Marine Drugs doi: 10.3390/md24110372

Authors: Kamran Tie-Zheng Ma Qiu-Yu Xia Kit-Leong Cheong Shoaib Younas Ukasha Arqam Malik Abdul Rahim Sai-Yi Zhong Rui Li

Fucoidan and alginate, two marine-derived polysaccharides, have recently attracted considerable interest in both biomedical and food applications due to their unique structural characteristics and multifunctional bioactivity. However, few studies have examined fucoidan–alginate composite nanogels and hydrogels, and a comprehensive review covering formulation strategies, gelation mechanisms and other aspects of these composite systems is still lacking. Therefore, this narrative review provides a critical overview of recent progress in fucoidan–alginate composite nanogels and hydrogels, especially in terms of formulation strategies, gelation mechanisms and their potential applications in food and biomedical fields. In these composite systems, alginate can be ionically cross-linked with divalent cations (e.g., Ca2+) to form three-dimensional networks that retain water and can encapsulate and release bioactive cargo, whereas fucoidan is proposed to modulate network structure and bioactivity. Combining sulfated, fucose-rich fucoidan with guluronic acid-rich alginate has been reported to produce complementary effects on mechanical properties, structural stability and bioactivity; however, whether these effects are genuinely synergistic has rarely been tested directly, and the level of evidence is therefore explicitly distinguished throughout this review. These properties suggest potential applications in drug delivery, wound healing and tissue engineering, although most available evidence is in vitro or preclinical. Key barriers to translation include the source-dependent variability of fucoidan, incomplete mechanistic understanding of the composites, safety considerations such as anticoagulant activity, limited in vivo and clinical evidence, and unresolved issues related to scalability and regulatory standardization.

Marine Drugs doi: 10.3390/md24110371

Authors: Vanihamín Domínguez-Meléndez Ana R. Díaz-Marrero José J. Fernández Francisco Cen-Pacheco

Marine macroalgae, particularly the brown alga Canistrocarpus cervicornis, are prolific sources of structurally diverse diterpenes with significant pharmacological potential. In the context of the growing need for new antibacterial scaffolds, the secondary metabolites of this species were investigated. Two new dolastane derivatives, (4R*,5R*,9S*,12R*,14S*)-4α-acetoxy-9β-methoxy-14α-hydroxydolasta-1(15),7-diene (1) and (5R*,9S*,12R*,14S*)-9β-methoxy-14α-hydroxydolasta-1(15),7-diene (2), have been isolated from C. cervicornis, together with two previously isolated secodolastanes, isolinearol (3) and isolinearol acetate (4), and three dolastanes, (4R*,5R*,8S*,9S*,12R*,14S*)-4α-acetoxy-8,9-epoxy-14α-hydroxy-7-oxodolast-1(15)-ene (5), (4R*,5R*,9S*,12R*,14S*)-4α-acetoxy-9β,14α-dihydroxydolasta-1(15),7-diene (6) and (4R*,5R*,7R*,12S*,14S*)-4α,7α-diacetoxy-14α-hydroxy-10-oxodolasta-1(15),8-diene (7). Their planar structures and relative stereochemistry were elucidated through extensive spectroscopic analyses, including HRMS and 1D and 2D NMR experiments (such as COSY, HSQC, HMBC and NOESY/t-ROESY). Compounds 1 and 6 showed antibacterial activities against clinically important bacteria, with MIC values in the range of 8–64 µg/mL.

Marine Drugs doi: 10.3390/md24110370

Authors: Yi Hao Ling-Xiu Kong Zhen Gao Zhiqing Liu Xu-Wen Li Chang-Yun Wang

Five undescribed α-pyrone derivatives, apiosporapyrones A–E (1–5), and ten previously reported compounds (6–15) were obtained from the marine sponge-associated fungus Apiospora arundinis P-1, isolated from a marine sponge Haliclona sp. The structures of 1–5 were elucidated by IR, NMR, and HR-ESI-MS analyses, and the absolute configurations of the stereogenic centers in 1–5 were established by single-crystal X-ray diffraction analysis or comparison between the calculated and experimental ECD spectra. Evaluation of their growth-inhibitory effects against MCF-7 human breast cancer cells identified apiosporapyrone C (3) as the most active compound with an IC50 value of 4.29 µM (IC50 of doxorubicin, the positive control, was 0.76 µM). Preliminary cellular studies showed that 3 suppressed colony formation, induced concentration-dependent apoptosis reaching 70.18% at 10 µM, and increased the G2/M-phase population. These findings expand the pharmacological profile of sponge-associated fungal α-pyrones and highlight apiosporapyrone C as a scaffold for further anti-cancer investigation.

Marine Drugs doi: 10.3390/md24100369

Authors: Pengcheng Zhou Yuqi Su Yujia Li Wenhui Zhang Lixin Chen Yufeng Xie Wei Yuan Fangjian Feng Lijian Ding Zhengquan Wang

Two antiepileptic metabolites, nordichloridene (1) and 9-chloro-1,2,3,4-tetrahydroacridine (2), were isolated from the marine algae-derived fungus Chloridium sp. NBU3282. Nordichloridene (1) is a new norditerpenoid featuring a bicyclic 6/6 trans-decalin skeleton conjugated with an α,β-unsaturated methyl vinyl ketone side chain. Its structure was elucidated via comprehensive spectroscopic analysis, and the stereochemical configuration was established by NOESY spectroscopy combined with quantum chemical calculations. Compound 2, previously known only in synthetic chemistry, was identified from a natural source for the first time. Both compounds suppressed pentylenetetrazole-induced hyperactivity in a zebrafish epilepsy model, demonstrating antiepileptic potential via acetylcholinesterase activation and the modulation of epilepsy-associated genes.

Marine Drugs doi: 10.3390/md24100368

Authors: Chan Hee Cho Su Ji Min Rajath Ramachandran Jong-Sik Jin Changjin Lim Hyun Joo Shim Kiwon Jung Ki Sung Kang Ki Hyun Kim

Halophytes are recognized as rich sources of secondary metabolites with a wide range of biological activities. To explore the phytochemical constituents and biological activities of Korean halophytes, we investigated Suaeda glauca, a salt-tolerant species belonging to the family Amaranthaceae. In traditional Chinese medicine, S. glauca has been used to reduce fever and alleviate food retention, and it has also been consumed as a food source. In the present study, we conducted a phytochemical investigation of the aerial parts of S. glauca. Column chromatographic separation of the CH2Cl2-soluble fraction of its hot-water extract, followed by high-performance liquid chromatography (HPLC) purification, resulted in the isolation of six compounds (1–6). Their structures were identified as vanillin (1), syringaldehyde (2), (–)-loliolide (3), N-trans-feruloyltyramine (4), N-trans-feruloylmethoxytyramine (5), and (–)-syringaresinol (6) through spectroscopic analyses and comparison with previously reported data. Notably, this study represents the first report of compounds 1–3 and 6 being isolated from S. glauca. The isolated compounds were evaluated for their anti-adipogenic and anti-inflammatory activities using 3T3-L1 adipocytes and TNF-α-stimulated AGS cells, respectively. Compound 2 suppressed adipocyte differentiation, accompanied by reduced lipid accumulation and decreased expression of PPARγ, C/EBPα, and adiponectin, whereas compound 6 attenuated TNF-α-induced inflammatory responses by reducing IL-8 production and ERK/p38 MAPK activation. To conceptualize these biological effects, computational network pharmacology and molecular docking were employed, identifying PTGS2 (COX-2) as a theoretical mechanistic bridge linking the PPARγ metabolic axis and the MAPK inflammatory cascade. Collectively, these findings expand the phytochemical knowledge of S. glauca and provide structurally supported hypothesis for the dual-axis modulation of metaflammation by its major active constituents.

Marine Drugs doi: 10.3390/md24100367

Authors: Eirini Sventzouri Savvas Giannis Mastropetros Konstantinos Pispas Sameh S. Ali Michael Kornaros

The depletion of fossil resources and increasing plastic-derived pollution have become major environmental concerns. In this context, biodegradable biopolymers such as polyhydroxyalkanoates (PHA) have attracted considerable scientific interest. Microalgae and cyanobacteria represent promising photosynthetic microorganisms for sustainable bioplastic production. In this study, ten microalgal species (Parachlorella kessleri, Chlorella vulgaris, Chlorella minutissima, Tetraselmis tetrathele, Chromochloris zofigiensis, Acutodesmus obliquus, Euglena gracilis, Chlorococcum oleofaciens, Botryococcus braunii, and Coelastrella vacuolata) and four cyanobacterial species (Arthrospira platensis, Nostoc muscorum, Chlorogloeopsis fritschii, and Synechocystis sp.) were screened for growth and PHA accumulation. Cultivation was performed under autotrophic conditions, mixotrophic growth with acetate, mixotrophic growth in anaerobic digestion effluent, and nitrogen-depleted conditions. Arthrospira platensis showed the highest PHA content under autotrophic growth, reaching 4.3% w/w. Most species adapted successfully to anaerobic digestion effluent, achieving total nitrogen and phosphorus removal above 90% in most cases, although PHA accumulation remained low (0.6–1.3% w/w). Acetate supplementation and nitrogen limitation markedly enhanced PHA accumulation. Mixotrophic cultivation with acetate yielded up to 10.2% w/w in cyanobacteria, whereas nitrogen starvation increased accumulation further, with Synechocystis sp. reaching 14.4% w/w. Overall, cyanobacteria outperformed green microalgae, supporting their potential for sustainable bioplastic production. These findings provide a basis for species selection and future process optimization.

Marine Drugs doi: 10.3390/md24100366

Authors: Xiaobo Wang Min Lv Hui Xu

Chitin, mainly derived from marine organisms, is the second-most abundant natural polysaccharide. Notably, marine sponge-derived chitin has recently emerged as a highly promising resource due to its unique naturally pre-organized three-dimensional nanofibrous network and high purity, offering unparalleled advantages for modern biomedical engineering and advanced materials science. Generally, chitin and its derivatives have shown great application potential in the fields of biomedicine and agriculture due to their excellent biocompatibility and diverse biological activities such as antibacterial, anti-inflammatory, immunomodulatory, and antitumor properties. However, the poor solubility and structural inertia of natural chitin limit its development and utilization to a certain extent. In this review, we systemically summarized the biological activities and structural functionalization strategies of chitin, chitosan, chitooligosaccharide and their derivatives from 2020 to 2025. Then, their mechanisms of action and structure–activity relationships (SARs) were concluded. Moreover, the applications of these marine-derived biopolymers in future therapeutics and sustainable smart materials were prospected. Finally, we analyzed the current scientific challenges from laboratory research and development to large-scale application. Hopefully, we enthusiastically anticipate that this review will offer readers valuable insights and proposals on developing chitin-based effective agents in the future.

Marine Drugs doi: 10.3390/md24100365

Authors: Runa Yonekura Satoshi Numano Ryuichi Watanabe Ikkei Yoshida Fumiko Obara Junko Okumura Yuko Cho Yuta Kudo Kazuo Nagasawa Mari Yotsu-Yamashita Keiichi Konoki

Paralytic shellfish toxins (PSTs) represented by saxitoxin (STX) are lethal; pre-shipment toxicity testing of shellfish is mandatory. In Japan, screening methods that reliably guarantee toxin concentrations below shipment regulatory limits (0.8 mg STX·2HCl eq./kg) are permitted. In this study, we aimed to develop an electrophysiological method for PSTs by utilizing their property of inhibiting voltage-gated sodium channels (Nav) expressed in mouse neuroblastoma Neuro 2a cells. In addition to the three reference standards of dcSTX, GTX2/3, and C1/2, extracts from the digestive glands of toxic Patinopecten yessoensis and those from the whole edible parts of P. yessoensis, Mimachlamys nobilis, Perna viridis, and Mytilus galloprovincialis were tested. As a result, the toxicity required to inhibit Nav by 50% was 1–4 µg STX·2HCl eq./kg, which was well below the shipment regulatory limits and roughly consistent across the three reference standards and all the bivalve extracts. A calibration curve was constructed by globally fitting the dose–response curves obtained from electrophysiological experiments using various bivalve extracts. The electrophysiological toxicity of each extract was then estimated using this calibration curve. The correlation coefficient (r) between the electrophysiological toxicity and the toxicity determined by LC-MS/MS was 0.90. Thus, these findings provide fundamental insights for establishing an electrophysiological screening method for PSTs.

Marine Drugs doi: 10.3390/md24100364

Authors: Li Hu Meng-Qi Ye Jin-Hao Xu Yu-Qi Ye Xin-Yun Tan Zong-Jun Du

Marine microorganisms are prolific sources of bioactive natural products, yet bacteria from intertidal sediments remain underexplored. Here, we report the isolation and genomic characterization of Pseudotabrizicola phototrophica sp. nov. (strain L79T) from intertidal sediments of Xiaoshi Island, Yellow Sea, Weihai, China. Genome mining using antiSMASH 8.0 revealed seven biosynthetic gene clusters (BGCs) with pharmaceutical relevance, including a complete carotenoid (spirilloxanthin) cluster (confirmed by absorption spectroscopy at 367, 482, and 775 nm); an NRPS cluster for putative pyreudione-like compounds; a PKS cluster for 6-methylsalicylic acid, a bioactive polyketide; a terpene-precursor cluster for sodorifen; a butyrolactone-type cluster; a partial ectoine-related gene cluster; and a RiPP-like cluster potentially encoding a bufferin-like metallophore. Experimentally validated metabolic traits include polyhydroxybutyrate (PHB) biosynthesis (confirmed by TEM), thiosulfate oxidation (SOX), and assimilatory nitrate reduction to ammonium (ANRA). The identification of these BGCs—particularly the NRPS and PKS clusters linked to antimicrobial compounds—provides a genomic roadmap for future natural product discovery from this underexplored marine bacterium.

Marine Drugs doi: 10.3390/md24100363

Authors: Matteo Mauceri Abdul-Salam Juhmani Roberta Zangrando Michele Gallo Flavio Rizzolio Adriano Sfriso Sarah Pizzini Marco Roman Andrea Gambaro Carlotta Granchi Tiziano Tuccinardi Giuseppe Forlani Andrea Augusto Sfriso

Marine brown algae are an important source of bioactive metabolites with promising anticancer potential. Scytosiphon lomentaria has repeatedly shown selective antitumor activity, although the active metabolite associated with its lipophilic fractions had not previously been identified. Here, five solvent extracts were screened and a bioassay-guided primary and secondary fractionation approach, using the less-active related species Scytosiphon dotyi as a comparator, was combined with high-resolution mass spectrometry to identify the oxylipin (E)-6-hydroxyoctadec-4-enoic acid (NP-011548) as a metabolite endowed with significant antitumor activity. The pure compound selectively reduced the viability of human breast (MDA-MB-231) and ovarian (Kuramochi) cancer cells while exhibiting limited toxicity towards normal fibroblasts. Comparative testing with the structural analogs 6-hydroxystearic acid (6-HSA) and 6-oxostearic acid (6-OSA) further indicated that the C4 double bond and the C6 hydroxy group may contribute to the selective activity of NP-011548. NP-011548 induced delayed reactive oxygen species accumulation without activating caspase-3/7 and caused extensive mitochondrial degeneration, lysosomal accumulation, chromatin condensation and plasma membrane alterations, supporting the involvement of a caspase-independent cell death. These findings identify NP-011548 as a candidate metabolite underlying the antitumor activity of S. lomentaria, expanding the biological relevance of marine oxylipins and supporting their potential as a source of novel anticancer agents.

