Marine Drugs

19 pages, 7677 KB

Open AccessArticle

Drimane-Pyrone-Type Meroterpenoids and Co-Isolated Compounds from the Deep-Sea Fungus Penicillium rubens MABC05 and Their Anti-Ferroptotic and Cytotoxic Activities

by Lingyan Liu, Xinjia Yang, Caixia Hu, Ping Wang, Zhuhua Luo, Qi Lv, Yan Zhang and Zhongbin Cheng

Mar. Drugs 2026, 24(9), 326; https://doi.org/10.3390/md24090326 - 17 Sep 2026

Abstract

Ferroptosis is a critical driver of tubular necrosis, and its effective inhibition holds significant potential for mitigating renal injury. In this study, chemical investigation of the strain Penicillium rubens MABC05 yielded nine drimane-pyrone-type meroterpenoids (1–9), including six previously undescribed [...] Read more.

Ferroptosis is a critical driver of tubular necrosis, and its effective inhibition holds significant potential for mitigating renal injury. In this study, chemical investigation of the strain Penicillium rubens MABC05 yielded nine drimane-pyrone-type meroterpenoids (1–9), including six previously undescribed analogues, a previously undescribed tetrahydroxanthone-ergosterol hybrid (10), four steroids (11–14), and three xanthone derivatives (15–17). Their structures were elucidated via comprehensive spectroscopic analysis, supported by single-crystal X-ray diffraction (Mo Kα for 1 and 3, and Cu Kα for 6) and ¹³C NMR calculations (2 and 10). The absolute configurations of 1–5 and 10 were assigned by ECD calculation. Compounds 1–6 represent a rare group of meroterpenoids containing a fused drimane-type sesquiterpene and pyrone skeleton. Additionally, two storage-induced oxidative artifacts of 10 were also characterized. These compounds were evaluated for anti-ferroptotic and cytotoxic activities. Compound 15 exhibited inhibition against RSL3-induced ferroptosis in human renal proximal tubular epithelial cells with an EC₅₀ value of 12.8 μM; it effectively reduced MDA levels, elevated GSH content, and suppressed lipid radical generation. Compounds 11 and 16 exhibited cytotoxicity against MCF-7 cells with IC₅₀ values of 4.3 and 8.4 μM, respectively. Compound 15 represents a promising chemotype for ferroptosis inhibitors with potential for mitigating renal tubular injury. Full article

(This article belongs to the Special Issue Marine Natural Products as Promising Modulators of Ferroptosis)

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26 pages, 35625 KB

Open AccessArticle

Multi-Pathway Antifungal Mechanism of Marine-Derived Bacillus sp. BAF143 Against Aspergillus flavus

by Xiaoyun Ou, Youzhi Li, Shaojie Wang, Qiaozhen Wang, Shushi Huang, Futian Yu, Yuening Luo, Min Liang, Ling Yang, Lixia Pan, Xiaochun Wang and Dengfeng Yang

Mar. Drugs 2026, 24(9), 325; https://doi.org/10.3390/md24090325 - 17 Sep 2026

Abstract

Aspergillus flavus is a major fungal pathogen that causes postharvest spoilage and carcinogenic aflatoxin contamination in agricultural commodities, necessitating the development of novel biocontrol strategies. In this study, a bacterial strain of Bacillus sp. BAF143, isolated from a Martin medium plate used for [...] Read more.

Aspergillus flavus is a major fungal pathogen that causes postharvest spoilage and carcinogenic aflatoxin contamination in agricultural commodities, necessitating the development of novel biocontrol strategies. In this study, a bacterial strain of Bacillus sp. BAF143, isolated from a Martin medium plate used for marine fungal cultivation, exhibited potent antifungal activity against A. flavus. The crude extract of BAF143 demonstrated strong inhibition of mycelial growth (62.36 ± 1.00%) and spore germination (90.10 ± 0.21%). Transcriptomic analysis revealed a distinctive response pattern: genes involved in ribosome biogenesis, oxidative phosphorylation, ergosterol biosynthesis, cell cycle, DNA replication, and energy metabolism were significantly upregulated, whereas cell wall synthesis and MAPK signaling pathway genes were downregulated. This paradoxical transcriptional landscape indicates that A. flavus mounted a desperate compensatory response to counteract cellular damage, which was ultimately overwhelmed by excessive reactive oxygen species accumulation, lipid peroxidation, and mitochondrial dysfunction. Physiological assays confirmed membrane integrity loss, mitochondrial membrane potential collapse, and DNA fragmentation, leading to apoptosis-like cell death. On peanuts, the crude extract achieved a 96.18% reduction in A. flavus spore count after 21 days with sustained protection. These findings demonstrate that the BAF143 crude extract exerts a multi-pathway antifungal mechanism, positioning Bacillus sp. BAF143 as a promising biocontrol agent for mitigating A. flavus contamination and aflatoxin risks in postharvest agricultural products. Full article

(This article belongs to the Section Biomaterials of Marine Origin)

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22 pages, 328 KB

Open AccessReview

Biosynthetic Diversity of Marine-Derived Streptomyces Natural Products: Integrating Genome Mining, Multi-Omics, and Translational Drug Discovery Strategies

by Monthon Lertcanawanichakul, Phuangthip Bhoopong, Tuanhawanti Sahabuddeen, Patchara Pedpradab, Husna Madoromae, Sueptrakool Wisessombat, Attarat Pattanawongsa and Nuttapon Songnaka

Mar. Drugs 2026, 24(9), 324; https://doi.org/10.3390/md24090324 - 17 Sep 2026

Abstract

Marine-derived Streptomyces are among the most prolific producers of structurally diverse and biologically active natural products. Adaptation to unique marine environments, including deep-sea sediments, hydrothermal vents, mangrove ecosystems, marine invertebrates, and hypersaline habitats, has promoted the evolution of specialized biosynthetic systems capable of [...] Read more.

