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Marine Drugs

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

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, PubAg, MarinLit, AGRIS, and other databases.
Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmacology, Toxicology and Pharmaceutics (miscellaneous))
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 13.3 days after submission; acceptance to publication is undertaken in 2.4 days (median values for papers published in this journal in the first half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.

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

Imprint Information Journal Flyer Open Access ISSN: 1660-3397

Latest Articles

16 pages, 7688 KiB

Open AccessArticle

Targeted Isolation of ω-3 Polyunsaturated Fatty Acids from the Marine Dinoflagellate Prorocentrum lima Using DeepSAT and LC-MS/MS and Their High Activity in Promoting Microglial Functions

by Chang-Rong Lai, Meng-Xing Jiang, Dan-Mei Tian, Wei Lu, Bin Wu, Jin-Shan Tang, Yi Zou, Song-Hui Lv and Xin-Sheng Yao

Mar. Drugs 2025, 23(7), 286; https://doi.org/10.3390/md23070286 - 10 Jul 2025

In this study, we integrated HSQC-based DeepSAT with UPLC-MS/MS to guide the isolation of omega-3 polyunsaturated fatty acid derivatives (PUFAs) from marine resources. Through this approach, four new (1–4) and nine known (5–13) PUFA analogues [...] Read more.

In this study, we integrated HSQC-based DeepSAT with UPLC-MS/MS to guide the isolation of omega-3 polyunsaturated fatty acid derivatives (PUFAs) from marine resources. Through this approach, four new (1–4) and nine known (5–13) PUFA analogues were obtained from large-scale cultures of the marine dinoflagellate Prorocentrum lima, with lipidomic profiling identifying FA18:5 (5), FA18:4 (7), FA22:6 (8), and FA22:6 methyl ester (11) as major constituents of the algal oil extract. Structural elucidation was achieved through integrated spectroscopic analyses of IR, 1D and 2D NMR, and HR-ESI-MS data. Given the pivotal role of microglia in Alzheimer’s disease (AD) pathogenesis, we further evaluated the neuroprotective potential of these PUFAs by assessing their regulatory effects on critical microglial functions in human microglia clone 3 (HMC3) cells, including chemotactic migration and amyloid-β42 (Aβ42) phagocytic clearance. Pharmacological evaluation demonstrated that FA20:5 butanediol ester (1), FA18:5 (5), FA18:4 (7), FA22:6 (8), and (Z)-10-nonadecenoic acid (13) significantly enhanced HMC3 migration in a wound-healing assay. Notably, FA18:4 (7) also significantly promoted Aβ42 phagocytosis by HMC3 microglia while maintaining cellular viability and avoiding pro-inflammatory activation at 20 μM. Collectively, our study suggests that FA18:4 (7) modulates microglial function in vitro, indicating its potential to exert neuroprotective effects. Full article

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

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11 pages, 1797 KiB

Open AccessArticle

Discovery of Secondary Metabolites from the Sponge-Derived Fungus Aspergillus templicola

by Kai Li, Yue Zhang, Lei Li, Sen Wang, Cili Wang and Pinglin Li

Mar. Drugs 2025, 23(7), 285; https://doi.org/10.3390/md23070285 - 9 Jul 2025

Combining biosynthetic gene cluster analysis with the OSMAC strategy, fractionation of the fermentation extract of Aspergillus templicola from the sponge Agelas sp. led to the isolation of four novel cytochalasins, colachalasins J–M (1–4), a novel cyclic pentapeptide, avellanin P [...] Read more.

Combining biosynthetic gene cluster analysis with the OSMAC strategy, fractionation of the fermentation extract of Aspergillus templicola from the sponge Agelas sp. led to the isolation of four novel cytochalasins, colachalasins J–M (1–4), a novel cyclic pentapeptide, avellanin P (5), together with five known compounds (6–10). The structures of 1–9 were elucidated using spectroscopic data, single crystal X-ray diffraction, and Marfey’s analysis. Compound 2 exhibited potent anti-inflammatory activity in zebrafish assays. Additionally, Compounds 4 and 6 showed modest cytotoxicity against several human cancer cell lines with IC₅₀ values ranging from 2.6 to 11.2 μm. 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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24 pages, 15362 KiB

Open AccessArticle

κ/ι-Carrageenan Blends in Plant Capsules: Achieving Harmony Between Mechanical and Disintegration Properties

by Zhenyu Liu, Chuqi He, Zhibin Yang, Qing Zhao, Yuting Dong, Jing Ye, Bingde Zheng, Ranjith Kumar Kankala, Xueqin Zhang and Meitian Xiao

Mar. Drugs 2025, 23(7), 284; https://doi.org/10.3390/md23070284 - 9 Jul 2025

The fast-disintegrating capsules rapidly disintegrate in various physiological environments, ensuring therapeutic efficacy. The formulation of plant-based capsules with balanced mechanical and fast disintegration characteristics continues to present technical challenges in pharmaceutical development. In this study, natural marine polysaccharides were utilized to achieve both [...] Read more.