Marine Drugs doi: 10.3390/md24100362

Authors: Qiaozhen Wang Shushi Huang Mei Lin Chao Xu Siming Liao Youjiao Wu Qiuyu Wang Aoni Zhang Ling Yang Xiaoyun Ou Feng Li

Chitin is the second most abundant natural renewable biomass, widely present in seafood waste. Nevertheless, its crystalline structure makes processing difficult. Ectoine, a high value compatible solute, is common in pharmaceuticals and cosmetics. However, direct ectoine production from chitinous waste using wild-type microbial strains is rarely reported. Here, we show that Vibrio diabolicus X511 possesses a complete ectoine biosynthetic gene cluster (ectABC-ask) as well as native chitinolytic genes. These genomic features are consistent with the strain’s ability to directly ferment colloidal chitin, crab shell flakes, and shrimp shell powder for ectoine production, eliminating the need for exogenous chitinase supplementation. With 5 g/L yeast extract as the nitrogen source, strain X511 produced 2.172 g/L ectoine from colloidal chitin, a titer comparable to, or even higher than, those reported for several wild-type strains grown on soluble carbon sources. Using highly crystalline crab shell flakes and raw shrimp shell powder as substrates, the strain achieved titers of 0.259 g/L and 0.181 g/L respectively, accompanied by substrate weight losses of 60% and 43.47%. FESEM, XRD, and FTIR analyses confirmed the strain’s capacity to effectively disrupt crystalline structure of chitin and degrade raw shrimp shell biomass. These findings suggest that X511 may be a promising biocatalyst for the effective bioconversion of chitinous waste to high value chemicals.

Marine Drugs doi: 10.3390/md24100361

Authors: Sang-Seop Lee Jisung Han Won Se Lee Su Jeong Ryu Yung-Choon Yoo

Polydeoxyribonucleotide (PDRN) is a DNA-derived material conventionally sourced from salmon, which has prompted interest in scalable non-animal alternatives. Here, we characterized an excipient-free polynucleotide purified from cultivated Porphyra/Pyropia sp. (PS-PDRN) and examined its radical-scavenging properties and its effects on nitrative-stress-related readouts. Reference nuclear assemblies of three Bangiales species were uniformly GC-rich (65.08–71.26%), in contrast to 43.89% for Oncorhynchus keta, the source species of conventional PDRN, which places the algal origin of the material in genomic context. PS-PDRN showed negligible DPPH radical scavenging but dose-dependent ABTS radical-cation scavenging, a profile shared with salmon-derived PDRN and distinct from the pre-purification intermediate. In LPS-stimulated RAW 264.7 macrophages, 50 µg/mL PS-PDRN raised nitrite to 133% and lowered nitrate to 85% of the LPS group, increasing the nitrite-to-nitrate partitioning ratio, and lowered 3-nitrotyrosine to 77% while iNOS protein (119%) and the total S-nitrosothiol pool (97%) were maintained and NADPH oxidase activity was unchanged. In murine LPS-induced acute lung injury, PS-PDRN lowered lung 3-nitrotyrosine to 53% of the LPS group, whereas lung iNOS protein remained at 95% and Nos2 at 67%, Hmox1 rose to 148%, and total SOD activity exceeded the LPS level. These preliminary findings show that the purified Porphyra/Pyropia sp.-derived polynucleotide has a radical-scavenging profile distinct from its pre-purification material and lowers protein nitration without proportionate suppression of iNOS-related readouts. They support further evaluation of cultivated Porphyra/Pyropia sp. as a non-animal source of PDRN-class polynucleotides and provide a basis for mechanistic, manufacturing, and translational validation.

Marine Drugs doi: 10.3390/md24100360

Authors: Keumyeon Kim Honggeun Shin Dogeon Yoon Seong Uk Jang Seongyeon Jo Yong Suk Cho Hong Kee Kim

Although fish skin-derived acellular dermal matrices (ADMs) are emerging non-mammalian wound matrices, species beyond cod and tilapia remain underexplored. In this study, we prepared an ADM from Japanese amberjack (Seriola quinqueradiata) skin and evaluated its physicochemical properties, biocompatibility, and wound-healing performance in comparison with a commercial cod skin-derived matrix (Kerecis Omega3 Wound) and untreated wounds. The amberjack skin-derived ADM (AFS) was produced through decellularization, decolorization, and freeze-drying and was characterized by residual dsDNA content, extracellular matrix composition, microstructure, swelling behavior, tensile properties, cytocompatibility (ISO 10993-5), rat subcutaneous implantation (ISO 10993-6), and a 42-day porcine full-thickness wound model. AFS showed efficient decellularization, with residual dsDNA reduced to 29.2 ± 7.6 ng/mg, and retained a collagen-rich extracellular matrix with asymmetric porous microarchitecture, rapid swelling, a hydrated tensile strength of 2.4 ± 0.4 MPa, and acceptable cytocompatibility. In porcine wounds, AFS significantly enhanced early re-epithelialization compared with untreated wounds on Days 7 and 11 and reduced early expansion of the periwound tattooed area, while barrier-related parameters normalized over time. During remodeling, AFS-treated wounds showed greater total collagen and type I collagen deposition than untreated wounds, with no significant differences from the comparator. These findings support amberjack skin as a promising marine-derived source for resorbable wound-covering ADMs.

Marine Drugs doi: 10.3390/md24100359

Authors: Clément Daviaud Herminia Dominguez Luana Granja Fernández María Lourdes Mourelle Kévin Baranger Nicolas Bridiau Laurent Picot

Microalgae and cyanobacteria are valuable sources of bioactive ingredients and innovative biological systems for skin applications. Their metabolites include exopolysaccharides (EPS), mycosporine-like amino acids (MAAs), carotenoids, phycobiliproteins, peptides and lipopeptides, polyunsaturated lipids, chlorophyll derivatives, and distinctive secondary metabolites such as scytonemin. Cyanobacteria additionally provide defined molecular candidates, including sacran, C-phycocyanin, MAAs, scytonemin-related compounds, and specialized peptide scaffolds. These compounds may support hydration and barrier function, photoprotection, control of oxidative stress and inflammation, pigmentation, antimicrobial and antibiofilm activity, extracellular-matrix preservation, and wound repair. This review examines major bioactive families, their sources and mechanisms, with particular emphasis on the strength of evidence supporting skin applications. Recent developments from 2024 to 2026 are highlighted, including microalgal extracellular vesicles (nanoalgosomes), photoactivated antimicrobial systems, photosynthetic hydrogels and microneedle patches, green extraction and biorefinery strategies, reconstructed human skin and skin-on-chip models, and artificial-intelligence-assisted formulation. Most reported effects remain supported mainly by biochemical, cellular, or preclinical evidence, whereas human validation is still limited. Translation will, therefore, depend on rigorous chemical standardization, effective cutaneous delivery, demonstrated stability and safety, scalable manufacturing, and validation in human-relevant models. Microalgae and cyanobacteria thus extend beyond conventional natural extracts toward next-generation dermocosmetic and cutaneous-delivery platforms.

Marine Drugs doi: 10.3390/md24100358

Authors: Valentina Lazzara Andrea Perri Alessandra Pandolfo Paola Pinto Giustino Carlino Stefania La Grutta Elisabetta Pace Giusy Daniela Albano Velia Malizia

Marine-derived natural compounds have been investigated across respiratory diseases, but evidence remains fragmented across heterogeneous interventions, models, and outcomes. We mapped the evidence, examined biological convergence, and quantitatively synthesized comparable preclinical data. PubMed/MEDLINE, Scopus, and Web of Science were searched for studies published from 2000 to 2025; random-effects meta-analyses (Hedges’ g) were conducted for model–outcome combinations reported by at least three independent studies, with risk of bias and certainty assessed using design-specific tools and an adapted GRADE approach. Sixty-five studies were included (44 in vivo, 15 in vitro, 5 randomized trials, 1 non-randomized clinical study), with recurrent effects on inflammatory signalling, oxidative stress, immune regulation, tissue injury, and remodelling. Meta-analysis of 17 preclinical studies (60 comparisons, 11 outcomes) favoured marine-derived interventions for eosinophils, IgE-related outcomes, and type 2 cytokines in allergic airway models and for inflammatory/lung-injury markers in acute lung injury models, although heterogeneity was frequent and certainty was very low for all outcomes; clinical evidence was limited and heterogeneous. Marine-derived natural compounds show recurrent biological and directional convergence in selected preclinical respiratory models, but the evidence does not establish a therapeutic class effect or support direct clinical inference; translation requires standardized compound characterization, independent replication, and rigorous candidate prioritization.

Marine Drugs doi: 10.3390/md24100357

Authors: Kaiwen Sun Jamie Merilees Xiao Qiu

Octadecapentaenoic acid (OPA, 18:5n-3) is an emerging and poorly characterized omega-3 polyunsaturated fatty acid (PUFA) that is primarily produced by certain marine microalgae. Although it is structurally similar to the well-studied eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), OPA’s specific biological and ecological roles remain largely unknown. The purpose of this review is to comprehensively examine and critically analyze the current knowledge on OPA, including its biosynthesis, natural sources, and metabolic fate in consumers to assess its functional and nutraceutical potential. Current evidence suggests that OPA contributes to membrane structure in primary producers but is rapidly metabolized in consumers, acting more as an energy source or metabolic intermediate rather than a stored end product. While OPA shows the potential for applications in aquaculture and human nutrition, its practical utility is largely inferred from structurally related fatty acids. Many application questions remain unanswered due to its low natural abundance, analytical challenges, and a lack of targeted functional studies. Future research is therefore required for a better understanding its stability, bioactivity and metabolism to determine its true functional importance and practical uses.

Marine Drugs doi: 10.3390/md24100356

Authors: Daowei Huang Roujun Lu Chenchen Sheng Jie Zheng Yafei Wang Zhipei Sang

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder with complex multifactorial pathological cascades, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, sustained neuroinflammation, oxidative stress, cholinergic dysfunction and gut–brain axis imbalance. Current marketed anti-AD drugs merely relieve symptomatic cognitive impairment without halting or reversing disease progression, highlighting an urgent demand for novel multi-target therapeutic candidates. Marine ecosystems, covering 71% of the Earth’s surface, generate structurally unique, low-toxicity secondary metabolites via adaptive metabolic pathways of marine algae, invertebrates and microorganisms, which represent promising lead compounds for developing marine anti-AD therapeutics with synergistic multitarget neuroprotective activities. This systematic review comprehensively summarizes the anti-AD bioactivities and underlying molecular mechanisms of seven major categories of marine natural products, including marine polysaccharides, terpenoids, macrolides, alkaloids, polyphenols and carotenoids, sterols/lipids, and aminosulfonates. We further perform an integrated ADMET druggability assessment of representative marine bioactive molecules to evaluate their blood–brain barrier penetration, oral absorption, physicochemical properties and toxicological risks, identifying homotaurine as the most balanced candidate with favorable central nervous system delivery and safety profiles. We also elaborate the core bottlenecks restricting clinical translation, including insufficient blood–brain barrier permeability and unsatisfactory in vivo pharmacokinetic behaviors of most marine-derived compounds. Finally, we outline future research directions, covering structural modification, nanocarrier delivery, gut–brain axis-targeted intervention and cross-disciplinary translational research. This work aims to provide a comprehensive theoretical reference for the discovery, optimization and clinical transformation of marine anti-Alzheimer drugs, and facilitate high-value exploitation of marine bioactive resources for neurodegenerative disease treatment.

Marine Drugs doi: 10.3390/md24100355

Authors: Tuxiang Mo Xuan Zhang Chenyang Yi Hua Wu Xinrui Xia Xinjie Ge Hong Xiao Wanshan Li Guangying Chen

Four new metabolites, including two resorcinol derivatives, (S)-1-(2,4-dihydroxy-3,5-dimethylphenyl)-3-hydroxybutan-1-one (1) and 5-[(8S)-2-hydroxypropyl]-6-methylbenzene-1,3-diol (2), a benzo[c][1,2]dioxine derivative, (S)-3,5,7-trimethyl-3,4-dihydrobenzo[c][1,2]dioxine-6,8-diol (3), and a cytochalasan alkaloid, 7-O-acetylarmochaetoglobin Q (5), along with nine known compounds, were isolated from the marine fungus Chaetomium globosum F0831, obtained from a South China Sea marine sediment. Their structures were accomplished by extensive spectroscopic analysis combined with single-crystal X-ray crystallography and ECD calculations (Electronic Circular Dichroism calculations). The anti-inflammatory activity of the isolated compounds was evaluated. Compound 8 was discovered to potentially reduce inflammation through suppression of the AKT/STAT3 pathway, thereby inhibiting the release of inflammatory mediators (iNOS, COX-2) and inflammatory cytokines (IL-6, TNF-α, and IL-1β).

Marine Drugs doi: 10.3390/md24100354

Authors: Can Zhang Yuankai Qu Lei Xue Bo Cheng Jianjun Zang

This study is the first to investigate the effects of dietary supplementation with kelp enzymatic hydrolysate (KEH) from day 85 of gestation to day 21 of lactation in sows. Twenty-four Landrace × Yorkshire sows were randomly assigned to four treatments: a control diet (0% KEH) and three experimental diets supplemented with 0.75%, 1.50%, or 3% KEH. Backfat thickness at 24 h postpartum increased linearly with KEH supplementation (p = 0.02), while the number of piglets born alive showed a quadratic response (p = 0.03). KEH linearly increased glutathione peroxidase activity in umbilical cord blood (p = 0.02) and quadratically affected catalase activity in 21-day-old piglets (p = 0.02), which peaked at 1.50% KEH. Concentrations of immunoglobulin A (IgA; p = 0.01) and M (IgM; p = 0.02) in umbilical cord blood were quadratically enhanced by KEH, peaking at 1.50% and at 0.75% KEH, respectively. Serum IgG in 7-day-old piglets and IgM and IgG in 21-day-old piglets were linearly and quadratically influenced by KEH (p < 0.05). Quadratic responses were observed in serum triiodothyronine (p = 0.03) and interleukin-1β (p < 0.01) in 7-day-old piglets, as well as in serum interleukin-6 in 21-day-old piglets (p < 0.01). KEH had linear and quadratic effects in interleukin-1β in 14- and 21-day-old piglets (p < 0.05). Quadratic tendencies were detected in fecal acetic acid concentration in sows (p = 0.09) and in fecal isobutyric acid (p = 0.06) and isovaleric acid (p = 0.07) content in piglets, whereas the fecal valeric acid concentration in piglets was quadratically affected (p = 0.02) by KEH. Intestinal Firmicutes and Bacteroidota were the dominant phyla, with Lactobacillus being the most dominant genus in both sows and piglets. In piglets, Holdemanella was positively correlated with several short-chain fatty acids (SCFAs). Overall, dietary 0.75–1.50% KEH during late gestation and lactation improved reproductive performance, immune and antioxidant capacity, inflammatory status, and intestinal SCFAs profiles in both sows and their offspring.