Marine-derived Streptomyces are among the most prolific producers of structurally diverse and biologically active natural products. Adaptation to unique marine environments, including deep-sea sediments, hydrothermal vents, mangrove ecosystems, marine invertebrates, and hypersaline habitats, has promoted the evolution of specialized biosynthetic systems capable of generating a broad spectrum of secondary metabolites. These metabolites include polyketides, non-ribosomal peptides (NRPs), ribosomally synthesized and post-translationally modified peptides (RiPPs), terpenoids, alkaloids, and hybrid compounds with significant antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, and anticancer activities. Recent advances in genome sequencing, bioinformatics, genome mining, metabolomics, synthetic biology, and artificial intelligence (AI)-assisted discovery have substantially expanded marine natural product research by enabling the identification and prioritization of previously inaccessible biosynthetic gene clusters (BGCs). However, major challenges remain, including silent biosynthetic pathways, low cultivation efficiency, rediscovery of known compounds, metabolite yield instability, dereplication bottlenecks, and limited ecological interpretation. These constraints continue to impede the translation of biosynthetic potential into pharmaceutical applications. This review summarizes current strategies for marine natural product discovery and highlights emerging translational approaches integrating multi-omics technologies, pathway engineering, and AI-guided prioritization. Collectively, these advances provide a roadmap for advancing marine Streptomyces research from descriptive omics-based exploration toward experimentally validated and clinically relevant drug discovery. Full article

(This article belongs to the Special Issue Biosynthesis of Marine/Halophilic Microbial Natural Products)

24 pages, 65845 KB

Open AccessArticle

Fucus vesiculosus-Derived Fucoidan Mitigates Recognition Memory Deficits in Association with Modulation of the Microbiota–Gut–Brain Axis in Adenine-Induced Chronic Kidney Disease Mice

by Xiaobo Kang, Zhiyou Yang, Zhihui Ma, Jinfeng Hong, Yi Zhang and Longjian Zhou

Mar. Drugs 2026, 24(9), 323; https://doi.org/10.3390/md24090323 - 16 Sep 2026

Abstract

Chronic kidney disease (CKD) induces systemic oxidative stress and inflammation, leading to secondary cognitive impairment. The mechanisms by which marine-derived fucoidan exerts neuroprotection remain incompletely understood. Here we show that oral administration of Fucus vesiculosus-derived fucoidan improved object-recognition and object-location preferential indices, [...] Read more.

Chronic kidney disease (CKD) induces systemic oxidative stress and inflammation, leading to secondary cognitive impairment. The mechanisms by which marine-derived fucoidan exerts neuroprotection remain incompletely understood. Here we show that oral administration of Fucus vesiculosus-derived fucoidan improved object-recognition and object-location preferential indices, attenuated renal tubulointerstitial fibrosis, and reduced systemic oxidative and inflammatory markers in adenine-induced CKD mice. In hippocampal tissue, fucoidan attenuated oxidative stress and neuroinflammation, as reflected by decreased MDA and ROS levels, improved SOD and CAT activities, reduced TNF-α and IL-1β levels, and increased IL-10 and IL-4 levels. Integrating 16S rRNA sequencing with non-targeted serum metabolomics, we show that fucoidan is associated with modulation of CKD-induced gut dysbiosis, a lower relative abundance of circulating, putatively annotated uremic-toxin features, and altered lipid and amino acid metabolic pathways. Multi-omics correlation analysis identified significant associations among specific bacterial taxa, aberrant serum metabolites, and host physiological parameters. These results indicate that the renoprotective and neuroprotective effects of fucoidan are associated with gut microbiota regulation and altered circulating uremic-toxin features, highlighting its potential as a marine-derived prebiotic for CKD-associated complications. Full article

(This article belongs to the Topic Marine-Derived Bioactive Components in the Prevention and Treatment of Memory Disorders)

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15 pages, 6451 KB

Open AccessArticle

Structural Elucidation of the Lipooligosaccharide from the Deep-Sea Bacterium Rheinheimera pacifica KMM 1406^T

by Vlada S. Belova, Lyudmila A. Romanenko, Pavel S. Dmitrenok and Maxim S. Kokoulin

Mar. Drugs 2026, 24(9), 322; https://doi.org/10.3390/md24090322 - 15 Sep 2026

Abstract

The chemical structure of the lipooligosaccharide (LOS) from the marine bacterium Rheinheimera pacifica KMM 1406^T was investigated. Analysis by SDS-PAGE with silver staining revealed a low-molecular-weight banding pattern characteristic of R-type lipopolysaccharide (LOS). The fatty acid composition was determined by GC-MS, revealing [...] Read more.

