this cell line. On the other hand, compounds 1, 2, and 4–7 moderately inhibited SW-1222 and PC-3 cells with IC₅₀ values ranging between 5.25 and 9.36 μM. Molecular docking analyses of the top three active compounds on each tested cell line exposed stable interactions into the active pockets of estrogen receptor alpha (ESR1), human topoisomerase II alpha (TOP2A), and cyclin-dependent kinase 5 (CDK5) which are contemplated as essential targets in cancer treatments. Thus, compound 1 represents a scaffold for the development of more effective anticancer drugs. Full article

(This article belongs to the Special Issue Antimicrobial Compounds from Marine and Island Ecosystems: Exploration, Characterization, and Application)

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30 pages, 3771 KiB

Open AccessReview

The Deep Mining Era: Genomic, Metabolomic, and Integrative Approaches to Microbial Natural Products from 2018 to 2024

by Zhaochao Wang, Juanjuan Yu, Chenjie Wang, Yi Hua, Hong Wang and Jianwei Chen

Mar. Drugs 2025, 23(7), 261; https://doi.org/10.3390/md23070261 - 23 Jun 2025

Abstract

Over the past decade, microbial natural products research has witnessed a transformative “deep-mining era” driven by key technological advances such as high-throughput sequencing (e.g., PacBio HiFi), ultra-sensitive HRMS (resolution ≥ 100,000), and multi-omics synergy. These innovations have shifted discovery from serendipitous isolation to [...] Read more.

Over the past decade, microbial natural products research has witnessed a transformative “deep-mining era” driven by key technological advances such as high-throughput sequencing (e.g., PacBio HiFi), ultra-sensitive HRMS (resolution ≥ 100,000), and multi-omics synergy. These innovations have shifted discovery from serendipitous isolation to data-driven, targeted mining. These innovations have transitioned discovery from serendipitous isolation to data-driven targeted mining. Genome mining pipelines (e.g., antiSMASH 7.0 and DeepBGC) can now systematically discover hidden biosynthetic gene clusters (BGCs), especially in under-explored taxa. Metabolomics has achieved unprecedented accuracy, enabling researchers to target novel compounds in complex extracts. Integrated strategies—combining genomic prediction, metabolomics analysis, and experimental validation—constitute new paradigms of current “deep mining”. This review provides a systematic overview of 185 novel microbial natural products discovered between 2018 and 2024, and dissects how these technological leaps have reshaped the discovery paradigm from traditional isolation to data-driven mining. Full article

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

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15 pages, 1687 KiB

Open AccessArticle

Effects of Salinity on the Growth Performance and Docosahexaenoic Acid Positional Distribution in Triacylglycerols of the Newly Isolated Schizochytrium sp. FJ-1

by Sitong Ye, Xiaonan Wang, Youcai Zhou, Xuehua Xiao, Pingying Liu, Chengdeng Chi, Peipei Sun, Mingmin Zheng, Bilian Chen, Ruoyu Mao and Yongjin He

Mar. Drugs 2025, 23(7), 260; https://doi.org/10.3390/md23070260 - 23 Jun 2025

Abstract

Schizochytrium-derived omega-3 polyunsaturated fatty acids (e.g., docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) are proven to be health-beneficial bioactive substances that have been widely applied in the pharmaceutical, nutraceutical, and food industries. In this work, the newly isolated Schizochytrium sp. FJ-1 strain [...] Read more.

Schizochytrium-derived omega-3 polyunsaturated fatty acids (e.g., docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) are proven to be health-beneficial bioactive substances that have been widely applied in the pharmaceutical, nutraceutical, and food industries. In this work, the newly isolated Schizochytrium sp. FJ-1 strain was selected to investigate the effects of salinity on the growth performance, lipid production, DHA yield, and positional distribution of triacylglycerols (TAGs). In addition, Schizochytrium sp. 20888 was used as a control strain. The obtained results showed that Schizochytrium sp. FJ-1 could grow with a low biomass in the absence of sea salt; however, Schizochytrium sp. 20888 did not grow in the medium without sea salt. Moreover, Schizochytrium sp. FJ-1 achieved the highest biomass in 10‰ salinity, whilst Schizochytrium sp. 20888 attained the greatest biomass in 40‰ salinity. In terms of the total lipid content and TAG fraction percentage, Schizochytrium sp. FJ-1 grown in 5–20‰ salinity had high total lipid contents (57.04–60.02%), with TAGs accounting for over 90% of the lipid fraction. The highest DHA contents for total lipids (41.38%) and TAGs (40.18%) were obtained when Schizochytrium sp. FJ-1 was grown under 10‰ salinity conditions. Additionally, under the same culture condition, EPA contents of lipids and TAGs were significantly higher for Schizochytrium sp. FJ-1 compared with Schizochytrium sp. 20888. Furthermore, nuclear magnetic resonance analysis found that the salinity level had a distinct impact on the positional distribution of DHA in TAGs in these two Schizochytrium strains. Schizochytrium sp. FJ-1 grown under 40‰ salinity conditions produced TAGs with the greatest percentage of sn-2 DHA (81.24%). The percentages were higher than those found for the other groups of this microalga and Schizochytrium sp. 20888. Taken together, Schizochytrium sp. FJ-1 could be a potential candidate to produce highly valued DHA lipids or TAG bioproducts by regulating salinity. Full article

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

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21 pages, 3486 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 - 21 Jun 2025

Abstract

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)

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