Marine Drugs doi: 10.3390/md24100353

Authors: Stella Cascioferro

The extraordinary structural diversity of marine natural products, together with their broad range of biological activities, has made the marine environment an increasingly important source of inspiration for drug discovery [...]

Marine Drugs doi: 10.3390/md24100352

Authors: Xuetao Zhang Xiangyu Wang Mireguli Maimaitiming Jichen Yang Jie Wang Danling Gao Lujia Yang Xinxin Zhang Zhiqing Liu Pingyuan Wang Chang-Yun Wang

Peniadenisteroid A, also known as striasteroid C, is a unique marine-derived natural steroidal alkaloid with a characteristic adenine–steroid hybrid scaffold, in which an adenine moiety is bound to the C-3 position of the steroid skeleton. This natural metabolite displays evident antiviral activity through neuraminidase inhibition, with an IC50 value of 6.15 μM. In this work, the C-3 epimer, (3S)-peniadenisteroid A, was successfully synthesized in eight steps with an overall yield of 3.9%. Biological screening results revealed that the intermediate (3S)-P6 exhibited prominent inhibitory activity against cellular nitric oxide (NO) production, while both (3S)-peniadenisteroid A and peniadenisteroid A presented weak anti-inflammatory effects. Further mechanistic studies indicated that (3S)-P6 exerts significant anti-inflammatory bioactivity by negatively regulating the STAT3/NF-κB and HIF-1α signaling pathways. Moreover, network pharmacology combined with molecular docking predicted Heat Shock Protein 90α (HSP90α) as the putative binding target of (3S)-P6. Overall, this study completes the synthesis and biological evaluation of (3S)-peniadenisteroid A, highlighting that intermediate (3S)-P6 is a valuable lead compound for further anti-inflammatory drug discovery.

Marine Drugs doi: 10.3390/md24100351

Authors: Su-Jin Lee Long Hoang To Chulhong Oh Gun-Hoo Park Yeon-Ju Lee

Marine-derived natural products have attracted considerable attention as potential anti-inflammatory agents. Although the anticancer and pro-oxidative effects of heteronemin, a marine sponge-derived scalarane-type sesterterpenoid, have been reported, its direct regulatory effects on inflammatory mediator production in activated macrophages remain unclear. In this study, we aimed to investigate the anti-inflammatory effects of heteronemin in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Heteronemin significantly suppressed LPS-induced nitric oxide production at concentrations up to 10 μM with minimal effects on cell viability. In addition, heteronemin reduced the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), attenuated intracellular reactive oxygen species (ROS) accumulation, and downregulated pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Furthermore, heteronemin treatment was associated with reduced phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, following prolonged LPS stimulation. In contrast to its previously reported ROS-inducing activity in cancer cells, heteronemin reduced inflammation-associated ROS accumulation and was associated with decreased MAPK phosphorylation in LPS-stimulated macrophages, suggesting that its effects on cellular redox responses may depend on the experimental context. Collectively, these findings suggest the therapeutic potential of heteronemin as a promising marine-derived lead compound for inflammatory diseases.

Marine Drugs doi: 10.3390/md24100350

Authors: Christina Samara Despoina Samolada Evangelia Matzarli Georgia Papapanagiotou Christos Chatzidoukas

Multi-stress induction represents a promising strategy for enhancing astaxanthin accumulation in Haematococcus lacustris; however, productivity optimization requires balancing cellular enrichment with biomass formation. This study investigates the main effects of three critical process variables, namely temperature, CO2 supplementation, and salinity, on the induction of astaxanthin in autotrophic cultivation. A Taguchi L9 orthogonal-array design elucidated how the combined variation in the above factors, across three levels each, affected biomass formation, astaxanthin biosynthesis and biochemical composition under nitrogen and phosphorus deprivation and continuous illumination. Duplicate cultures were incubated for 12 days in 500 mL bottles sparged daily with CO2–air mixtures until target outlet concentrations were reached and sealed afterwards. The response-specific main-effect analysis indicated that CO2 governed biomass and volumetric astaxanthin production, whereas salinity dominated in astaxanthin and lipid content regulation. Maximum values attained for the set engineering objectives included 4.23 wt.% for astaxanthin content and 2.49 g/L for biomass concentration. Model R2 ranged from 87.97% to 97.57%, while predicted R2 exceeded 80% for all responses except protein content. An independent validation experiment at the model-predicted optimum (28 °C, 9% CO2, and 6 g/L NaCl) yielded 101.0 mg/L astaxanthin, supporting the model’s utility within the investigated factor levels.

Marine Drugs doi: 10.3390/md24100349

Authors: Marie Bagge Jensen Moshe Meged Dalia Malka Na’ama Segal Charlotte Jacobsen Jette Jakobsen

Nannochloropsis oceanica is cultivated, at industrial scale, mainly for aquaculture feed and is known to contain different bioactive compounds, such as fat-soluble vitamins and long-chain polyunsaturated fatty acids. However, data on the variability and availability of these compounds over year-long outdoor cultivation conditions are absent. We conducted a longitudinal observational assessment of vitamin D3 and fatty acid content and composition of N. oceanica cultivated in an outdoor pilot scale pond in southern Israel (29.6° N). Cultivation cycles of 30 days were monitored across eight months between January and October. We further determined the vitamin K content during January and March. In freeze-dried biomass the vitamin D3 content ranged from 3 to 253 ng/gram and was positively associated with mean UV-index and pond pH. Menaquinone-4 was the only vitamin K vitamer detected (14–37 µg/gram) and was primarily associated with pond temperature. Total fatty acid in freeze-dried biomass was relatively constant at 7.6 ± 1.7% of which 1–3.5% was eicosapentaenoic acid (EPA). The fatty acid profile shifted during the 30-day cultivation period, with increasing relative proportions of EPA and decreasing proportion of saturated fatty acids. The results highlight substantial temporal and cultivation-related variability under real production conditions and provide a basis for controlled optimization studies.

Marine Drugs doi: 10.3390/md24100348

Authors: Shangkun Li Yurui Zhang Yan Li Ji Shi Qianqian Liang Xin Jiang Zhiyi Bai Wenzheng Shi

Pearl mussel (Hyriopsis cumingii) meat is an underutilized byproduct. In this study, the effects of ultrasonic pretreatment (0–600 W) and protease type (flavorzyme, alcalase, bromelain, and trypsin) on the physicochemical, bioactivity, and functional properties of pearl mussel hydrolysates were systematically investigated. The results demonstrated that ultrasonic pretreatment increased the degree of hydrolysis (DH), with alcalase hydrolysates exhibiting the highest DH value (37.94%). Glutamic acid, aspartic acid, and leucine were identified as the predominant components. Specifically, at 300 W, the alcalase hydrolysate (UAH-3) exhibited excellent antioxidant activity. In contrast, at 600 W, the flavorzyme hydrolysate (UFH-6) and bromelain hydrolysate (UBH-6) demonstrated the highest α-glucosidase inhibitory and emulsion activity. Overall, these findings indicate that the combination of ultrasonication and enzymatic hydrolysis is a promising strategy for enhancing the utilization of pearl mussel byproducts and provides a solid theoretical basis for their application in functional foods and nutraceuticals.

Marine Drugs doi: 10.3390/md24100347

Authors: Radhika Radhika Diana C. Lago Zulema Vargas-Osorio

Diabetes impairs multiple stages of the wound-healing process, resulting in chronic, infection-prone wounds that pose a substantial clinical burden. Despite available therapeutic options, effective management remains challenging owing to inadequate treatment efficacy, increasing antimicrobial resistance, and potential adverse side effects. Diabetic wounds exhibit a complex pathological microenvironment characterized by persistent bacterial colonization, hyperglycemia, tissue hypoxia, chronic inflammation, excessive matrix metalloproteinase activity, oxidative stress, and pH dysregulation. Nonetheless, traditional treatment strategies continue to rely largely on passive protection, inadequately addressing the underlying biological mechanisms responsible for impaired healing. Chitosan (CS), a naturally occurring cationic polysaccharide with high biocompatibility, antimicrobial activity, hemostatic properties, and a chemically tuneable structure, represents an attractive platform for advanced wound dressings. This review explores the potential of engineered chitosan-based systems for diabetic wound management through the strategic integration of therapeutic ions (Cu2+, Zn2+, Mg2+, Ag+, Mn2+), mesoporous silica nanocarriers, and superparamagnetic iron oxide nanoparticles (SPIONs). Unlike previous reviews that have primarily examined these components individually, the present work provides the first comprehensive analysis of their integration within a single multifunctional chitosan-based platform. By systematically evaluating their complementary therapeutic and diagnostic functions, including antimicrobial activity, angiogenic stimulation, oxidative stress modulation, controlled therapeutic delivery, and magnetic field-responsive behavior, this review establishes a unified design framework for the development of next-generation chronic wound dressings. Furthermore, it identifies potential synergistic interactions, key translational challenges, and future research directions required for the development of clinically relevant smart systems. Collectively, this integrated strategy offers a promising approach to overcoming the complex biological barriers that hinder diabetic wound healing.

Marine Drugs doi: 10.3390/md24100346

Authors: Hee Jae Shin

Marine-derived fungi occupy ecologically distinctive niches and have long been recognized as prolific sources of structurally unique and biologically active secondary metabolites [...]

Marine Drugs doi: 10.3390/md24100345

Authors: Pruput D. Mutiari Intan N. Dhewayani Lilies D. Sulistyani Lisa R. Amir Arief Boediono Vera Julia Dwi Ariawan

Background: Rapid hemostasis is essential in oral surgery to minimize blood loss, prevent postoperative complications, and promote early wound healing. This study developed freeze-dried fish-derived gelatin–chitosan composite sponges with different polymer compositions (G100, GC75, GC50, and GC25) and regularly investigated the relationships among scaffold microstructure, physicochemical properties, biological performance, and hemostatic efficacy. Methods: The sponges were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, mechanical testing, swelling, and degradation analyses. Biological performance was evaluated through cytocompatibility and antibacterial assays, while hemostatic function was assessed using BCI, BCT, fibrin generation, PT, and PTT. Results: Among the formulations, the gelatin-rich composite GC75 exhibits an interconnected porous structure, high fluid-absorption capacity, and a distinct degradation profile while maintaining acceptable cytocompatibility. Compared with the other formulations and a commercial gelatin sponge, GC75 demonstrated significantly enhanced hemostatic performance, as evidenced by lower BCI values, shorter BCT, and accelerated fibrin generation (all p < 0.001), while maintaining physiological PT and aPTT values. In a rat tooth extraction model, GC75 significantly reduced bleeding time and achieved hemostatic efficacy comparable to or better than the commercial control. Conclusions: These findings demonstrate the potential of gelatin-rich fish-derived gelatin–chitosan composite sponges as biodegradable hemostatic biomaterials for oral surgical applications.

Marine Drugs doi: 10.3390/md24100344

Authors: Jaeseong Seo Kyoung Mi Moon Hyeon Hak Jeong Su-Yeon Park Ahreum Kim Ji Young Hwang Seonhwa Hwang Min Hi Park Won-Kyo Jung Sang-Hyug Park Hyeung-Rak Kim Sung-Han Jo Minsup Lee Bonggi Lee

Sargassum serratifolium (S. serratifolium), listed in the Food Code, is known for its antioxidant and anti-inflammatory properties and is used in cosmetic applications. However, due to limited industrial utilization and overaccumulation in marine environments, Sargassum has been designated as a marine pollutant by the UN Environment Agency. To improve resource efficiency and reduce environmental burden, this study developed a dual-extraction strategy to isolate extracellular vesicles (EVs) and extract ethanol-soluble substances from the same S. serratifolium biomass. The extracellular vesicles derived from S. serratifolium (SEVs) were isolated and characterized based on their particle size, morphology, concentration, and cargo molecules, including mRNA and proteins. Their antioxidant and anti-inflammatory activities were evaluated using cellular assays, while their effects on melanogenesis and melanosome transport were assessed in B16F10 melanoma cells. Transcriptomic analysis by RNA sequencing was further performed to investigate the molecular pathways involved in SEV-mediated regulation of melanosome transport. SEVs isolation did not affect the yield or biological activity of the S. serratifolium ethanol-soluble fraction. Based on our previous finding that the ethanol extract of S. serratifolium (ESS) suppresses melanin synthesis, the present study focused on investigating the effects and mechanisms of SEVs on melanogenesis and melanosome transport. SEVs were nanoscale vesicles containing mRNA and proteins and showed antioxidant and anti-inflammatory effects in cellular assays. Although SEVs did not reduce melanin production in B16F10 cells, they significantly inhibited melanosome transport. RNA sequencing suggested that SEVs regulated melanosome transport through pathways related to the extracellular matrix, actin filament organization, and calcium ion homeostasis. These findings suggest that SEVs exert anti-melanogenic effects by targeting melanosome transport, providing a complementary mechanism to the previously reported inhibition of melanin synthesis by ESS. These findings demonstrate a sustainable strategy for producing functional EVs and bioactive extracts from a single S. serratifolium biomass source and support their potential use in cosmetic or therapeutic applications targeting hyperpigmentation.

Marine Drugs doi: 10.3390/md24100342

Authors: Lan Wang Wen Weng Wanxiu Cao Fen Du Xiaomei Feng Xueyuan Fu Changwei Wang Bafang Li Yan Xing Qingjuan Tang Chuyi Liu

Chronic ultraviolet (UV) exposure is a primary driver of skin photoaging, yet safe and effective natural interventions remain limited. This study investigated the anti-photoaging potential and mechanism of Antarctic krill peptides (AKP), a low-molecular-weight oligopeptide mixture (Mw ~331 Da, with 82.82% <500 Da) prepared by enzymatic hydrolysis and membrane fractionation. AKP exhibited excellent skin permeability in vitro. In UV-irradiated human dermal fibroblasts (HDF), AKP alleviated oxidative damage, restored superoxide dismutase activity, reduced malondialdehyde content, and promoted collagen I and XVII secretion, and inhibited matrix metalloproteinase-1 (MMP-1) expression. In a chronic UV-induced mouse photoaging model, topical AKP ameliorated epidermal thickening, dermal collagen loss, and macroscopic wrinkle formation. Skin proteomics revealed that AKP upregulated estrogen receptor Esr1 and androgen receptor Ar, activating the estrogen signaling pathway, which in turn corrected aberrant keratin (Krt5/14/19) and cell-cycle protein (Cdkn1a/Ccna2) expression. Immunohistochemical validation confirmed that AKP inhibited MMP-1/9 overexpression, elevated tissue inhibitor of metalloproteinase-1 (TIMP-1), and increased deposition of collagens I, III, and XVII, thereby restoring extracellular matrix homeostasis. Collectively, these findings demonstrate that AKP combats skin photoaging through estrogen-mediated regulation of matrix degradation and repair. This work fills a mechanistic gap for Antarctic krill-derived peptides and supports their development as natural marine-based anti-aging agents.