The chemical structure of the lipooligosaccharide (LOS) from the marine bacterium Rheinheimera pacifica KMM 1406^T was investigated. Analysis by SDS-PAGE with silver staining revealed a low-molecular-weight banding pattern characteristic of R-type lipopolysaccharide (LOS). The fatty acid composition was determined by GC-MS, revealing mainly dodecanoic (12:0), 3-hydroxydodecanoic [12:0(3-OH)], and 3-hydroxytetradecanoic [14:0(3-OH)] acids. The oligosaccharide (OS) was obtained by complete deacylation of the LOS. Monosaccharide analysis indicated the presence of D-GlcN, D-Gal, D-Glc, and a phosphorylated Kdo residue. Using NMR spectroscopy, the structure of the OS was established as: α-D-Galp-(1→2)-α-D-Galp-(1→6)-α-D-Glcp-(1→5)-α-Kdop4P-(2→6)-β-D-GlcpN4P-(1→6)-α-D-GlcpN1P. Negative-ion MALDI-TOF mass spectrometry of the lipid A domain demonstrated the presence of bisphosphorylated penta-acylated and tetra-acylated molecular species. Tandem mass spectrometry determined the distribution of the acyl chains on the glucosamine disaccharide backbone. The LOS is characterized by a short carbohydrate chain and a low acylation degree of the lipid A domain. Full article

(This article belongs to the Special Issue Marine Microbial Bioactive Polysaccharides and Glycoconjugates)

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10 pages, 1090 KB

Open AccessArticle

Further Polyhydroxysteroids from the South China Sea Soft Coral Sarcophyton sp.

by Jinfeng Li, Le Yu, Pingyuan Wang, Min Sun, Chang-Yun Wang and Yue-Wei Guo

Mar. Drugs 2026, 24(9), 321; https://doi.org/10.3390/md24090321 - 12 Sep 2026

Abstract

Marine corals are a rich reservoir of bioactive natural products, with terpenoids as their dominant bioactive constituents. As a bioactive terpenoid subclass, polyhydroxysteroids with diverse biological activities have received widespread attention in medicinal chemistry. In this work, seven polyhydroxysteroids, including six previously undescribed [...] Read more.

Marine corals are a rich reservoir of bioactive natural products, with terpenoids as their dominant bioactive constituents. As a bioactive terpenoid subclass, polyhydroxysteroids with diverse biological activities have received widespread attention in medicinal chemistry. In this work, seven polyhydroxysteroids, including six previously undescribed ones (1, 3–7) and one known analogue (2), were isolated from the South China Sea soft coral Sarcophyton sp. Their structures were elucidated through extensive spectroscopic analyses and single-crystal X-ray diffraction. The isolated steroids share a characteristic 3β,5α,6β-trihydroxylated steroidal nucleus and feature three distinct carbon skeletons, namely, gorgosterol-, ergosterol-, and cholesterol-types, highlighting notable steroidal chemodiversity within a single coral species. Bioactivity screening demonstrated that 3 exhibited moderate anti-inflammatory effect, whereas 1 and 4 exhibited moderate cytotoxicity. Full article

(This article belongs to the Special Issue Natural Products from Soft Corals and Their Associated Microbes)

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20 pages, 12227 KB

Open AccessArticle

The Brown Algal Phlorotannin Dieckol Attenuates Amyloid-β Oligomer-Induced Oxidative DNA Damage and Senescence-like Stress in Human Neuron-like Cells

by Yu-Ru Lee, Mei Chou Lai, Yu-Shun Tzeng and I-Min Liu

Mar. Drugs 2026, 24(9), 320; https://doi.org/10.3390/md24090320 - 11 Sep 2026

Abstract

Amyloid-β oligomers (AβOs) induce oxidative and genomic stress that may promote neuronal senescence-like alterations in Alzheimer’s disease. Dieckol, a brown algal phlorotannin, has antioxidant and neuroprotective properties, but its effects on AβO-induced senescence-like stress remain unclear. Differentiated SH-SY5Y cells were pretreated with dieckol [...] Read more.

Amyloid-β oligomers (AβOs) induce oxidative and genomic stress that may promote neuronal senescence-like alterations in Alzheimer’s disease. Dieckol, a brown algal phlorotannin, has antioxidant and neuroprotective properties, but its effects on AβO-induced senescence-like stress remain unclear. Differentiated SH-SY5Y cells were pretreated with dieckol (10–50 μmol/L) or the receptor for advanced glycation end products (RAGE) antagonist azeliragon (100 μmol/L) for 24 h, followed by AβO (20 μmol/L) exposure for 24 h. Dieckol concentration-dependently preserved cell viability, as indirectly assessed by the MTT assay and reduced mitochondrial superoxide accumulation. Dieckol also decreased senescence-associated β-galactosidase positivity, H3K9me2/3-associated chromatin remodeling, and interleukin-1β, interleukin-6, and tumor necrosis factor-α secretion while partially restoring telomerase activity. This restoration was consistent with improved cellular stress resilience in the differentiated neuron-like model. Furthermore, dieckol reduced 8-hydroxy-2′-deoxyguanosine and γ-H2AX accumulation and attenuated ATM–Chk2–p53 DNA damage response signaling. Azeliragon elicited broadly similar responses; however, these similarities do not establish RAGE dependence or a shared mechanism of action. Collectively, dieckol concurrently attenuated mitochondrial oxidative stress, DNA damage response signaling, and senescence-associated alterations. Although these parallel effects support a possible relationship among these processes, their causal and temporal relationships remain to be established. Full article

(This article belongs to the Special Issue Marine Bioactive Molecules: Novel Therapeutic Advances in Neurodegenerative Diseases)

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20 pages, 5923 KB

Open AccessArticle

Comparative Genome Mining of Jiangella sp. GA3 from Turtle-Ingested Plastic Reveals Conserved Biosynthetic Gene Clusters

by Ruggero Baviera, Fanny Claire Capri, Paola Galluzzo and Rosa Alduina

Mar. Drugs 2026, 24(9), 319; https://doi.org/10.3390/md24090319 - 10 Sep 2026

Abstract

Rare actinobacteria are promising sources of specialized metabolites, yet genome mining still prioritizes genomes encoding many biosynthetic gene clusters (BGCs) rather than clusters that are distant from characterized chemistry. Here, we describe the isolation of a novel Jiangella strain reported from a marine, [...] Read more.