The fast-disintegrating capsules rapidly disintegrate in various physiological environments, ensuring therapeutic efficacy. The formulation of plant-based capsules with balanced mechanical and fast disintegration characteristics continues to present technical challenges in pharmaceutical development. In this study, natural marine polysaccharides were utilized to achieve both rapid disintegration and excellent mechanical properties by combining κ-Carrageenan (κ-C) and ι-Carrageenan (ι-C). Additionally, the selection of KCl + NaCl mixed coagulants, along with the evaluation of their types, mass fractions, and ratios, enhanced the mechanical properties and transmittance of the capsules. FTIR analysis revealed that the membrane with a 5:5 κ-C/ι-C ratio formed hydrogen bonds, which were beneficial to its fast disintegration. SEM analysis revealed a dense microstructure in this formulation, contributing to its improved mechanical properties. Finally, this study hypothesizes that the disintegration behaviors of the capsules exhibited significant pH dependence, with ion exudation predominating in pH 1.2 and pH 7.0 media, while swelling dominated under pH 4.5 and pH 6.8 media. The prepared carrageenan blend-based capsules exhibited fast disintegration properties while maintaining excellent mechanical and barrier properties, thereby broadening the application of plant-based capsules in the field of medicine. Full article

(This article belongs to the Special Issue Marine Biopolymers and Their Applications in Drug Delivery, 2nd Edition)

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40 pages, 2915 KiB

Open AccessReview

Marine-Derived Compounds: A New Horizon in Cancer, Renal, and Metabolic Disease Therapeutics

by Jinwei Zhang

Mar. Drugs 2025, 23(7), 283; https://doi.org/10.3390/md23070283 - 9 Jul 2025

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., [...] Read more.

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A₂-2), ilimaquinone, and Aplidin (plitidepsin). Key mechanisms include autophagy modulation, immune checkpoint inhibition, anti-inflammatory effects, and mitochondrial homeostasis. Novel findings reveal glycosides’ dual role in cytotoxicity and immunomodulation, ilimaquinone’s induction of the DNA damage response, and Aplidin’s disruption of protein synthesis via eEF1A2 binding. Pharmacokinetic challenges and structure–activity relationships are critically analyzed, emphasizing nanodelivery systems and synthetic analog development. This review bridges mechanistic insights with translational potential, offering a cohesive framework for future drug development. Full article

(This article belongs to the Special Issue Marine Bioactive Agents with Anticancer Potential: Discovery and Molecular Mechanisms)

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15 pages, 4009 KiB

Open AccessArticle

Metabolomic Profiling and Anti-Helicobacter pylori Activity of Caulerpa lentillifera (Sea Grape) Extract

by Chananchida Thacharoen, Thisirak Inkaewwong, Watthanachai Jumpathong, Pornchai Kaewsapsak, Thiravat Rattanapot and Tippapha Pisithkul

Mar. Drugs 2025, 23(7), 282; https://doi.org/10.3390/md23070282 - 7 Jul 2025

Helicobacter pylori is a gastric pathogen implicated in peptic ulcer disease and gastric cancer. The increasing prevalence of antibiotic-resistant strains underscores the urgent need for alternative therapeutic strategies. In this study, we investigated the chemical composition and antibacterial activity of an aqueous extract [...] Read more.

Helicobacter pylori is a gastric pathogen implicated in peptic ulcer disease and gastric cancer. The increasing prevalence of antibiotic-resistant strains underscores the urgent need for alternative therapeutic strategies. In this study, we investigated the chemical composition and antibacterial activity of an aqueous extract from Caulerpa lentillifera (sea grape), a farm-cultivated edible green seaweed collected from Krabi Province, Thailand. Ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) revealed that the extract was enriched in bioactive nucleosides and phenolic compounds. In vitro assays demonstrated dose-dependent inhibition of H. pylori growth following exposure to sea grape extract. Furthermore, untargeted intracellular metabolomic profiling of H. pylori cells treated with the extract uncovered significant perturbations in central carbon and nitrogen metabolism, including pathways associated with the tricarboxylic acid (TCA) cycle, one-carbon metabolism, and alanine, aspartate, and glutamate metabolism. Pyrimidine biosynthesis was selectively upregulated, indicating a potential stress-induced shift toward nucleotide salvage and DNA repair. Of particular note, succinate levels were markedly reduced despite accumulation of other TCA intermediates, suggesting disruption of electron transport-linked respiration. These findings suggest that bioactive metabolites from C. lentillifera impair essential metabolic processes in H. pylori, highlighting its potential as a natural source of antimicrobial agents targeting bacterial physiology. Full article