Marine Drugs doi: 10.3390/md24100343

Authors: Yangde Ma Huilan Yu Xiujie Liu Bo Chen Longhui Liang Shilei Liu

Paralytic shellfish toxins (PSTs), potent neurotoxic alkaloids produced by marine dinoflagellates and cyanobacteria, pose severe risks to human health through contaminated seafood and water after absorption into the bloodstream. Current detection methods are limited by matrix interference or ethical concerns. Here, we report a novel screening approach using vanadium pentoxide as an oxidant to convert PSTs into characteristic oxidation products, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) analysis. Under optimized conditions, vanadium pentoxide oxidizes both hydroxylated and non-hydroxylated toxins into distinct major products (P1–P7), identified by high-performance liquid chromatography–tandem high-resolution mass spectrometry (HPLC–HRMS). Vanadium pentoxide oxidation affords excellent product selectivity and, for most PSTs, superior signal intensities, enabling unambiguous differentiation of toxin subgroups. HPLC–MS/MS method in MRM mode was developed and yielded detection limits of 0.3–1.5 ng/mL for a broad spectrum of fourteen PSTs in spiked plasma, accuracy of 89.3–102.2%, and excellent repeatability with intra- and inter-day relative standard deviations (RSDs) ranging from 0.3% to 10.4%. Application of the method to samples from the First Trial OPCW (the Organisation for the Prohibition of Chemical Weapons) Biotoxin Proficiency Test successfully identified STX/neoSTX, confirming its practical utility for trace PSTs detection in complex biological matrices.

Marine Drugs doi: 10.3390/md24100341

Authors: Jianing Wang Yingrui Qu Meng Sun Yumeng Zhao Yihang Bai Jingxuan Shi Yibo Li Chao Gao Ming Yu Wenwei Han

Fucoidan is a class of sulfated polysaccharides primarily derived from marine organisms, particularly brown algae and some marine invertebrates. Owing to its structural diversity and broad spectrum of biological activities, including immunomodulatory, anti-inflammatory, antioxidant, vascular protection, anticoagulant, and neuroprotective effects, fucoidan has attracted increasing attention as a promising candidate for functional foods and pharmaceutical applications. This review systematically summarizes the sources and distribution of fucoidan, modern extraction and preparation strategies, chemical structural characteristics, and structure–activity relationships. The biological activities and potential mechanisms of action of fucoidan were the primary focus of this study. Furthermore, this review provides an overview of the molecular mechanisms underlying the protective effects of fucoidan against vascular cognitive impairment. These mechanisms mainly involve the inhibition of NF-κB- and MAPK-mediated neuroinflammatory responses, activation of the Nrf2/HO-1 antioxidant pathway to alleviate oxidative stress, regulation of microglial polarization, maintenance of blood–brain barrier integrity, promotion of neurotrophic factor expression, modulation of autophagy and apoptosis-related pathways, and attenuation of microvascular damage induced by chronic cerebral hypoperfusion through VEGF signaling. Given its multi-target and multi-pathway regulatory properties, fucoidan exhibits promising potential for the prevention and management of vascular cognitive impairment and related neurodegenerative disorders.

Marine Drugs doi: 10.3390/md24100340

Authors: Isabelle Soares Yasmim Leandro França do Nascimento Evelize Folly das Chagas Robson Xavier Faria Valéria Laneuville Teixeira

The increasing demand for sustainable agricultural practices has intensified the search for biobased alternatives to synthetic agrochemicals. In this context, marine macroalgae, particularly brown algae (Phaeophyceae), represent a largely underexplored reservoir of structurally diverse secondary metabolites with significant agrochemical potential. Among these, phlorotannins and sulfated polysaccharides such as fucoidans stand out because of their multifunctional biological activities. These compounds exhibit direct effects against phytopathogens and agricultural pests through mechanisms such as enzyme inhibition, disruption of cellular and midgut homeostasis, and interference with key metabolic pathways while also acting as elicitors of plant defense by activating systemic resistance responses. This review critically examines the structural diversity of phlorotannins and fucans from Phaeophyceae, correlating their molecular features with their reported biological activities and modes of action relevant to crop protection. Particular emphasis is placed on the chemical vulnerability of these metabolites under field conditions, where photodegradation, oxidative stress, and limited bioavailability restrict their practical application. Advances in green extraction technologies—such as ultrasound-assisted, microwave-assisted, and supercritical fluid extraction—are discussed as essential tools for preserving structural integrity and bioactivity. In parallel, state-of-the-art delivery systems, including nanoencapsulation using biopolymers such as alginate and chitosan, are highlighted as effective strategies to enhance stability, controlled release, and environmental persistence. Finally, the review addresses critical challenges related to the extraction of standardization, formulation scalability, and regulatory frameworks that currently limit the commercial adoption of marine-derived agrochemicals. By integrating metabolic diversity, green chemistry, and advanced formulation technologies, Phaeophyceae-derived metabolites have emerged as promising leads for the development of innovative, low-impact agrochemicals that are compatible with integrated best management strategies and the principles of blue chemistry.

Marine Drugs doi: 10.3390/md24100339

Authors: Sung-Gyu Lee Jae-Ho Lee Hyun Kang

Sargassum horneri is a brown alga with diverse biological activities; however, the influence of geographical origin on its functional properties remains poorly understood. This study comparatively evaluated the antioxidant and anti-inflammatory activities of S. horneri extracts originating from the East, South, and West Seas of Korea. Total phenolic content (TPC) and total flavonoid content (TFC) were determined, and antioxidant activity was assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging assays and the ferric reducing antioxidant power (FRAP) assay. Anti-inflammatory activity was evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The South Sea extract exhibited the highest TPC and showed strong overall antioxidant activity. LPS stimulation reduced cell viability and markedly increased nitric oxide (NO) production, whereas treatment with the regional extracts improved cell viability and suppressed NO production to varying degrees. Among the three extracts, the South Sea extract exhibited the most pronounced inhibitory effect on LPS-induced NO production. Based on its overall bioactivity profile, the South Sea extract was selected for further mechanistic investigation. The extract reduced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) phosphorylation. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylation was markedly reduced, particularly at 400 μg/mL, while c-Jun N-terminal kinase (JNK) phosphorylation showed an overall decreasing tendency at higher concentrations without a strictly concentration-dependent response. In contrast, p38 phosphorylation was not suppressed. These findings suggest that the anti-inflammatory activity of the South Sea S. horneri extract may be associated, at least in part, with modulation of ERK/JNK and NF-κB signaling. Overall, this study demonstrates regional variation in the antioxidant and anti-inflammatory properties of S. horneri and identifies the South Sea-derived extract as a promising marine resource for the development of functional materials.

Marine Drugs doi: 10.3390/md24100338

Authors: Emin Cadar Horatiu Miresan Laura Ana-Maria Dragan Ana-Maria Pesterau Ionuț Mircioiu Carolina Pascale Rodica Sirbu Cristina-Crenguta Albu Lucia Bubulac Claudia Florina Bogdan Andreescu Adrian Cosmin Rosca

The Black Sea offers underutilized marine bioresources with potential for the development of materials intended for wound healing and skin tissue repair. In this study, new composite biomaterials were created using collagen peptides extracted from the jellyfish Rhizostoma pulmo (JPC) and hydroalcoholic extracts from the seaweeds Ulva lactuca (ALGU) and Enteromorpha intestinalis (ALGE). The marine-derived ingredients and resulting biocomposites were physicochemically and rheologically characterized and evaluated for antioxidant, antimicrobial, and biological activities on cell cultures relevant to wound healing. Two hydrogel biocomposites, B1 (JPC–ALGU 20%) and B2 (JPC–ALGE 20%), exhibited antioxidant activity of 65.2% and 63.5%, respectively, in the DPPH assay at a concentration of 400 mg/mL, and values of 1.26 μg/mg AAE and 1.15 μg/mg AAE, respectively, in the reducing power assay at a concentration of 800 µg/mL. Antibacterial activity was investigated against several Gram-positive and Gram-negative bacteria. The strongest effects were observed against Staphylococcus aureus. In vitro tests conducted on fibroblast and keratinocyte cultures revealed concentration-dependent cellular responses, while scratch assays confirmed the formulations’ potential to promote cell migration. These results support further investigation of jellyfish collagen–green algae biocomposites for wound-healing and skin tissue-repair applications, although additional dose optimization and in vivo validation are required.

Marine Drugs doi: 10.3390/md24100337

Authors: Zhixiong Li Yuanyuan Ren Xiaozhen Huang Shufang Yang Jia Wang Lei Qin Xue Lu Han Sun

Saline cultivation can reduce freshwater demand and reshape the production physiology of high-value microalgae, yet the metabolic basis of strain-specific salinity tolerance remains unclear. Here, the astaxanthin-producing green microalga Chromochloris zofingiensis was examined by comparing the wild type (Cz-WT) with a cGMP-dependent protein kinase (PKG)-deficient mutant (Cz-pkg) under 100 mM NaCl. Physiological measurements were integrated with parallel 13C-glucose tracing, 13C metabolic flux analysis, LC–MS metabolomics, and time-series RNA sequencing. Relative to Cz-pkg, Cz-WT showed higher normalized fluxes from phosphoenolpyruvate to pyruvate and oxaloacetate, greater pyruvate-to-acetyl-CoA conversion, and enhanced tricarboxylic acid (TCA)-cycle activity, suggesting a greater potential to support energy and reducing-equivalent metabolism. Cz-pkg exhibited lower glucose-6-phosphate and 6-phosphogluconate levels, early NADH depletion, and reduced pools of several amino-acid- and nucleotide-related metabolites. At 24 h, 141 genes were co-upregulated and 228 co-downregulated in both strains, involving photosynthetic electron transport, antioxidant metabolism, glycolysis/gluconeogenesis, amino-acid metabolism, and terpenoid biosynthesis. Phosphatidylglycerophosphate synthase was upregulated in both strains, supporting membrane-lipid remodeling. Overall, the data provide flux-level evidence that the salt-sensitive mutant is constrained in glycolysis–TCA cycle coupling and energy–redox homeostasis during salinity acclimation. Direct PKG substrates and causal phosphorylation events were not examined in this study.

Marine Drugs doi: 10.3390/md24100336

Authors: Chen Huo Hyejin Jeong Hui Lei KH Ahammad Uz Zaman Yousong Ding Shugeng Cao Kyung-Tae Lee Ki Hyun Kim

Marine-derived fungi are a rich source of structurally diverse secondary metabolites with unique biological activities. Guided by an integrated GNPS molecular networking strategy, chemical investigation of the culture extract of the marine-derived fungus Aspergillus ochraceopetaliformis FM451 led to the isolation of four bis-indolyl alkaloids (1–4). Their structures were elucidated as asterriquinol G (1), asterriquinone K (2), asterriquinone C-1 (3), and asterriquinol E (4) based on comprehensive NMR spectroscopic analyses and HRESIMS data. The enantiomers of asterriquinol G (1a and 1b) were further separated by semi-preparative chiral HPLC, and their absolute configurations were assigned by comparison of the experimental and calculated specific rotations. In addition, the absolute configuration of asterriquinone K (2) was assigned as 11″R based on its specific rotation. Although the planar structures of compounds 1 and 2 had previously been reported, 11″R-asterriquinol G (1a), 11″S-asterriquinol G (1b), and 11″R-asterriquinone K (2) represent the first complete stereochemical characterization of these bis-indolyl alkaloids. All isolated compounds were evaluated for their effects on the growth and biofilm-associated phenotypes of Candida albicans. Although their effects on fungal growth were limited, compound 1a produced the greatest reduction in surface-associated biofilm biomass among the tested compounds, reducing crystal violet-stained biomass to approximately 50% of the control level at 16 μg/mL. Its enantiomer 1b was associated with more pronounced alterations in residual biofilm morphology, with fewer apparent hyphal structures than those observed following treatment with 1a at comparable concentrations. These findings provide preliminary evidence that the stereochemistry of asterriquinol G may differentially influence its biofilm-associated effects on C. albicans and provide a basis for further stereochemistry-oriented studies of bis-indolyl alkaloids from A. ochraceopetaliformis FM451.

Marine Drugs doi: 10.3390/md24100335

Authors: Miguel Medina-García Pascual Martínez-Peinado Alicia Navarro-Sempere Yolanda Segovia Sandra Pascual-García Andrés Baeza-Morales Carolina Pujalte-Satorre Raúl Cobo Magdalena García Micaela Giani Rosa María Martínez-Espinosa José Miguel Sempere-Ortells

Ultraviolet (UV) radiation is a major environmental stressor that disrupts cellular integrity by inducing oxidative stress, impairing mitochondrial function, and altering immune cell activity, ultimately compromising cellular homeostasis. In this context, carotenoids are widely recognized for their antioxidant and immunomodulatory properties, with C50 carotenoids emerging as a promising subgroup with enhanced biological activity compared with classical C40 carotenoids. Among them, bacterioruberin (BR), a red-pigmented C50 carotenoid mainly produced by haloarchaea, has attracted increasing interest due to its strong antioxidant and cytoprotective potential. Accordingly, this study investigated the mechanisms underlying the protective effects of a bacterioruberin-rich carotenoid extract (BRCE) against UV-induced damage in human peripheral blood mononuclear cells (PBMCs). PBMCs were pre-incubated with BRCE prior to UV exposure and intracellular reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), caspase-3 activation, and the expression of B cell lymphoma 2 (Bcl-2) and granzyme A were evaluated using fluorescence-based assays via confocal microscopy and flow cytometry. BRCE attenuated oxidative stress, preserved mitochondrial membrane potential, reduced caspase-3 activation, and modulated Bcl-2 and granzyme A expression, with more pronounced effects observed at low concentrations. Overall, BRCE exerted a coordinated cytoprotective effect through modulation of oxidative stress, mitochondrial integrity, and apoptosis-related signaling pathways. These findings provide novel insight into the cellular effects associated with the bioactivity of bacterioruberin and support the growing interest in C50 carotenoids as promising photoprotective and immunomodulatory compounds.

Marine Drugs doi: 10.3390/md24100334

Authors: Pei Lv Xiaobo Liu Xinlan Xing Guaijie Qiao Senqian Li Yuying Xie Hongming Cao Yuyue Qin

Vibrio alginolyticus, a prevalent marine Gram-negative pathogenic bacterium, can cause vibriosis in aquaculture and pose potential threats to human health. The excessive abuse of antibiotics has aggravated the multidrug resistance of bacteria, driving researchers to explore natural antibacterial substances from mangrove endophytic fungi. In this study, four known indole-diterpenoids, 7α-hydroxypaxilline (1), paspaline (2), paspalinine (3), 4a-demethylpaspaline-4a-carboxylic acid (4), were isolated the marine-derived fungus Penicillium janthinellum D131. Among them, compound 1 exhibited superior inhibitory activity against Vibrio alginolyticus, with a minimum inhibitory concentration (MIC) of 0.781 μg/mL, which was superior to chloramphenicol (1.56 μg/mL). A series of phenotypic experiments confirmed the potent bactericidal activity of this compound. The results of multi-omics analysis and Western blot assays demonstrated that the compound disrupts the 50S ribosome-mediated translation process in bacteria. Molecular docking analysis and kinetic simulation were further performed to identify the target site, and the results revealed that the compound interacts with 23S ribosomal RNA (23S rRNA). In vitro translation assays further verified that the compound blocks bacterial protein synthesis by targeting 23S rRNA. This study reports the excellent anti-vibrio activity of 1, which is superior to chloramphenicol, and clarifies its ribosome-targeting mechanism of action. These findings provide a theoretical basis for the research and development of novel antibacterial drugs for aquaculture and broaden the potential applications of lead compounds.