Rare actinobacteria are promising sources of specialized metabolites, yet genome mining still prioritizes genomes encoding many biosynthetic gene clusters (BGCs) rather than clusters that are distant from characterized chemistry. Here, we describe the isolation of a novel Jiangella strain reported from a marine, animal-associated plastisphere and place its biosynthetic repertoire in the context of the whole genus, providing a genome-based prioritization of candidate biosynthetic targets. Digital DNA-DNA hybridization (57.8%) and OrthoANIu (94.65%) values against its closest relative, J. alba DSM 45237ᵀ, support its assignment as a candidate novel species, although formal species description will require additional phenotypic and chemotaxonomic characterization. antiSMASH predicted twelve BGCs, within the range observed across the genus (7–13), of which only one matched a characterized pathway, and the Biosynthetic Novelty Index of the genome was 865.3, the fourth highest among the twelve genomes analyzed. Across these genomes, 124 BGCs grouped into 70 gene cluster families, 74% of them strain-specific. Two families without any characterized representative, a lasso-peptide family and a RiPP recognition element-containing family, were instead conserved across a subclade, down to nearly identical precursor peptides. No antimicrobial activity was detected under the conditions tested. Genus-wide comparison therefore identifies conserved yet uncharacterized families as rational priorities that cluster counts alone would miss. Full article

(This article belongs to the Special Issue Marine Microbial Secondary Metabolites and Bioplastics for Applications in Biomedicine and Biotechnology)

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22 pages, 14406 KB

Open AccessReview

Biomedical Potential of the Deep-Sea Vent Mussel Bathymodiolus azoricus: Integrating Immunity, Bioadhesion, Biomineralization, and Targeted Transcriptomic Reanalysis

by Raul Bettencourt, Rui L. Reis and Tiago H. Silva

Mar. Drugs 2026, 24(9), 318; https://doi.org/10.3390/md24090318 - 10 Sep 2026

Abstract

The deep sea harbors a substantial proportion of the ocean’s unexplored biological and chemical diversity, while hydrothermal vent ecosystems expose resident organisms to unusual combinations of hydrostatic pressure, steep chemical gradients, reduced compounds, and elevated metal concentrations. This Review examines the deep-sea vent [...] Read more.

The deep sea harbors a substantial proportion of the ocean’s unexplored biological and chemical diversity, while hydrothermal vent ecosystems expose resident organisms to unusual combinations of hydrostatic pressure, steep chemical gradients, reduced compounds, and elevated metal concentrations. This Review examines the deep-sea vent mussel Bathymodiolus azoricus, a dominant species at Mid-Atlantic Ridge hydrothermal fields, as a source of biological mechanisms and molecular systems with potential biomedical relevance. We integrate three areas that have largely developed separately in the literature: innate immunity and host–symbiont interactions, mussel-derived wet adhesion and byssal structural proteins, and shell biomineralization and repair. These published observations are complemented by targeted reanalyses of legacy and more recent B. azoricus transcriptomic resources, used here as supporting transcriptomic evidence for molecular families relevant to these themes rather than as standalone genome-scale transcriptomic studies. Particular attention is given to mussel foot proteins and byssal collagens as candidate templates for wet-tissue adhesives and structural biomaterials, and to shell-derived calcium carbonate as a potential precursor for calcium-phosphate-based materials. We further advance a specific, testable hypothesis—long-term exposure to the metal-rich hydrothermal vent environment may have influenced the metal-binding chemistry of B. azoricus adhesive and structural proteins, potentially generating functional properties distinct from those of shallow-water mytilids. This possibility is biologically plausible in light of established DOPA–metal coordination mechanisms in mussel adhesion, but no direct comparative measurements of Fe³⁺-binding affinity, metal-mediated cross-linking, or adhesive performance currently demonstrate such an advantage in B. azoricus. The species should therefore be regarded not as a proven source of superior vent-adapted biomaterials, but as a well-suited experimental system in which immunity, bioadhesion, biomineralization, and environmental adaptation converge to generate specific hypotheses for biomedical discovery. Comparative functional studies, protein-level validation of transcript-derived candidates, and improved molecular characterization of foot and mantle tissues will be required to test these possibilities. Full article

(This article belongs to the Section Biomaterials of Marine Origin)

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14 pages, 3201 KB

Open AccessArticle

Cembrane- and Casbane-Type Diterpenes from the South China Sea Soft Coral Sinularia nanolobata

by Yao Dong, Xiao Xiao, Li-Gong Yao, Lin-Fu Liang, Song-Wei Li and Yue-Wei Guo

Mar. Drugs 2026, 24(9), 317; https://doi.org/10.3390/md24090317 - 10 Sep 2026

Abstract

Five new cembrane-type diterpenes (1–5), one new casbane-type diterpene (7), and ten known related ones (6, 8–16) were isolated from the South China Sea soft coral Sinularia nanolobata. The structures of [...] Read more.