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

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22 pages, 2976 KiB

Open AccessArticle

Photoautotrophic Batch Cultivation of Limnospira (Spirulina) platensis: Optimizing Biomass Productivity and Bioactive Compound Synthesis Through Salinity and pH Modulation

by Matteo Rizzoli, Giovanni Antonio Lutzu, Luca Usai, Giacomo Fais, Deborah Dessì, Robinson Soto-Ramirez, Bartolomeo Cosenza and Alessandro Concas

Mar. Drugs 2025, 23(7), 281; https://doi.org/10.3390/md23070281 - 5 Jul 2025

This study investigates the effects of salinity and pH modulation on the growth, biochemical composition, and bioactive compound production of Limnospira platensis under photoautotrophic batch cultivation. Cultures were grown in cylindrical photobioreactors using modified Jourdan medium, with controlled variations in NaCl concentrations (0.2–10 [...] Read more.

This study investigates the effects of salinity and pH modulation on the growth, biochemical composition, and bioactive compound production of Limnospira platensis under photoautotrophic batch cultivation. Cultures were grown in cylindrical photobioreactors using modified Jourdan medium, with controlled variations in NaCl concentrations (0.2–10 g L⁻¹) and pH levels (9–11) to simulate moderate environmental stress. Maximum biomass productivity (1.596 g L⁻¹) was achieved at pH 11 with 10 g L⁻¹ NaCl, indicating that L. platensis can tolerate elevated stress conditions. Phycocyanin (PC) content peaked at 9.54 g 100 g⁻¹ dry weight (DW) at pH 10 and 5 g L⁻¹ NaCl, triple the value at pH 9, highlighting optimal physiological conditions for pigment synthesis. Protein fraction dominated biomass composition (40–60%), while total lipid content increased significantly under high pH and salinity. Polyphenol content reached 19.5 mg gallic acid equivalents (GAE) gDW⁻¹ at pH 10 with 0.2 g L⁻¹ NaCl, correlating with the highest antioxidant activity (Trolox equivalent antioxidant capacity). These findings underscore the potential of L. platensis as a valuable source of proteins, pigments, and antioxidants, and emphasize the utility of moderate environmental stress in enhancing biomass quality, defined by protein, pigment, and antioxidant enrichment. While this study focused on physiological responses, future research will apply omics approaches to elucidate stress-response mechanisms. This study provides insights into optimizing cultivation strategies for large-scale production exploitable in food, pharmaceutical, and bio-based industries. Full article

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

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15 pages, 2550 KiB

Open AccessArticle

Anti-Inflammatory Secondary Metabolites from Penicillium sp. NX-S-6

by Hanyang Peng, Jiawen Sun, Rui Zhang, Yuxuan Qiu, Yu Hong, Fengjuan Zhou, Chang Wang, Yang Hu and Xiachang Wang

Mar. Drugs 2025, 23(7), 280; https://doi.org/10.3390/md23070280 - 4 Jul 2025

Five new natural products, including two sorbicillinoids (1–2), one indolinone alkaloid (10), one tetracyclic steroid (11), and one α-pyrone derivative (14), were identified from the endophytic Penicillium sp. NX-S-6, together with thirteen known [...] Read more.

Five new natural products, including two sorbicillinoids (1–2), one indolinone alkaloid (10), one tetracyclic steroid (11), and one α-pyrone derivative (14), were identified from the endophytic Penicillium sp. NX-S-6, together with thirteen known natural products. The structures of new compounds were unambiguously elucidated by comprehensive spectroscopic analyses (NMR, MS), as well as electronic circular dichroism (ECD) calculation. Notably, quinosorbicillinol (1) was identified as a rare hybrid sorbicillinoid incorporating a quinolone moiety, representing a unique structural scaffold in this natural product class. Biological evaluation revealed that Compounds 1, 4 and 8 potently inhibited the production of nitric oxide and interleukin 6 in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mechanistic studies furthermore demonstrated that Compounds 4 and 8 effectively suppressed interleukin-1β secretion in LPS-induced immortalized mouse bone marrow-derived macrophages (iBMDMs) by blocking NLRP3 inflammasome activation. This inhibition was attributed to their ability to disrupt the assembly of the NLRP3-caspase-1 complex, a key event in the pathogenesis of inflammatory disorders. These findings not only expand the structural diversity of endophyte-derived natural products but also highlight their potential as lead compounds for developing anti-inflammatory therapeutics targeting the NLRP3 pathway. Full article

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

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49 pages, 5285 KiB

Open AccessReview

Insights into Natural Products from Marine-Derived Fungi with Antimycobacterial Properties: Opportunities and Challenges

by Muhammad Azhari, Novi Merliani, Marlia Singgih, Masayoshi Arai and Elin Julianti

Mar. Drugs 2025, 23(7), 279; https://doi.org/10.3390/md23070279 - 3 Jul 2025

Tuberculosis (TB) poses a persistent global health threat exacerbated by the emergence of drug-resistant strains; hence, there is a continuous quest for novel antimicrobial agents. Despite efforts to develop effective therapies, existing treatments require a relatively long duration of therapy to eradicate the [...] Read more.