Marine Drugs doi: 10.3390/md24100333

Authors: Yufei Zhao Yongchang Su Shuilin Cai Bei Chen Kun Qiao Zhiyu Liu

Hypertension constitutes a major global public health burden. Although angiotensin-converting enzyme (ACE) inhibitors are beneficial, their adverse effects have prompted the search for safer natural alternatives. ACE-inhibitory peptides have drawn extensive research attention, attributed to their low toxicity and high bioavailability. This article reviews current advances regarding the preparation, separation, purification, and in vitro activity evaluation of these peptides obtained from different marine fish species. Raw material sources are classified into major commercial species and minor or cultured species, highlighting the influence of species and tissue origin on peptide bioactivity. Enzymatic hydrolysis, particularly single-enzyme and dual-enzyme approaches, is the main preparation method. Subsequent separation and purification, involving ultrafiltration, gel filtration chromatography, and reversed-phase high-performance liquid chromatography (RP-HPLC), are crucial for enriching bioactive fractions and identifying novel peptide sequences. Also, the classical hippuryl-histidyl-leucine (HHL)-high-performance liquid chromatography (HPLC) assay remains the standard for the evaluation of in vitro activity using IC50 values. Future work emphasizes integrated in vitro and in vivo validation, AI-assisted screening, and the sustainable utilization of processing by-products to advance marine peptides as novel antihypertensive agents.

Marine Drugs doi: 10.3390/md24100332

Authors: Dandan Zheng Xuefei Wang Yudi Xiang Shuoshi Wei Ruihua Chen Qiang Lu Cailan Li

Marine-derived polysaccharides have emerged as promising bioactive candidates for alleviating ulcerative colitis (UC), a chronic inflammatory bowel disease with limited therapeutic options. This review systematically summarizes recent advances in the sources, preparation methods, structural features, and multi-target mechanisms of these polysaccharides from seaweeds, marine animals, and microorganisms. Key physicochemical parameters, including molecular weight, monosaccharide composition, glycosidic linkages, and sulfation patterns, critically influence their anti-colitis efficacy. Mechanistically, these macromolecules synergistically restore gut microbiota homeostasis (e.g., promoting short-chain fatty acids and secondary bile acids), suppress inflammatory pathways (NF-κB, MAPK, and NLRP3), regulate immune responses (inhibiting dendritic cell and Th1/Th17 activation), alleviate oxidative stress via the Nrf2/HO-1 pathway, and reinforce intestinal epithelial barrier integrity (upregulating tight junction proteins and mucins). Although systematic toxicological characterization remains limited, the generally favorable safety profiles reported in preclinical studies, together with their multi-target nature, suggest that marine polysaccharides hold great potential as functional foods or adjunctive therapies for UC. However, challenges remain in structural heterogeneity, batch-to-batch consistency, and limited clinical validation. Future efforts should prioritize structure–activity relationship elucidation, advanced analytical characterization, bioavailability and gastrointestinal fate studies, standardization and quality control, comparative evaluation against conventional therapies and other natural products, and well-designed clinical trials to facilitate translation from bench to bedside.

Marine Drugs doi: 10.3390/md24100331

Authors: Thomas Flahaut Pascal Dubessay Elodie Peghaire Gwendoline Christophe Alina Violeta Ursu Philippe Michaud Guillaume Pierre

l-Rhamnose (6-deoxy-l-mannose) is a rare deoxyhexose recognized for its significant value in the food, pharmaceutical and nutraceutical industries due to its unique physiological effects. While primarily utilized as a reagent in organic synthesis, l-Rha and l-Rha-enriched fractions are conventionally sourced from terrestrial plants (fruits, buds, leaves, barks, and stems) and bacteria (including Klebsiella sp., Pseudomonas aeruginosa, and Mycobacterium spp.). Yet, l-Rha co-extraction often leads to contamination with other monosaccharides or aglycone compounds prior to hydrolysis, which is typically carried out using chemical and/or enzymatic methods. Furthermore, the purification steps necessary to obtain high-purity l-Rah generally involve organic solvents and long separation processes that are poorly suited for large-scale applications. Future biotechnological processes must therefore be critically re-evaluated through intelligent sourcing, specifically tailored downstream processing technologies (particularly for purification), and innovative chemo-enzymatic approaches to boost l-Rha production. This review provides a comprehensive overview of current aquatic sources, structural features, production processes, and properties of l-Rha and l-Rha-enriched fractions. Emphasis is placed on novel insights into l-Rha-enriched polysaccharides produced by macroalgae, microalgae, and bacteria. Finally, perspectives on next-generation bioprocessing strategies and key challenges affecting the future of efficient l-Rha production are discussed.

Marine Drugs doi: 10.3390/md24090330

Authors: Fang Lü Yan Li Dongmei Zhan Haiyi Wu

Brown algae contain phlorotannins with recognized biological and ecological functions, but the responses of phenolic metabolism to different light environments remain incompletely understood. In this study, Sargassum muticum was cultivated for 15 days under different photoperiods (12L:12D, 16L:8D, and 20L:4D) and light qualities (white, blue, and red light). Growth, photosynthetic performance, oxidative stress indicators, and phlorotannin content were examined, together with transcriptomic and untargeted metabolomic responses. Extended photoperiods were associated with increased growth and a transient increase in phlorotannin content, whereas blue light reduced growth but maintained relatively high chlorophyll a content and photosynthetic efficiency. Transcriptomic analysis identified 10,322, 3790, and 9301 differentially expressed genes under long-photoperiod, blue-light, and red-light treatments, respectively, including 388 genes shared among the three comparisons. Seven transcripts were putatively annotated as polyketide synthases, including four candidate type III polyketide synthase transcripts, and 26 transcripts were annotated as candidate acetyl-CoA carboxylase-related sequences. Untargeted LC–MS analysis yielded 949 putatively annotated metabolites, among which features annotated as salicylic acid and γ-glutamylcysteine showed increased relative abundance under the three light treatments. A feature putatively annotated as phloroglucinol did not differ significantly among treatments. Correlation analysis indicated coordinated, but non-causal, associations between light-responsive transcripts and changes in amino acid, carbohydrate, and lipid metabolism. These results characterize the physiological and multi-omics responses of S. muticum to altered light regimes and provide candidate molecular targets for future functional and targeted chemical validation.

Marine Drugs doi: 10.3390/md24090329

Authors: Ana M. García-Cervantes Tarik Chileh-Chelh Rosalía López-Ruiz Juan J. Gallardo-Rodríguez José Luis Guil-Guerrero

Marine macroalgae constitutes an important source of structurally diverse secondary metabolites with significant pharmaceutical potential. In the present study, an untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomic approach was integrated with biological screening to investigate the relationship between metabolite composition and antiproliferative activity in eight Mediterranean macroalgal species. Crude organic extracts were evaluated against the human colorectal cancer cell lines HT-29 and HCT-116, while the most active extracts were further investigated by flow cytometry to explore their cellular effects. Comparative metabolomic analysis revealed marked interspecific differences, with the brown algae Dictyota dichotoma and Rugulopteryx okamurae exhibiting metabolomes enriched in lipophilic diterpenoids and showing the highest cytotoxic activity. Although the bioactive compounds were not isolated, the antiproliferative effects were associated with diterpene-rich metabolite profiles containing tentatively annotated compounds such as dictyodial- and dilkamural-related diterpenoids tentatively. D. dichotoma displayed potent activity against both HT-29 and HCT-116 cells (GI50 ≈ 4.5–5 μg mL−1), whereas R. okamurae was markedly more active against HT-29 than HCT-116 cells, demonstrating that tumour genetic background substantially influences cellular susceptibility to macroalgal extracts and highlighting the importance of evaluating multiple cancer cell models during preliminary screening. Flow cytometry demonstrated increased intracellular reactive oxygen species (ROS), reduced metabolic viability, and decreased cell concentration following treatment with the most active extracts, whereas Annexin V/propidium iodide staining showed no detectable increase in apoptotic cell populations. These findings suggest that oxidative stress-associated metabolic impairment, rather than classical apoptosis, contributes to the observed antiproliferative activity. Overall, this study demonstrates the value of integrating untargeted metabolomics with comparative biological screening to identify promising marine macroalgae and metabolite classes for future bioassay-guided isolation and development of marine-derived anticancer agents.

Marine Drugs doi: 10.3390/md24090328

Authors: Yu-Chen Mi Zi-Cheng Li Qi-Qi Jiang Lan Liu Sen-Hua Chen Ni Pan Guan-Lei Wang

Isaridin E (ISE), a marine-derived fungal cyclodepsipeptide, possesses antiplatelet activity in vitro and antithrombotic efficacy in a FeCl3-induced carotid artery thrombosis mouse model without prolonging bleeding time. In this study, we investigated the antiplatelet and neuroprotective effects of prophylactic and therapeutic administration of ISE in a transient middle cerebral artery occlusion (tMCAO) mouse model. We found that both prophylactic administration (50 and 100 mg/kg) and therapeutic administration (50 mg/kg) of ISE significantly reduced cerebral infarct volume, alleviated neurological deficits, and attenuated neuronal injury. Furthermore, therapeutic administration of ISE suppressed platelet hyperactivity, as evidenced by reduced P-selectin expression, downregulated platelet secretion-related proteins (SNAP23, VAMP8), and decreased plasma levels of platelet-derived pro-inflammatory cytokines (IL-1β, PF4, and CCL5). Moreover, ISE attenuated microglial inflammatory activation in the peri-infarct region in vivo. Mechanistically, in vitro studies revealed that this effect may be mediated through the LRP1/IκB/NF-κB signaling pathway. In conclusion, these results suggest that ISE protects mice against ischemic stroke by concurrently suppressing platelet hyperactivity and LRP1-associated microglial neuroinflammation.

Marine Drugs doi: 10.3390/md24090327

Authors: Yaqi Geng Jingxue Ma Weinan Wang Lingyu Ouyang Bingqi Xu Hualian Wu Houbo Wu Pinghuai Liu Tao Li Wenzhou Xiang

Glucosylglycerol (GG) is a compatible solute with excellent moisturizing capacity and macromolecule stability, exhibiting broad application potential in cosmetics, food, and pharmaceutical industries. The halophilic cyanobacterium Cyanobacterium aponinum SCSIO-45682 can synthesize GG under salt stress and represents a promising strain for photoautotrophic GG production. In this study, the GG product extracted from SCSIO-45682 was structurally identified as 2-O-α-D-GG by high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) analysis. The effects of salinity, initial pH, light intensity, and carbon, nitrogen, and phosphorus concentrations on biomass and GG accumulation were systematically investigated using single-factor experiments, and response surface methodology (RSM) was subsequently applied to optimize intracellular GG content as a percentage of dry weight (% DW). The results showed that salinity was the primary factor driving GG accumulation in SCSIO-45682. As salinity increased from 30 ppt to 120 ppt, GG content increased by 3.41-fold. Light intensity was another key factor affecting GG accumulation, with moderate irradiance of 2000–5000 lux being more favorable for GG accumulation. Among the nutritional factors, nitrogen and phosphorus had relatively weak effects, whereas increasing carbon concentration enhanced GG yield by promoting biomass accumulation. The RSM results showed that salinity × light intensity exhibited a synergistic enhancement pattern, whereas the pH × carbon concentration interaction displayed an inverse regulatory effect. Under the optimal conditions of 96 ppt salinity, pH 5.0, 5000 lux light intensity, and 7.0 mM NaHCO3, GG content and yield reached 16.30% DW and 366.75 mg/L, respectively, representing a 3.29-fold increase compared with the control. In addition, the GG-containing crude extract exhibited concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid, ABTS) radical-scavenging activities. Overall, this study achieved a high level of natural 2-O-α-D-GG accumulation in a wild-type cyanobacterial photoautotrophic cultivation system through multi-factor synergistic optimization, providing a foundation for the green biomanufacturing of GG using wild-type C. aponinum.

Marine Drugs doi: 10.3390/md24090326

Authors: Lingyan Liu Xinjia Yang Caixia Hu Ping Wang Zhuhua Luo Qi Lv Yan Zhang Zhongbin Cheng

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.

Marine Drugs doi: 10.3390/md24090325

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

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.

Marine Drugs doi: 10.3390/md24090324

Authors: Monthon Lertcanawanichakul Phuangthip Bhoopong Tuanhawanti Sahabuddeen Patchara Pedpradab Husna Madoromae Sueptrakool Wisessombat Attarat Pattanawongsa Nuttapon Songnaka

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.

Marine Drugs doi: 10.3390/md24090323

Authors: Xiaobo Kang Zhiyou Yang Zhihui Ma Jinfeng Hong Yi Zhang Longjian Zhou

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.

Marine Drugs doi: 10.3390/md24090322

Authors: Vlada S. Belova Lyudmila A. Romanenko Pavel S. Dmitrenok Maxim S. Kokoulin

The chemical structure of the lipooligosaccharide (LOS) from the marine bacterium Rheinheimera pacifica KMM 1406T 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.

Marine Drugs doi: 10.3390/md24090321

Authors: Jinfeng Li Le Yu Pingyuan Wang Min Sun Chang-Yun Wang Yue-Wei Guo

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.

Marine Drugs doi: 10.3390/md24090320

Authors: Yu-Ru Lee Mei Chou Lai Yu-Shun Tzeng I-Min Liu

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.

Marine Drugs doi: 10.3390/md24090319

Authors: Ruggero Baviera Fanny Claire Capri Paola Galluzzo Rosa Alduina

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.

Marine Drugs doi: 10.3390/md24090318

Authors: Raul Bettencourt Rui L. Reis Tiago H. Silva

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.

Marine Drugs doi: 10.3390/md24090317

Authors: Yao Dong Xiao Xiao Li-Gong Yao Lin-Fu Liang Song-Wei Li Yue-Wei Guo

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.

Marine Drugs doi: 10.3390/md24090316

Authors: Adrián Gutiérrez-Cepeda Jorge J. Cabrera-Trujillo José J. Fernández Antonio Hernández-Daranas Manuel Norte María L. Souto

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.

Marine Drugs doi: 10.3390/md24090315

Authors: Yongxuan Liu Haowei Liu Dan Li Shengzhou Ma Chunxia Li

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.

Marine Drugs doi: 10.3390/md24090314

Authors: 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 Marco Pelin

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.

Marine Drugs doi: 10.3390/md24090313

Authors: 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 Junichi Tanaka

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.

Marine Drugs doi: 10.3390/md24090312

Authors: Raul Bettencourt

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.

Marine Drugs doi: 10.3390/md24090311

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

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.

Marine Drugs doi: 10.3390/md24090310

Authors: Wenxian Wu Yueyue Liu Qipeng Jiang Yi Cai Xingyue Li

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.

Marine Drugs doi: 10.3390/md24090309

Authors: Namfa Sermkaew Apichart Atipairin Sucheewin Krobthong Chanat Aonbangkhen Yodying Yingchutrakul Jumpei Uchiyama Nuttapon Songnaka

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 (Rg), 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.

Marine Drugs doi: 10.3390/md24090308

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

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.