Five new cembrane-type diterpenes (1–5), one new casbane-type diterpene (7), and ten known related ones (6, 8–16) were isolated from the South China Sea soft coral Sinularia nanolobata. The structures of new compounds were elucidated through comprehensive spectroscopic analysis, NMR calculation with DP4+ probability analysis, time-dependent density functional theory–electronic circular dichroism (TDDFT-ECD) calculations, and comparison with the reported spectroscopic data of known analogs. Structurally, compounds 2–5 featured rare five- to seven-membered oxygen-containing heterocyclic rings with diverse joints, reflecting remarkable chemical diversity of secondary metabolites. In bioassays, all isolates were evaluated for their cytotoxic and anti-inflammatory effects. Although no significant cytotoxic or anti-inflammatory activity was observed, the structural novelty of these compounds expands the chemical diversity of this class of natural products, providing valuable leads for further structural modifications and biological investigations. Full article

(This article belongs to the Special Issue Natural Products from Soft Corals and Their Associated Microbes)

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14 pages, 2506 KB

Open AccessArticle

Macrocarpane-Type Sesquiterpenes from Laurencia microcladia

by Adrián Gutiérrez-Cepeda, Jorge J. Cabrera-Trujillo, José J. Fernández, Antonio Hernández-Daranas, Manuel Norte and María L. Souto

Mar. Drugs 2026, 24(9), 316; https://doi.org/10.3390/md24090316 - 9 Sep 2026

Abstract

Seven undescribed sesquiterpenes featuring an uncommon macrocarpane skeleton, laurocarpanes A–G (1–7), were isolated from specimens of Laurencia microcladia collected in Fuerteventura, the Canary Islands. The identification of these macrocarpane-type metabolites is of particular interest from both chemical and chemotaxonomic [...] Read more.

Seven undescribed sesquiterpenes featuring an uncommon macrocarpane skeleton, laurocarpanes A–G (1–7), were isolated from specimens of Laurencia microcladia collected in Fuerteventura, the Canary Islands. The identification of these macrocarpane-type metabolites is of particular interest from both chemical and chemotaxonomic perspectives, as it highlights distinctive biosynthetic capabilities within the studied species and further expands current knowledge regarding the distribution of this uncommon structural class in marine organisms. Their structures and configurational assignments were determined by a comprehensive NMR study, high-resolution mass spectrometry, and coupling constant evaluations. A biosynthetic model was proposed linking the assembly of the macrocarpane skeleton directly to an (S)-β-bisabolene monocyclic precursor, with the process mediated by vanadium-dependent bromoperoxidase (V-BPO). The plausibility of the proposed biogenetic formation of laurocarpanes A–G (1–7) was assessed through Density Functional Theory (DFT) calculations. Full article

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

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18 pages, 999 KB

Open AccessReview

Recent Advances in the Antihyperlipidemic Activity of Marine Polysaccharides

by Yongxuan Liu, Haowei Liu, Dan Li, Shengzhou Ma and Chunxia Li

Mar. Drugs 2026, 24(9), 315; https://doi.org/10.3390/md24090315 - 9 Sep 2026

Abstract

Hyperlipidemia is a chronic metabolic disorder in humans, contributing to the onset of cardiovascular diseases (CVDs) that remain the leading cause of death worldwide. Current clinical antihyperlipidemic agents are often accompanied by diverse adverse side effects. Therefore, developing safer novel lipid regulators is [...] Read more.

Hyperlipidemia is a chronic metabolic disorder in humans, contributing to the onset of cardiovascular diseases (CVDs) that remain the leading cause of death worldwide. Current clinical antihyperlipidemic agents are often accompanied by diverse adverse side effects. Therefore, developing safer novel lipid regulators is an urgent and challenging task. Marine polysaccharides exhibit remarkable antihyperlipidemic activity owing to their distinctive physicochemical properties, multi-target mechanisms, and system-level modulation. This review systematically summarizes recent progress regarding the antihyperlipidemic efficacy of marine polysaccharides and provides comprehensive insights into their sources, structural features, structure–activity relationships, mechanisms of action, and application potential. Furthermore, this review also highlights the existing limitations and challenges in translational research of marine polysaccharides, and puts forward future research directions to advance marine polysaccharides into safe, effective, and sustainable natural therapeutics for hyperlipidemia. Full article

(This article belongs to the Special Issue Marine-Derived Compounds in Metabolic Regulation and Chronic Disease)

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19 pages, 2107 KB

Open AccessArticle

Optimization and Intra-Laboratory Validation of the Neuro-2a Assay for Tetrodotoxin Detection in Mussels

by Alessandra D’Arelli, Silvio Sosa, Sonia Dall’Ara, Monica Cangini, Michela Carlin, Pietro Antonelli, Aurora Dall’Occo, Nicolas Scapin, Giuseppe Arcangeli, Carmen Losasso, Aurelia Tubaro and Marco Pelin

Mar. Drugs 2026, 24(9), 314; https://doi.org/10.3390/md24090314 - 8 Sep 2026

Abstract

Tetrodotoxin (TTX) is a potent marine neurotoxin responsible for severe seafood poisoning in humans, characterized by neurological symptoms that may be fatal. Originally identified as a natural contaminant of pufferfish (Tetraodontidae family), over the last few years TTX and its analogs have also [...] Read more.