Tuberculosis (TB) poses a persistent global health threat exacerbated by the emergence of drug-resistant strains; hence, there is a continuous quest for novel antimicrobial agents. Despite efforts to develop effective therapies, existing treatments require a relatively long duration of therapy to eradicate the pathogen due to its virulence factors, pathogenesis patterns, and ability to enter dormant states. This can lead to a higher risk of treatment failure due to poor patient adherence to the complex regimen. As a result, considerable research is necessary to identify alternative antituberculosis agents. The marine environment, particularly marine-derived fungi, has recently gained interest due to its potential as an abundant source of bioactive natural products. This review covers 19 genera of marine-derived fungi and 139 metabolites, 131 of which exhibit antimycobacterial activity. The integrated dataset pinpoints the fungal genera and chemical classes that most frequently yield potent antimycobacterial hits while simultaneously exposing critical gaps, such as the minimal evaluation of compounds against dormant bacilli and the presence of underexplored ecological niches and fungal genera. Several compounds exhibit potent activity through uncommon mechanisms, including the inhibition of mycobacterial protein tyrosine phosphatases (MptpB/MptpA), protein kinase PknG, ATP synthase and the disruption of mycobacterial DNA via G-quadruplex stabilization. Structure–activity relationship (SAR) trends are highlighted for the most potent agents, illuminating how specific functional groups underpin target engagement and potency. This review also briefly proposes a dereplication strategy and approaches for toxicity mitigation in the exploration of marine-derived fungi’s natural products. Through this analysis, we offer insights into the potency and challenges of marine-derived fungi’s natural products as hit compounds or scaffolds for further antimycobacterial research. 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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21 pages, 5721 KiB

Open AccessArticle

Macroalgae-Inspired Brominated Chalcones as Cosmetic Ingredients with the Potential to Target Skin Inflammaging

by Ana Jesus, Sara Gimondi, Sónia A. Pinho, Helena Ferreira, Nuno M. Neves, Andreia Palmeira, Emília Sousa, Isabel F. Almeida, Maria T. Cruz and Honorina Cidade

Mar. Drugs 2025, 23(7), 278; https://doi.org/10.3390/md23070278 - 2 Jul 2025

Skin aging is mainly caused by external factors like sunlight, which triggers oxidative stress and chronic inflammation. Natural halogenated flavonoids have demonstrated anti-inflammatory properties. Inspired by the macroalgae-derived bromophenol BDDE, we investigated the anti-inflammatory potential of structure-related chalcones (1–7 [...] Read more.

Skin aging is mainly caused by external factors like sunlight, which triggers oxidative stress and chronic inflammation. Natural halogenated flavonoids have demonstrated anti-inflammatory properties. Inspired by the macroalgae-derived bromophenol BDDE, we investigated the anti-inflammatory potential of structure-related chalcones (1–7). Chalcones 1 and 7 showed the least cytotoxicity in keratinocyte and macrophage cells. Chalcones 1, 2, 4, and 5 exhibited the most significant anti-inflammatory effects in murine macrophages after lipopolysaccharide stimulation, with chalcone 1 having the lowest IC₅₀ value (≈0.58 μM). A SNAP assay confirmed that chalcones do not exert their effects through direct NO scavenging. Symmetrical bromine atoms and 3,4-dimethoxy groups on both aromatic rings improved the anti-inflammatory activity, indicating a relevant structure–activity relationship. Chalcones 1 and 2 were selected for study to clarify their mechanisms of action. At a concentration of 7.5 μM, chalcone 2 demonstrated a rapid and effective inhibitory action on the protein levels of inducible nitric oxide synthase (iNOS), while chalcone 1 exhibited a gradual inhibitory action. Moreover, chalcone 1 effectively activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway with around a 3.5-fold increase at the end of 24 h at 7.5 μM, highlighting its potential as a modulator of oxidative stress responses. These findings place chalcone 1 as a promising candidate for skincare products targeting inflammation and skin aging. Full article

(This article belongs to the Special Issue Synthetic Chemistry in Marine Drug Discovery: Challenges and Opportunities)

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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

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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19 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

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

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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37 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

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, 8585 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

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

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

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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16 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

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

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

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

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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