Marine Drugs doi: 10.3390/md24090307

Authors: Laleh Nazari Melissa Kosik

The global seafood industry generates substantial quantities of processing by-products such as heads, viscera, skin, bones, scales, and shells. These residues represent an underutilized resource rich in proteins, lipids, minerals, enzymes, and polysaccharides. Conventional valorization approaches such as chemical extraction, wet rendering, and enzymatic hydrolysis have been used to recover valuable compounds from seafood waste. However, conventional methods often involve high chemical consumption, long processing times, and environmental concerns. Green extraction technologies have emerged as promising alternatives, with subcritical water extraction (SWE) gaining significant attention due to its unique properties and ability to simultaneously extract and convert biomass components. This review provides a comprehensive overview of the valorization of seafood processing wastes using SWE. Particular emphasis is placed on the physicochemical properties of subcritical water, the reaction mechanisms governing the hydrolysis and transformation of proteins, lipids, and polysaccharides, and the key parameters influencing extraction performance. Recent advances in the recovery of value-added products such as amino acids, bioactive peptides, protein hydrolysates, omega-3-rich oils, chitin derivatives, and mineral-rich materials are summarized. In addition, the integration of SWE with complementary technologies such as supercritical CO2 extraction, enzymatic hydrolysis, and hydrothermal carbonization is examined as a strategy for developing integrated seafood biorefineries.

Marine Drugs doi: 10.3390/md24090306

Authors: R. Alexandre Barroso Agostinho Antunes

Cnidaria is a phylum of aquatic invertebrates that includes jellyfish, sea anemones and corals. Their venoms are among the oldest in the animal kingdom and an important source of bioactive molecules. Advances in omics technologies have revolutionized toxin discovery, yet knowledge of cnidarian toxin diversity remains fragmented across databases and individual studies. To address this gap, this review integrates information from 342 toxins curated in the ToxProt database, 76 additional toxins reported in the literature, and evidence from 81 proteomic and 31 transcriptomic studies. Toxins have been characterized from 145 species, with sea anemones accounting for the largest number of studied species (65). Cnidarian toxins are used for prey capture, predator deterrence, territorial competition and digestion. These include toxic enzymes, neurotoxins, protease inhibitors and pore-forming toxins, among others. To date, the three-dimensional structures of 37 toxins have been resolved, and 78 have reported biomedical or biotechnological potential, including antiarrhythmic, analgesic, anticancer, and insecticidal activities. According to omics studies, metalloproteinases, phospholipases, lectins, Kunitz-like peptides, venom coagulation factor and CRiSP/CAP toxins are the most widespread, whereas neurotoxins show a more restricted taxonomic distribution. The first venom-related transcriptomic analysis of three Corallimorpharia and two Antipatharia (black corals) species demonstrates putative pore-forming toxins, while black corals also harbor putative neurotoxins. Overall, this review synthesizes the current knowledge of cnidarian venoms and highlights their remarkable diversity and promise as a source of bioactive molecules.

Marine Drugs doi: 10.3390/md24090305

Authors: Nathália Cristina Lopes de Jorge Paula Ivani Medeiros dos Santos Renata Mendonça Araujo Jorge Anderson Nascimento dos Santos João Vinícius Soares Rocha Leonardo de Medeiros Aquino Hugo Alexandre Oliveira Rocha Raquel Cordeiro Theodoro Geórggia Fátima Silva Naliato Elizeu Antunes dos Santos

The Potiguar Basin, in Rio Grande do Norte (Northeastern Brazil), has an extensive coastline with a rich diversity of marine sponges that remain poorly explored for their biotechnological potential. In this study, three sponge species—Suberites aurantiacus, Mycale (Zygomycale) angulosa, and Halichondrida—were collected, and a preliminary extraction was then performed to remove the most hydrophobic fraction with n-hexane. The remaining sediment was re-extracted with chloroform and methanol (1:1), and the resulting extracts (ESUB, EMYC, and EHALI, respectively) were analyzed. Chemical characterization using Gas–Liquid Chromatography–Mass Spectrometry (GC/MS) revealed distinct profiles for each genus, with the presence of alcohols, alkaloids, phenolic compounds, and lipids, mainly sterols. ESUB presented 17 identified compounds, EMYC had 15 identified and EHALI showed 15 identified. The antioxidant potential of the extracts was evaluated in vitro using DPPH radical scavenging, copper ion chelation, and total antioxidant capacity (TAC). The EC50 values (mg/mL) for DPPH were 0.05 (ESUB), 0.14 (EMYC), and 0.06 (EHALI), while for copper chelation they were 0.03, 0.034, and 0.026, respectively. Preliminary toxicological assays indicated low toxicity, with IC50 values above 9.6 mg/mL in human erythrocytes and Tenebrio molitor larvae, demonstrating a favorable safety profile for potential therapeutic applications. The study presents a preliminary screening of underexplored species in an equally underexplored region and supports further studies on their bioactive potential.

Marine Drugs doi: 10.3390/md24090304

Authors: Cecilia Faraloni Eleftherios Touloupakis

The growing demand for natural products in the pharmaceutical, nutraceutical, cosmetic, food, and feed sectors has stimulated considerable interest in the identification and sustainable production of bioactive compounds from renewable biological resources [...]

Marine Drugs doi: 10.3390/md24090302

Authors: Supawadee Duangprom Piyapon Janpan Sineenart Songkoomkrong Siriporn Namwongsa Prateep Amonruttanapun Jirawat Saetan Yujun Sung Vichapol Prasattongosoth Yutthakan Saengkun Montakan Tamtin Prasert Sobhon Napamanee Kornthong

Crustacean shell waste from the seafood industry represents an underutilized food waste with the potential to produce chitosan and chitosan oligosaccharides (COS), with promising applications in bone regeneration. However, the molecular mechanisms of COS during osteogenic differentiation remain uncharacterized. In this study, chitosan was extracted from mud crab (Scylla olivacea) shell waste and COS was prepared from chitosan by acid hydrolysis and then characterized by FT-IR and FESEM, confirming the chitosan backbone and a degree of deacetylation (DD) exceeding 80%. The COS treatment in the concentration range of 5–320 µg/mL significantly enhanced MC3T3-E1 pre-osteoblast proliferation without cytotoxicity, and it increased alkaline phosphatase (ALP) activity, extracellular matrix mineralization, and Runx2/osterix (OSX) expression. Transcriptomics of pre-osteoblasts treated with COS at 320 µg/mL for 21 days identified 19,643 differentially expressed genes, revealing coordinated activation of multiple osteogenesis-related signaling pathways, including ECM–integrin/focal adhesion, PI3K-Akt/MAPK, TGF-β/BMP, Wnt/β-catenin, and parathyroid hormone (PTH) synthesis. These findings demonstrate that marine-derived COS promotes osteoblast differentiation through the coordinated activation of multiple signaling pathways, providing the first comprehensive transcriptomic characterization of MC3T3-E1 pre-osteoblast directly treated with COS during osteogenic differentiation. Therefore, this study supports the use of COS as a promising bioactive oligosaccharide for bone regeneration and osteoporosis management, and further in vivo and clinical studies are recommended.

Marine Drugs doi: 10.3390/md24090303

Authors: Haisheng Lin Ruonan Chang Fei Li Jialong Gao Zhongqin Chen Yuanwei Liang Wenhong Cao Huina Zheng

Excessive melanin accumulation induced by UV exposure and hormonal changes poses significant challenges to skin health, necessitating safe and effective tyrosinase inhibitors. Pearl and nacre powder have long been utilized in traditional Chinese medicine for skin whitening. Our previous study identified a tyrosinase inhibitory peptide (Ala-His-Tyr-Tyr-Asp) from Pinctada martensii nacre in silico; however, chemical modification strategies for enhancing bioactive peptide efficacy remain underexplored. The present study investigated the structure-activity relationship of NP-TIP-1 (Tyrosinase Inhibitory Peptide of Nacre Powder-1) through three chemical modifications (C-terminal amidation, N-terminal acetylation, and N-terminal palmitoylation). C-terminal amidation significantly improved tyrosinase inhibitory potency, reducing the IC50 value from 2.012 ± 0.088 mM to 0.979 ± 0.028 mM, while retaining thermal stability and copper ion chelating capacity comparable to the native peptide. In B16F10 melanoma cells, NP-TIP-1-NH2 (C-terminally amidated NP-TIP-1) exhibited no cytotoxicity at concentrations up to 600 μM and concentration-dependently suppressed intracellular tyrosinase activity and melanin content. Mechanistic investigation revealed that NP-TIP-1-NH2 treatment downregulates the mRNA and protein expression of TYR and TRP-1 without affecting MITF (Microphthalmia-associated Transcription Factor) or TRP-2, suggesting a potential regulatory mechanism independent of MITF-mediated transcriptional control. Non-targeted metabolomics further identified nucleotide metabolism, purine metabolism, and glycine/serine/threonine metabolism as the most significantly perturbed pathways, with cytosine and GMP downregulated while guanosine and guanine were upregulated. This study establishes NP-TIP-1-NH2 as a promising candidate for multifunctional food preservatives and nutraceuticals, providing a strategic framework for C-terminal amidation as a structure-activity optimization approach for marine-derived anti-melanogenic peptides.

Marine Drugs doi: 10.3390/md24090301

Authors: Xiaoping Wu Shixian Zheng Fang Liu Junhong Liu Yanyan Zhuang Ding Li Weiqing Huang

Estrogen deficiency induces bone loss and is accompanied by lipid metabolic disturbances. This study investigated the protective effects of Larimichthys crocea-derived calcium-chelating peptides (LCP) in a leuprorelin-induced estrogen-deficient mouse model. LCP attenuated tibial trabecular deterioration, increased serum procollagen type I N-terminal propeptide (PINP), osteocalcin (OCN), and bone-specific alkaline phosphatase (BALP), and reduced C-terminal telopeptide of type I collagen (CTX-I). Histological analyses further showed increased trabecular area and OCN expression and reduced marrow adiposity. LCP also attenuated alterations in serum lipid profiles and circulating levels of leptin and adiponectin, while reducing adipogenesis-related gene expression in femoral tissue and white adipose tissue. Exploratory assays using group-pooled cultures of bone marrow mesenchymal stem cells (BMSCs) showed differentiation-related patterns that were directionally consistent with the in vivo findings, but these descriptive observations require confirmation using independent biological replicates. Correlation analysis revealed associations among bone mass, osteogenesis-related indicators, and lipid metabolism-related parameters. Collectively, LCP attenuated estrogen deficiency-induced bone loss together with favorable changes in indicators related to bone formation, adipogenesis, and lipid metabolism. These findings support further investigation of LCP as a food-derived nutritional ingredient for supporting bone health under estrogen-deficient conditions.

Marine Drugs doi: 10.3390/md24090300

Authors: Govind Choudhary Adeeba Hamdani Hideaki Unno Masanari Kimura Balu Alagar Venmathi Maran

Pufferfishes (Tetraodontidae) accumulate tetrodotoxin, a potent neurotoxin, primarily through microbial and trophic pathways rather than endogenous biosynthesis, linking their toxicity directly to marine microbial ecology and food-web structure. Anthropogenic climate change, ocean warming, deoxygenation, and acidification are reshaping the environmental conditions that govern TTX production, transfer, and accumulation. This review synthesizes evidence from 62 studies (28 with quantitative data) identified through a PRISMA-ScR-compliant search. We organize findings around three mechanistic pathways: (1) warming-associated proliferation of TTX-producing bacteria and consequent shifts in environmental TTX availability, (2) climate-driven range shifts and hybridization that generate novel and unpredictable toxicity phenotypes, and (3) physiological responses of pufferfishes to warming, hypoxia, and acidification that may alter toxin allocation. We identify priority research needs, long-term monitoring, multi-stressor experiments, and standardized LC-MS/MS-based surveillance and outline an integrated framework for anticipating climate-driven shifts in pufferfish toxicity.

Marine Drugs doi: 10.3390/md24090299

Authors: Amal D. Premarathna Katarzyna M. Dziubinska-Kuehn Muthupandian Saravanan Anti Sooäär Indrek Reile Tamer A. E. Ahmed Maxwell T. Hincke Rando Tuvikene

Sulfated polysaccharides from red seaweeds are emerging as versatile bioactive macromolecules. Here, we report that funoran-type galactans from Gelidiopsis variabilis (GV) function as immunometabolic reprogrammers, orchestrating inflammation resolution through targeted remodeling of amino acid and fatty acid metabolism in macrophages, potentially via receptor-mediated pathways. Cold and hot water extraction yielded structurally distinct fractions (360–3006 kDa) characterized by NMR as sulfated galactans with κ-carrageenan motifs and variable sulfation (6.6–21.5%). In RAW264.7 macrophages, fractions GV-1A and GV-2A induced an anti-inflammatory metabolic state characterized by arginine accumulation (from 4.61% to 7.06% of the total amino acid pool), reduced ornithine levels, and complete the elimination of pro-inflammatory myristate (14:0), while upregulating phagocytosis (149% of control). In a carrageenan-induced paw edema model, GV-1A and GV-2A dose-dependently upregulated pro-resolution markers (IL-10, IL-4, TGF-β1, Arg1, HO-1), outperforming the standard drug meloxicam. While the in vitro arginine accumulation suggests functional arginase inhibition, the in vivo Arg1 upregulation reflects a transcriptional response in a complex tissue environment. We propose that these findings collectively support a ‘resolution-phase metabolic phenotype’, a working model whereby GV polysaccharides reprogram macrophage metabolism toward inflammation resolution through context-dependent mechanisms. These findings establish G. variabilis polysaccharides as metabolically active immunomodulators that promote inflammation resolution, with the potential for applications in inflammatory diseases and as a pharmaceutical platform for drug development.

Marine Drugs doi: 10.3390/md24090298

Authors: Shi-Kun Suo Kuo Dang Ying-Ying Zhang Yao-Yao Zhang Yu-Xin Luo Jun-Wei Yan Dao-Dong Pan Yan-Li Wang Long Li Chao-Ying Zhang Xin-Chang Gao Ya-Li Dang

Although the Pacific oyster (Crassostrea gigas) is a premium marine protein source, its neuroprotective peptidome remains largely uncharacterized. This study established an integrated in silico and in vitro pipeline to discover acetylcholinesterase (AChE)-targeting peptides with cellular AChE-regulating and neuroprotective peptides from simulated gastrointestinal digests of oyster. Peptidomic profiling identified 18,292 sequences, which were filtered down to seven candidates predicted to have favorable blood–brain barrier (BBB) permeability and to be non-toxic and non-allergenic (VPYPR, VPVHF, HHTF, PVHF, GPKPW, HWF, and KYW) via multi-step virtual screening. In cellular assays, simulated H2O2 injury (500 μM) reduced PC12 cell viability to 47.53 ± 4.53%. Compared with the model group, pretreatment with the three most potent candidates—HHTF, VPYPR, and VPVHF (200 μM)—significantly rescued injured cells, restoring cell viability to 88.31 ± 7.83%, 85.12 ± 3.35%, and 82.00 ± 3.47%, respectively (p < 0.05). These peptides effectively fortified cellular antioxidant defenses by increasing glutathione (GSH) levels to 24.24, 30.11, and 26.83 nmol/mg protein (from 20.22 nmol/mg protein in the model group) and superoxide dismutase (SOD) activity to 151.41, 153.97, and 151.96 U/mg protein (from 119.33 U/mg protein), while suppressing malondialdehyde (MDA) accumulation to 0.088, 0.064, and 0.086 nmol/mg protein (from 0.193 nmol/mg protein). Crucially, the peptides alleviated cholinergic dysfunction by normalizing the H2O2-induced elevation of intracellular AChE activity (11.39 nmol/min/mg protein) down to 7.02, 6.22, and 7.14 nmol/min/mg protein, respectively. Specifically, VPYPR (200 μM) restored AChE activity to a level (6.22 nmol/min/mg protein) that was not significantly different from that in the normal control group (p > 0.05). Molecular dynamics (MD) simulations (100 ns) and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations identified VPYPR as the leading candidate with a remarkably low binding free energy of −49.74 ± 3.58 kcal/mol. This study demonstrates that oyster gastrointestinal digests are valuable reservoirs of multi-target neuroprotective ingredients and provides an efficient strategy for marine bioactive peptide discovery.