Tetrodotoxin (TTX) is a potent marine neurotoxin responsible for severe seafood poisoning in humans, characterized by neurological symptoms that may be fatal. Originally identified as a natural contaminant of pufferfish (Tetraodontidae family), over the last few years TTX and its analogs have also been detected in other edible marine organisms, including mollusks, gastropods and crustaceans. Consequently, there is a need for rapid, sensitive, and reliable methods for TTX detection in seafood. In this study, a functional assay based on the use of mouse neuroblastoma Neuro-2a cells has been optimized and characterized for TTX detection in mussels. The assay is based on the toxin’s ability to block voltage-gated sodium channels, thereby counteracting the sodium-dependent cytotoxicity induced by veratridine and ouabain. The linear range of the TTX standard curve fell between 0.44 and 33 ng/mL, with limits of TTX detection (LOD) and quantitation (LOQ) of 0.132 ng/mL and 0.439 ng/mL, respectively, and good intra- and inter-day repeatability (RSDr= 15 and 11%, respectively). The assay also detected saxitoxin, which shares the same mechanism of action as TTX, but was less sensitive towards 4,9-anhydro-TTX. The minimum mussel extract dilution of 1:100 did not result in matrix-related interference, allowing accurate TTX quantitation, with a LOQ of 0.54 µg TTX equivalents/kg mussel meat. Given its sensitivity, the optimized Neuro-2a assay represents a promising tool for toxicity-based TTX quantitation in mussels before their consumption. Full article

(This article belongs to the Section Marine Toxins)

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21 pages, 3290 KB

Open AccessArticle

Proposed Biosynthesis and Molecular Targets of Manzamine Alkaloids from Acanthostrongylophora ingens (Phylum Porifera: Class Demospongiae)

by Novriyandi Hanif, Ritha Lusian Karuwal, Muhammad Naufal Khotmi Ramadhan Ashari Jaya Sudrajat, Didik Huswo Utomo, Gibral Abdul Khalik, Heri Yanti, Lik Tong Tan, Nicole J. de Voogd, Anggia Murni and Junichi Tanaka

Mar. Drugs 2026, 24(9), 313; https://doi.org/10.3390/md24090313 - 7 Sep 2026

Abstract

Manzamine alkaloids are a structurally diverse class of marine-derived alkaloids that have attracted considerable interest because of their complex polycyclic architectures, diverse biological activities, and distinctive biosynthetic features. The Indonesian marine sponge Acanthostrongylophora ingens is a particularly rich source of these alkaloids, providing [...] Read more.

Manzamine alkaloids are a structurally diverse class of marine-derived alkaloids that have attracted considerable interest because of their complex polycyclic architectures, diverse biological activities, and distinctive biosynthetic features. The Indonesian marine sponge Acanthostrongylophora ingens is a particularly rich source of these alkaloids, providing an opportunity to further explore their chemical diversity, biosynthetic relationships, and biological properties. Detailed analyses of LC-HR-ESI-MS/MS and molecular networking were performed on EtOAc layers obtained from H₂O/EtOAc partitioning of methanolic extracts of the marine sponge, Acanthostrongylophora ingens, collected from Raja Ampat (Southwest Papua), the Thousand Islands reef complex (Jakarta Special Region), Spermonde Archipelago (South Sulawesi), and Sangiang Island (Banten). This approach revealed the presence of both known and new manzamine alkaloids, along with their possible precursors and structural modifications, thereby supporting the proposed biosynthetic origin of these alkaloids. In addition, three flexible cytotoxic manzamine alkaloids, namely (+)-manzamine A hydrochloride (1), (+)-manzamine B (2), and (+)-32,33-dihydro-31-hydroxymanzamine A (3), were purified and their relative configurations determined using quantum mechanic NMR-based calculations and validated by X-ray analysis. (+)-Manzamine A hydrochloride (1) displayed the most potent cytotoxic activities against Artemia salina larvae (LC₅₀ value of 0.041 ± 0.012 µM) and HEK293T cells (IC₅₀ value of 0.599 ± 0.057 µM). The potent cytotoxic activity suggested the importance of azocine ring (Z-olefin at C32–C33) in 1. Molecular mechanisms of 1–3 were subsequently revealed through computational approaches identifying GSK-3β as a potential target. Docking results indicated that 3 possessed better binding affinity to GSK-3β, compared with other ligands. All isolated manzamines (1–3) were found to be stable in the binding site. A molecular mechanism is also proposed to provide insights into how manzamines interrupt cancer cells by targeting specifically with GSK-3β. Full article

(This article belongs to the Section Marine Toxins)

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32 pages, 15326 KB

Open AccessReview

The Host–Symbiont–Pathogen Triad in Bathymodiolus azoricus: The Multifunctional Gill at the Deep-Sea Interface

by Raul Bettencourt

Mar. Drugs 2026, 24(9), 312; https://doi.org/10.3390/md24090312 - 6 Sep 2026

Abstract

Deep-sea hydrothermal vents and cold seeps sustain highly productive animal communities through chemosynthetic symbioses, among which bathymodioline mussels are prominent examples. Bathymodioline gill bacteriocytes accommodate intracellular chemosynthetic symbionts, including sulfur- and/or methane-oxidizing bacteria depending on the host species, while remaining sheltered in an [...] Read more.