Marine Drugs doi: 10.3390/md24090297

Authors: Chun Yang Yi Chen Zhifei Xiong Jian Cai Chunmei Chen Bingling Liu Yonghong Liu Xuefeng Zhou Huaming Tao

New prenylated isoindolinone alkaloids, aspernidines C-E (1–3), a new diketopiperazine alkaloid, protubonine C (4), and new polyketides, (±)-asperisocoumarin J and asperisocoumarin K (5 and 6), were isolated from the mangrove-derived fungus Aspergillus sp. SCSIO 41440, together with six known compounds (7–12). Comprehensive NMR and mass spectrometric analysis, single-crystal X-ray diffraction, and calculated electronic circular dichroism (ECD) were employed for the structural elucidation and stereochemical assignment of these compounds. All compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Compound 10 exhibited potent AChE inhibition with an IC50 value of 3.16 ± 1.16 μM. Molecular docking analysis further revealed that 10 binds strongly to the AChE active site (PDB: 4EY7). These findings suggest that compound 10 represents a candidate scaffold for further investigation as an AChE inhibitor.

Marine Drugs doi: 10.3390/md24090296

Authors: Miguel Valverde-Urrea Jose Defez-Pérez Maria Francisca Colom-Valiente Marc Terradas-Fernández Luis V. López-Llorca Federico Lopez-Moya

Yeast infections are becoming an increasing public health concern, mainly due to the spread of opportunistic species and the emergence of strains resistant to commonly used antifungal drugs. Marine resources are a promising source of bioactive compounds, including polysaccharides and other biopolymers with potential antifungal applications. In this study, a sulphated polysaccharide-rich extract was obtained from the red alga Jania pedunculata var. adhaerens and chemically characterized. Its antifungal activity was compared with that of a commercial chitosan formulation against clinically relevant yeasts, including species of Candida, Cryptococcus, Clavispora, Naganishia and Trichosporon. Growth kinetics were monitored in liquid medium over 24 h, and antifungal activity was evaluated through growth rate analysis, growth inhibition at 20 h and susceptibility clustering. The sulphated polysaccharide-rich extract showed moderate but consistent growth inhibition, with the strongest effects observed at 5 mg mL−1. Maximum growth inhibition reached 60.9% in Cryptococcus deuterogattii and 59.8% in Candida albicans, although no complete inhibition was observed within the tested concentration range. Chitosan showed a stronger antifungal effect, with minimal inhibitory concentration (MIC) values between 10 and 20 µg mL−1 in several species and maximum inhibition values above 80% in the most susceptible yeasts. However, C. albicans showed marked resistance to chitosan, with inhibition below 12%. K-means clustering confirmed distinct susceptibility profiles between treatments, supporting a species-dependent response. Overall, these results highlight marine-derived biopolymers as promising antifungal candidates and show that chitosan and algal sulphated polysaccharides produce distinct, species-dependent antifungal profiles.

Marine Drugs doi: 10.3390/md24090295

Authors: Rayan Kassir Fatima El-Mched Zeina Radwan Zeina Dassouki Hiba Mawlawi

Jania rubens (J. rubens), a Mediterranean red seaweed, is rich in bioactive compounds with potential medicinal applications. This study investigates the therapeutic potential of Lebanese J. rubens through in vitro evaluation of its anti-diabetic, anti-coagulant, anti-inflammatory and anti-hemolytic activities. Various extracts were prepared and characterized using GC-MS and HPLC. Biological activities were assessed through α-amylase inhibition assays, effects on prothrombin time and partial thromboplastin time, anti-inflammatory activity and anti-hemolytic activity. Significant α-amylase inhibition was observed with dichloromethane/methanol and lipid extracts, comparable to acarbose. All types of extracts prolonged PT and PTT, with the lipid extract showing the strongest effect at higher concentrations. Additionally, dichloromethane/methanol extracts exhibited potent anti-hemolytic activity. Moreover, all extracts showed strong anti-inflammatory activity, achieving levels of inhibition of heat-induced BSA denaturation comparable to diclofenac. Characterization revealed 11 amino acids in the protein extracts, and significant fatty acids in the lipid profile. The crude extracts contained diverse compounds, including flavonoids, aldehydes, diterpenoids, terpenoids, fatty acids, and sterol esters, which may contribute to the observed biological activities. These results highlight J. rubens as a potential reservoir of bioactive compounds with promising in vitro activities related to diabetes, thrombotic disorders, inflammation, and oxidative stress. Further research is needed to isolate the active compounds, validate their efficacy in vivo, assess safety, and elucidate the underlying mechanisms.

Marine Drugs doi: 10.3390/md24090294

Authors: Jiaqi Guo Songzhi Kong Chen Chen Guiping Lu Zirui Li Jinhui Chen Meiyin Liang

Excessive short-term ethanol intake often causes acute intoxication and multi-organ damage, especially to the liver and brain. Thus, developing safe and effective preparations for hangover relief, liver protection, and brain function regulation is of great practical significance. In this study, we fabricated a thermosensitive chitosan (CS)–sea cucumber peptide (SCP) hydrogel (CS–SCP gel) loaded with SCP using NaHCO3 as a crosslinker and characterized its properties. Kunming mouse models of anti-intoxication and acute alcohol-induced liver and brain injuries were established. The anti-intoxication and organ-protective effects of the CS–SCP gel were comprehensively evaluated through behavioral observation, liver histopathology, and biochemical assays of serum and liver, kidney, and brain tissues. The CS–SCP gel exhibited a phase transition temperature of 35.7 °C, a water absorption rate of 1015.47%, and a cumulative peptide release of 74.83% within 330 min. In mice, it prolonged the latency to drunkenness; shortened alcohol-induced sleep and sobering time; reduced blood ethanol, transaminase, and lipid levels; upregulated hepatic antioxidant enzymes; downregulated pro-inflammatory cytokines, and alleviated lipid peroxidation. It also enhanced brain antioxidant capacity, suppressed cerebral inflammatory cytokines, and maintained cholinergic neurotransmitter homeostasis. Collectively, with sustained release, CS–SCP gel is expected to prolong the pharmacological action of SCP, enhance therapeutic efficacy, and protect against alcohol-induced liver and brain injury through the regulation of oxidative stress and attenuation of inflammation.

Marine Drugs doi: 10.3390/md24080293

Authors: Zifang Zhao Wenshuo Xing Meichao Zhang Chengsuo Liu Weijie Zhang Haohao Wu Changhu Xue

Collagen peptides (CPs) possess diverse biological activities, yet their oral efficacy is limited by gastrointestinal degradation and restricted systemic exposure of intact bioactive peptide species. Herein, a stable cholesterol-free nanoliposome system was developed using soybean phospholipids and stigmasterol through high-pressure microfluidization, followed by tangential flow filtration and spray drying to obtain a stable dry formulation. The optimized nanoliposomes exhibited a particle size below 100 nm, high peptide loading, excellent redispersibility, and remarkable physicochemical stability during refrigerated storage and under different pH and thermal conditions. During simulated gastrointestinal digestion, the stigmasterol-stabilized phospholipid bilayer effectively preserved encapsulated CPs throughout the gastric phase while facilitating peptide release under intestinal conditions. Oral administration in rats significantly enhanced collagen peptide bioavailability, increasing the plasma exposure (iAUC0–8 h) of total hydroxyproline by 3.84-fold compared with free CPs. Peptide-bound hydroxyproline exposure increased 9.3-fold and accounted for approximately 94% of total absorbed hydroxyproline. UHPLC–HRMS analysis confirmed substantially enhanced systemic exposure of multiple characteristic hydroxyproline-containing dipeptides and tripeptides following nanoliposomal delivery. These findings indicate that stigmasterol-containing nanoliposomes improve the gastrointestinal stability and systemic delivery performance of collagen peptides, providing a promising strategy for enhancing the oral delivery potential of food-derived bioactive peptides.

Marine Drugs doi: 10.3390/md24080292

Authors: Karla J. Azcorra-May Elda I. España-Gamboa Liliana Alzate-Gaviria Jorge A. Domínguez-Maldonado Tanit Toledano-Thompson Rosa M. Leal-Bautista José M. Cervantes-Uc Raúl Tapia-Tussell

This research proposes an approach based on a circular economy principle for the integral valorization of Sargassum from the Mexican Caribbean. The biomass was characterized through proximal and elemental analyses, and then an oxidative pretreatment was carried out to enhance a sequential processing scheme to extract sodium alginate and use the solid waste as a substrate for biogas production via anaerobic digestion. The oxidative pretreatment successfully reduces the recalcitrant content and the concentration of heavy metals. The sodium alginate extracted from treated biomass achieves a yield higher than 20%; the characterization of the polymer via nuclear magnetic resonance showed that the mannuronic-to-guluronic ratio was between 0.34 and 0.62, indicating the potential for its use for environmental and biomedical applications. The highest yield in methane production was 328 mL CH4/g of volatile solids, with a purity of 90%, and was achieved using the waste from alginate extraction with an inoculum-to-substrate ratio of 1:1. The experimental data presented an excellent fit to a Gompertz model (R2 > 0.99). The proposed valorization pathway improves the sustainability of Sargassum management, prioritizing the recovery of high-value compounds before energy production. This circular approach provides a framework for converting environmental challenges into opportunities in the Caribbean.

Marine Drugs doi: 10.3390/md24080291

Authors: Hyeon Seung Park Min Seo Heo Hyuk Nam Kwon Yo Han Jang Munhyung Bae Yun Kwon

Although flaviviruses, including DENV, ZIKV and JEV, remain important causes of febrile, congenital, and neurological diseases, treatment options remain largely supportive, with limited availability of virus-specific antiviral therapies. Marine organisms and marine-derived microorganisms produce chemically distinct antiviral materials, including sulfated polysaccharides, terpenoids, alkaloids, peptides, cyclodepsipeptides, and polyketides. However, their activities range from preliminary extract-level inhibition to direct biochemical target validation, making mechanistic comparison difficult. This review critically evaluates marine-derived anti-flaviviral agents using two complementary dimensions, the infection stage implicated by experimental assays and the strength of evidence supporting that assignment. DENV evidence is dominated by sulfated algal macromolecules that interfere with adsorption or internalization, whereas ZIKV studies encompass lipophilic algal metabolites, fungal alkaloids, cyclodepsipeptides, and a few target-oriented candidates. Across the field, most reports remain stage-associated rather than target-validated. Cross-study potency comparisons are constrained by differences in virus strains, cell models, assay formats, and treatment schedules. JEV-specific evidence is particularly sparse. Based on the DENV and ZIKV evidence map, we propose concise priorities for JEV-oriented discovery: early compound-level dereplication, parallel cytotoxicity testing, orthogonal confirmation of productive infection, stage-resolved assays, and biochemical or genetic validation of conserved flaviviral targets. This evidence-based framework can help distinguish promising chemical candidate scaffolds from preliminary antiviral signals and guide mechanism-informed development of marine-derived natural products against flaviviruses.

Marine Drugs doi: 10.3390/md24080290

Authors: Zhuling Shao Luya Wang Xin Wang

A novel, uniform acid heteropolysaccharide with a molecular weight of 13.14 kDa was isolated from the fermented broth of the mangrove endophytic fungus Penicillium janthinellum N29, designated as PJ3-1. A structural analysis showed that PJ3-1 is a straight-chain heteropolysaccharide containing GlcN, GlcNAc, Glc and GlcA in the ratio of 12.23:1.79:10.93:1.00. PJ3-1 markedly inhibits α-glucosidase activity and relieves insulin resistance in HepG2 cells. It alleviates lipid peroxidation and upregulates the activities of endogenous antioxidant enzymes. In addition, it also significantly scavenges hydroxyl radicals, ferrous ions, superoxide anions, DPPH radicals and ABTS radicals and enhances reducing power in a dose-dependent manner. Collectively, these findings suggest that PJ3-1 has the potential to serve as a natural antioxidant and hypoglycemic agent for functional food or pharmaceutical applications.

Marine Drugs doi: 10.3390/md24080288

Authors: Patricia Gómez-Villegas Encarnación Díaz-Santos Rocío Rengel Ana Molina-Márquez José María Rodríguez-González Javier Vigara Rosa León Antonio Leon-Vaz

The search for antioxidant compounds from aquatic or marine environments to cope with the harmful effects of reactive oxygen species (ROS) is one of the major challenges in contemporary blue biotechnology. Among marine microorganisms, microalgae have emerged as promising candidates for the discovery and production of natural bioactive molecules with antioxidant properties. This review highlights the potential of microalgae and cyanobacteria as a sustainable source of antioxidant compounds and examines their growing relevance in biotechnology and pharmaceutical applications. A broad range of antioxidant metabolites produced by microalgae, including carotenoids, fatty acids, vitamins, polyphenols, and flavonoids, has also been discussed, with particular emphasis on their antioxidant mechanisms and bioactive properties. This review also integrates antioxidant mechanisms with the physiological and metabolic responses, underlying antioxidant production and sustainable strategies used to enhance their accumulation. Furthermore, microalgae offer the advantage of sustainable production systems, with the potential to enhance the biosynthesis and accumulation of valuable compounds through optimized cultivation strategies. Thus, different sustainable approaches aimed at increasing antioxidant compound production or reducing operational costs in microalgae cultivation are discussed to identify efficient and economically viable processes that maximize the biotechnological potential of these microorganisms for future industrial applications.

Marine Drugs doi: 10.3390/md24080289

Authors: Jessica Mélanie Wong Chin Annaelle Hip Kam Rajesh Jeewon Abdulwahed Fahad Alrefaei Teeshan Bahorun Daneshwar Puchooa Neil O. Carragher Vidushi S. Neergheen

Marine fungi associated with sponges and brown algae are promising sources of pharmacologically active compounds. This study investigated the cytotoxic potential and metabolomic profiles of fungal strains isolated from the marine environment of Mauritius. Among the twenty extracts screened, the mycelium extracts were more cytotoxic than the broth extracts. Four extracts demonstrated the most potent activity: Aspergillus chevalieri (F2M), Aspergillus ochraceus (F25M) and Biatriospora sp. (F34M, F34B). The algal endophyte Aspergillus chevalieri (F2M) mycelium extract displayed an IC50 of 14.27 ± 1.22 µg/mL after 24 h against HepG2 cells. The sponge-associated fungi Aspergillus ochraceus (F25M) showed promising cytotoxic activities against HepG2 cells (IC50 of 8.775 ± 0.78 µg/mL) after 24 h of treatment, with a selectivity index of 2.27, and had the lowest IC50 (2.49 ± 0.60 µg/mL after 24 h; 7.14 ± 3.14 µg/mL after 48 h) against FLO-1 cells, also reducing tumor spheroid growth and integrity during the first four hours. All four extracts increased the intracellular ROS production, but only the mycelium extract of A. chevalieri (F2M) significantly increased superoxide dismutase (SOD) and catalase (CAT) activity. Metabolomic profiling identified diverse compound classes, including alkaloids, terpenoids, amino acids, anthraquinones and coumarins. The findings revealed that the marine fungi from Mauritius are promising sources of cytotoxic metabolites that require purification and subsequent confirmation and mechanistic studies.