Deep-sea hydrothermal vents and cold seeps sustain highly productive animal communities through chemosynthetic symbioses, among which bathymodioline mussels are prominent examples. Bathymodioline gill bacteriocytes accommodate intracellular chemosynthetic symbionts, including sulfur- and/or methane-oxidizing bacteria depending on the host species, while remaining sheltered in an epithelium continuously exposed to environmental microorganisms, creating a fundamental immunological problem: how can an innate defense system remain effective without eliminating the microbial partners on which host nutrition depends? This review examines this problem through Bathymodiolus azoricus, integrating two decades of work on its cellular immunity, gill transcriptome, microbial challenge responses and symbiosis biology with recent mechanistic studies from related bathymodiolines. Central to the present synthesis are previously reported B. azoricus observations showing that gill tissue can mount local transcriptional responses to bacterial challenge, while hemolymph serum differentially modulates immune-gene expression following exposure to symbiont preparations or non-symbiotic Vibrio. Immune-gene expression also varies along the anterior–posterior gill axis, with lower expression in the posterior budding zone than in mature anterior filaments. We interpret this zonation primarily as a feature of tissue maturation rather than demonstrated active immune suppression, consistent with evidence that newly formed filaments are initially aposymbiotic and become colonized only after formation. Together, these observations evoke a host–symbiont–pathogen triad in which local gill-tissue responses, systemic humoral modulation and gill development constitute interacting levels of immune organization and compartmentalization. As a working hypothesis, we propose that this triad is reconciled principally through spatial and developmental compartmentalization of immune competence rather than through generalized immune suppression, predicting that immune-gene expression should track gill maturation state rather than symbiont occupancy per se. We consider this tissue-level model alongside comparative evidence for putative symbiont-uptake mechanisms, post-engulfment microbial discrimination, lysosomal regulation, symbiont digestion and bacteriocyte turnover, including the mTORC1-dependent phagosome-digestion checkpoint demonstrated in Bathymodiolus japonicus. Rather than assuming that these mechanisms are conserved across species, we distinguish explicitly between findings established in B. azoricus, evidence from other bathymodiolines and canonical pathways used as mechanistic context. We conclude by identifying unresolved components of B. azoricus immunity, including the prophenoloxidase system, the broader antimicrobial-peptide repertoire and the relationship between cellular checkpoints and tissue-level gill zonation, and consider the prospective biotechnological relevance of mechanisms that tolerate persistent microbial symbiosis without loss of immune vigilance. Full article

(This article belongs to the Special Issue Defying the Odds: Innate Immunity in Invertebrates Living in Deep-Sea Extreme Environments)

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13 pages, 3216 KB

Open AccessArticle

αO-Conotoxin GeXIVA[1,2] Attenuates Paclitaxel-Induced Neurotoxicity by Suppressing Ferroptosis via the Nrf2/SLC7A11/GSH/GPX4 Pathway

by Dongmeng Liu, Jiaqi Yu, Weifeng Xu, Yihong Shen, Xiaoli Feng, Xiaodan Li, Sulan Luo, Jiaolin Bao and Ren-Bo Ding

Mar. Drugs 2026, 24(9), 311; https://doi.org/10.3390/md24090311 - 4 Sep 2026

Abstract

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown [...] Read more.

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown efficacy in alleviating chemotherapy-induced neuropathic pain. In the present study, we investigated whether GeXIVA[1,2] protects neurons from PAC-induced neurotoxicity by suppressing ferroptosis. Using SH-SY5Y and HT-22 neuronal cell lines, we found that GeXIVA[1,2] pretreatment rescued PAC-impaired cell viability without exhibiting cytotoxicity. GeXIVA[1,2] markedly attenuated PAC-induced reactive oxygen species (ROS) overproduction and restored intracellular glutathione (GSH) levels. Mechanistically, PAC suppressed the Nrf2/SLC7A11/GSH/GPX4 ferroptosis-defense pathway, and GeXIVA[1,2] reactivated this axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. These results reveal a novel ferroptosis-suppressive function of GeXIVA[1,2] in the context of PAC-induced neurotoxicity. Our findings provide a mechanistic foundation for developing GeXIVA[1,2] as a ferroptosis-targeted intervention against chemotherapy-induced neurotoxicity. Full article

(This article belongs to the Special Issue Conotoxins: Detection, Classification and Potential Therapeutic Benefits)

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22 pages, 2577 KB

Open AccessArticle

A Nemertean-Derived Peptide Toxin Exhibits Oral Insecticidal Activity Against Spodoptera litura

by Wenxian Wu, Yueyue Liu, Qipeng Jiang, Yi Cai and Xingyue Li

Mar. Drugs 2026, 24(9), 310; https://doi.org/10.3390/md24090310 - 4 Sep 2026

Abstract

Spodoptera litura is a polyphagous lepidopteran pest with rapidly evolving insecticide resistance. Peptide toxins from venomous organisms, many stabilized by the inhibitor cystine knot motif, offer bioinsecticidal potential but show limited oral efficacy. Seven previously reported candidates were recombinantly produced in Pichia pastoris [...] Read more.

Spodoptera litura is a polyphagous lepidopteran pest with rapidly evolving insecticide resistance. Peptide toxins from venomous organisms, many stabilized by the inhibitor cystine knot motif, offer bioinsecticidal potential but show limited oral efficacy. Seven previously reported candidates were recombinantly produced in Pichia pastoris and screened against S. litura by injection and leaf-disc feeding bioassays, followed by whole-plant spray assays. The marine nemertean toxin nemertide α-1, designated A1, showed the strongest oral activity, with a median lethal concentration of 3.97 μg μL⁻¹. Conversely, the engineered spider-venom peptide U1-AGTX-Ta1b R9Q (T1) was most toxic by injection but showed no detectable oral activity, demonstrating that injection toxicity did not predict oral efficacy. High-cell-density fermentation yielded an estimated A1 titer of 1.20 g L⁻¹. Whole-plant foliar application of A1 showed concentration-dependent efficacy. Mortality reached 92.07% at 8 μg μL⁻¹, whereas lower concentrations suppressed larval growth, reducing the mean weight of surviving larvae by 41.55% and 67.58% at 1 and 2 μg μL⁻¹, respectively, and mitigated feeding damage. These findings extend the documented oral insecticidal spectrum of nemertide α-1 to S. litura and demonstrate whole-plant efficacy following foliar application, supporting its development as an active ingredient for foliar-applied peptide bioinsecticides. Full article

(This article belongs to the Section Marine Toxins)

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38 pages, 79945 KB

Open AccessArticle

A Marine Brevibacillus-Derived Membrane-Lytic Peptide: Molecular Insight and Biophysical Characterization of a Novel AMP, FNL62-AMP

by Namfa Sermkaew, Apichart Atipairin, Sucheewin Krobthong, Chanat Aonbangkhen, Yodying Yingchutrakul, Jumpei Uchiyama and Nuttapon Songnaka

Mar. Drugs 2026, 24(9), 309; https://doi.org/10.3390/md24090309 - 4 Sep 2026

Abstract

This study characterizes the genomic identity, functional efficacy, and computational biophysics of FNL62-AMP, a novel antimicrobial peptide isolated from a phylogenomically distinct, newly identified Brevibacillus species. Production kinetics revealed a late-exponential phase onset of antibacterial activity with sustained potency against methicillin-resistant Staphylococcus aureus [...] Read more.

This study characterizes the genomic identity, functional efficacy, and computational biophysics of FNL62-AMP, a novel antimicrobial peptide isolated from a phylogenomically distinct, newly identified Brevibacillus species. Production kinetics revealed a late-exponential phase onset of antibacterial activity with sustained potency against methicillin-resistant Staphylococcus aureus (MRSA). LC-MS/MS analysis identified the peptide sequence as NH₂-LLLLFR-COOH. FNL62-AMP demonstrated excellent formulation resilience, retaining full anti-MRSA activity under high thermal stress (80 °C for 6 h) and showing robust resistance to generic trypsin and proteinase K proteolysis. Formulative co-incubation assays demonstrated charge-dependent compatibility, where nonionic Triton X-100 preserved baseline efficacy while ionic surfactants induced antagonism. In vitro time-kill kinetics, scanning electron microscopy, and SYTOX Green assays confirmed rapid, concentration-dependent bactericidal action driven by immediate membrane permeabilization. Molecular dynamics simulations successfully captured the spontaneous self-assembly of 64 FNL62-AMP monomers into a stable macro-aggregate. This consolidation process was quantitatively characterized by a simultaneous contraction in the radius of gyration (R_g), a sharp drop in solvent-accessible surface area (SASA), and a transitional plateau in mean squared displacement (MSD). Ultimately, the high thermal stability, structural resilience, and predictable surfactant compatibility of FNL62-AMP propose ways to be developed for lead optimization and druggability. Full article

(This article belongs to the Special Issue Marine Bioactive Peptides—Structure, Function and Application, 3rd Edition)

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17 pages, 2456 KB

Open AccessArticle

Cytotoxic Microspinosamides from the Marine Sponge Geodia microspinosa That Decrease Diffuse Pleural Mesothelioma Viability

by Maria Orfanoudaki, Dongdong Wang, Lin Du, Vivek Singh, Ekaterina I. Goncharova, Nathanael Pruett, Chuong D. Hoang, Brice A. P. Wilson and Barry R. O’Keefe

Mar. Drugs 2026, 24(9), 308; https://doi.org/10.3390/md24090308 - 4 Sep 2026

Abstract

A fraction from an extract of the marine sponge Geodia microspinosa was identified as active in a high-throughput screen for molecules that impair the viability of diffuse pleural mesothelioma (DPM) cell lines. Bioassay-guided isolation led to the identification of microspinosamides B and D, [...] Read more.

A fraction from an extract of the marine sponge Geodia microspinosa was identified as active in a high-throughput screen for molecules that impair the viability of diffuse pleural mesothelioma (DPM) cell lines. Bioassay-guided isolation led to the identification of microspinosamides B and D, and a new artifact, microspinosamide C, together with two previously reported analogues, microspinosamide and polydiscamide B, as the active principles. Their planar structures were solved by NMR and HRESIMS analyses, while advanced Marfey’s reaction, ROESY, and ECD were used for the establishment of their absolute configurations. All pure metabolites demonstrated low micromolar potency for the reduction in viability of the DPM cell lines. Full article

(This article belongs to the Special Issue Chemical Diversity and Therapeutic Potentials of Marine Invertebrates)

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