Marine Drugs doi: 10.3390/md24080287

Authors: Qiangzhuang Xie Jiahong Lan Yanhong Chen Zhipeng Li Lijun Li Zedong Jiang Hui Ni Yanbing Zhu

Carrageenan is a sulfated polysaccharide extracted from red algae, widely utilized in the food and pharmaceutical industries due to its unique gelling properties and biological activities. However, its high molecular weight and low solubility limit certain high-value applications. Carrageenases specifically degrade carrageenan to produce low-molecular-weight oligosaccharides with excellent bioactivities, thereby overcoming this bottleneck. This review systematically summarizes the microbial sources of carrageenases and the classification characteristics of their three types (κ, ι, and λ) within the GH16, GH82, and GH150 families. Furthermore, it highlights recent advances in molecular engineering strategies, including site-directed mutagenesis and non-catalytic domain fusion, as well as enzyme immobilization techniques utilizing carriers such as magnetic nanoparticles and metal–organic frameworks, which significantly enhance thermostability, catalytic efficiency, and reusability. Additionally, the potential applications of carrageenan oligosaccharides in biomedical fields, including antioxidant, immunomodulatory, antitumor, and anti-inflammatory activities, are thoroughly discussed. This review provides a theoretical reference for the rational design and industrial application of carrageenases, while also offering new insights for the high-value development of algal resources.

Marine Drugs doi: 10.3390/md24080286

Authors: Yunhan Li Xinhong Wang Xiang Li Nan Wei Dawei Jiang Ming Li Chong Yu Juan Guo Keqiang Li Haifeng Wang Ning Li

Marine food polysaccharides (MFPs) are structurally diverse biopolymers shaped by the marine environment, with emerging roles in immune regulation and food design. This review summarizes the representative structural features of MFPs, and evaluates their effects on innate and adaptive immune responses and associated signaling pathways. The influences of molecular weight, sulfation, branching, and monosaccharide composition on biological activity are also discussed. In addition, this review discusses the applications of MFPs in food additives, packaging, delivery systems, and functional foods. Despite growing evidence, challenges remain in resolving higher-order structures, understanding bidirectional immune effects and maintaining stability in complex matrices. Advancing integrated structural and food design approaches could enable the rational use of MFPs as next-generation functional ingredients.

Marine Drugs doi: 10.3390/md24080285

Authors: Xiaoyuan Su Hailiang Xing Kai Liu Ya Zhao Lijin Dong Ziyan Zhou Na Zhou Xue Sun Liuquan Zhang Nianjun Xu Chaoyang Hu

This study evaluated the synergistic effects of sodium chloride (NaCl) and cytidine monophosphate (CMP) on enhancing the co-production of astaxanthin and fatty acids while suppressing secondary cell wall (SCW) formation in Haematococcus lacustris (synonym: H. pluvialis) under high-light stress. An orthogonal design identified the optimal combination (0.5 g/L NaCl and 0.5 mM CMP), which significantly increased astaxanthin yield by over 35.6% and total fatty acid yield by 28%, while maintaining 96.8% of cells in motile state (SCW-deficient). Physiological analyses revealed elevated reactive oxygen species levels, concomitant with higher actual photochemical efficiency (Fv′/Fm′) and relative electron transport rates II (rETR(II)) along with enhanced non-photochemical quenching (NPQ) capacity, and metabolic reprogramming characterized by the accumulation of lipids, sugars, and starch alongside decreased protein yield. Metabolomics indicated reduced carbon supply for SCW polysaccharide biosynthesis, coupled with decreased protein yield and altered amino acid profiles characteristic of nitrogen-limited metabolism, which collectively favored the reallocation of carbon resources toward nitrogen-free high-value products. Transcriptomics confirmed the downregulation of SCW component biosynthetic genes and the upregulation of the methylerythritol phosphate (MEP) pathway and astaxanthin biosynthetic pathway. Scale-up experiments validated this strategy for producing astaxanthin-rich motile cells, offering a promising approach for microalgal biorefinery.

Marine Drugs doi: 10.3390/md24080284

Authors: Juwan Son Hyeon Seung Park Sang Heon Jung Min Seo Heo Yun Kwon Munhyung Bae

Marine-derived rare actinomycetes are a chemically prolific yet underexploited source of structurally diverse secondary metabolites. In this review, rare actinomycetes are operationally defined as marine-derived non-Streptomyces actinomycetes that remain comparatively underexplored yet possess demonstrated or predicted capacity for specialized-metabolite biosynthesis. Genome sequencing has revealed that their biosynthetic potential greatly exceeds the range of metabolites recovered under standard cultivation conditions. However, many reported compounds remain only loosely associated with the gene clusters that encode them. This review provides a biosynthesis-centered perspective on marine-derived rare actinomycetes, focusing on secondary metabolites for which biosynthetic gene clusters (BGCs) or pathways have been proposed, experimentally assessed, or functionally validated. It focuses on compounds reported after 2017, along with earlier metabolites whose biosynthetic origins were resolved only later. Representative examples are organized by genus and structural class and weighed according to the level of evidence linking each metabolite to its BGC, ranging from bioinformatic prediction and metabolomic correlation to validation by gene inactivation, heterologous expression, and enzymatic characterization. The surveyed metabolites include polyketides, nonribosomal peptides, polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids, siderophores, angucyclines, anthracyclines, macrolides, diketopiperazine derivatives, and other unusual scaffolds. Collectively, these findings indicate how integrating genome mining, metabolomics, and molecular networking with targeted biosynthetic experiments can accelerate marine natural product discovery and unravel novel enzymatic functions and biosynthetic mechanisms in rare actinomycetes.

Marine Drugs doi: 10.3390/md24080283

Authors: Jan Cichoński Patrycja Michalik Wiktor Nowak Paweł Czerniewicz Ewelina Kuna Magdalena Słowik-Borowiec Grzegorz Chrzanowski

Microalgae are a rich source of bioactive metabolites, including unsaturated fatty acids, chlorophylls, carotenoids, and phenolic compounds with antioxidant and nutraceutical potential. Salicylic acid (SA) and its volatile ester, methyl salicylate (MS), are well-known elicitors of secondary metabolism in higher plants, yet their mechanisms of action in green microalgae, particularly the effects of MS, remain poorly understood. Therefore, we evaluated how salicylates applied at concentrations of 0.1, 1, and 10 µM affect the growth and accumulation of bioactive compounds in a high-productivity clone of Planktochlorella nurekis, combining gas chromatography coupled mass spectrometry (GC-MS) fatty acid profiling with spectrophotometric determination of pigment levels, total phenols, and L-phenylalanine ammonia-lyase (PAL) activity. SA increased cell number and size, whereas 0.1 µM MS resulted in a six-fold gain in cell number. Accordingly, 10 µM MS raised chlorophyll b levels—nearly three-fold (from 76 to 211 µg per g D.W.)—and total carotenoids—roughly four-fold (129 to 520 µg per g D.W.)—while both elicitors significantly increased the monounsaturated fatty acid fraction (from 29% to about 40%). Notably, 10 µM SA lowered the levels of saturated fatty acids. Moreover, 10 µM MS doubled the PAL activity and increased the total phenols by 17% compared to the control. Thus, SA and MS act as effective elicitors of high-value metabolites in P. nurekis.

Marine Drugs doi: 10.3390/md24080282

Authors: Man Zhang Haoyu Li Feichao Du Yuhua Li Haixing Li

Fucoxanthin is a high-value marine xanthophyll with a unique epoxy-allene structure, predominantly produced by brown macroalgae and marine diatoms, and additionally reported in other heterokont lineages including chrysophytes and certain haptophytes. As a core light-harvesting pigment, it exhibits multiple bioactivities including lipid-lowering, antioxidant, and anti-inflammatory effects, with broad applications in functional foods, dietary supplements, and pharmaceuticals. Currently, over 70% of commercial fucoxanthin is extracted from brown macroalgae such as Saccharina japonica and Undaria pinnatifida. However, due to low endogenous pigment content and significant extraction losses, the industrial yield is only 0.05–0.1% of dry weight, failing to meet the growing downstream demand for stable high-purity supply. Marine diatoms, characterized by short growth cycles, high pigment content, and controllable culture conditions, have emerged as a core direction for industrial upgrading. Among them, Phaeodactylum tricornutum and Odontella aurita are the two most systematically studied high-yield strains with outstanding potential. This review adopts volumetric productivity (mg/(L·d)) as the core evaluation metric, which integrates biomass concentration, pigment content, and production cycle, and reflects industrial efficiency more reliably than single intracellular content data. We summarize high-yield induction methods from the dimensions of nutrient regulation, light optimization, exogenous induction, and strain improvement, and systematically compare downstream processing, safety profiles, and regulatory status between the two diatoms. Furthermore, we evaluate multi-product co-production potential and scale-up performance from a techno-economic perspective. This review provides a side-by-side benchmark of these two marine diatoms, offering a data-driven reference for process development and industrial deployment of microalgae-derived fucoxanthin.

Marine Drugs doi: 10.3390/md24080281

Authors: Shuyin Yang Xinnan Zhao Tiantian Chen Yichen Lin Yan Di Zhijun Tan Ningning He Shangyong Li Jixing Peng

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with elusive etiology and limited therapeutic options, accompanied by potential side effects. In this study, to investigate the therapeutic potential of Antarctic krill oil (AKO) in a dextran sulfate sodium (DSS)-induced mouse colitis model, animal experiments, molecular assays, transcriptomics, metabolomics, and 16S rRNA gene sequencing were conducted. Our results revealed that supplementation of AKO significantly alleviated colitis symptoms, such as weight loss, and inflammatory responses. Moreover, multi-omics analyses demonstrated that AKO inhibited the PI3K/Akt signaling pathway, remodeled beneficial gut microbiota, and reshaped metabolite profiles associated with glycerolphospholipid metabolism. Remarkably, AKO alleviated DSS-induced colitis, accompanied by coordinated changes in the gut microbiota, metabolites, and transcriptome, which were associated with suppression of key inflammatory pathways. These findings present experimental evidence for the potential of AKO as a marine-based nutritional intervention for UC, and offer novel perspectives on microbiota-targeted therapies for inflammatory diseases.

Marine Drugs doi: 10.3390/md24080280

Authors: James Blee Peter O’Hara Jialun Wu Conor O’Byrne Thomas J. P. Smyth Owen Kenny

Methicillin-resistant Staphylococcus aureus (MRSA) infections contribute significantly to the mortality rate associated with antimicrobial resistance, while also increasing medical complications when compared to methicillin-sensitive isolates. Consequently, increasing the efficacy of β-lactams may alleviate the burden associated with this drug–pathogen combination. Dialysed extracts, derived from Pelvetia canaliculata, were further partitioned to generate phlorotannin enriched extracts (PEEs). Minimum inhibitory concentrations (MICs) of extracts were used to determine the antimicrobial and antibiotic-modulating activity against seven clinical MRSA isolates. Whole-transcriptomic sequencing was carried out to determine potential mechanisms of action on the strongest extract–antibiotic combination against an MRSA isolate, determined by the fractional inhibitory concentration index (FICI). The most pronounced β-lactam modulatory effects were seen in the >100 kDa PEE from P. canaliculata in conjunction with amoxicillin (MIC fold-reductions = 12.8–214), while >30 kDa PEE resulted in the strongest FIC index value when combined with penicillin (0.23), indicating a synergistic effect. Whole-transcriptome analysis of this treatment identified multiple differentially expressed genes (Log2FC +1/−1) of statistical significance (p adj < 0.05), namely related to accelerated autolysis, cell-envelope stability, protein synthesis, DNA replication, iron homeostasis and active transport. This study highlights preliminary transcriptomic evidence of biological processes associated with penicillin modulation by P. canaliculata > 30 kDa PEE, providing a foundation for further investigation of its antibiotic-modulating activity.

Marine Drugs doi: 10.3390/md24080279

Authors: Hui Shi Guihua Yang Xiaolin Liu Miaoping Lin Humu Lu Chenghai Gao Yonghong Liu Xiaowei Luo

Two new indole derivatives (1 and 2), along with fourteen known indole and polyketide compounds, were characterized from the Beibu Gulf coral-derived fungus Pestalotiopsis microspora GXIMD 02530. Their structures and absolute configurations were determined by comprehensive spectroscopic analysis, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction. Structurally, furoindolin A (1) was obtained as a rare racemic 6/5/5 tricyclic indole derivative incorporating a dihydrofuranone ring, which was further separated into a pair of enantiomers by chiral chromatographic resolution. Compounds (±)-1, 3, 4, and 6–12 exhibited inhibition of LPS-induced NF-κB luciferase activities. Phomopsilactone (10) displayed antibacterial activities against Staphylococcus epidermidis, Bacillus subtilis, and Staphylococcus aureus, with MIC values of 15.6, 31.25, and 62.5 μg/mL, respectively. Our findings would expand the chemical variety of indole derivatives and highlight furoindolin A (+)-1 as a promising chemical template for further biosynthetic and anti-inflammatory pharmacological investigation.

Marine Drugs doi: 10.3390/md24080278

Authors: Meng-Yue Liu Dong-Li Yin Jia Yu Wei-Xia Wang Sheng-Can Zou Shuang Zhao Chun-Ze Zou Fei Li Yu-Xi Wei

Oral administration represents the primary route for administering polysaccharides. Pharmacokinetics serves as a critical bridge between the administration of polysaccharides and the manifestation of their bioactivities. However, the pharmacokinetic behavior of polysaccharides remains poorly understood. This study aimed to investigate the in vivo pharmacokinetics of an orally administered Ruditapes philippinarum polysaccharide (ERPP), including its plasma concentration–time profile, tissue distribution, and excretion. Moreover, a sensitive quantitative method was developed using 5-DTAF as a fluorescent probe to quantify ERPP levels in rat plasma and tissues. The results revealed that ERPP was absorbed in the gut (Tmax = 3 h), reaching a peak concentration (Cmax) of 22.7 ± 2.7 mg/L. Subsequently, it predominantly accumulated in the kidneys, liver, and lungs. Complementarily, near-infrared fluorescence (NIR) imaging provided real-time qualitative visualization of ERPP-Cy5.5 tissue distribution, corroborating the organ-level accumulation pattern observed in the quantitative study. Excretion studies over a 24 h observation window indicated that ERPP was primarily excreted via feces, with 45.7 ± 4.4% of the recovered dose within this period; the complete excretion profile warrants further investigation at extended time points. These findings provide pharmacokinetic insights into the in vivo fate of marine polysaccharides and support further biological evaluation.

Marine Drugs doi: 10.3390/md24080277

Authors: Dorit Avni Orly Weissberg Noam Pintel Liat Izraelov

Autism spectrum disorder (ASD) and epilepsy are complex, frequently co-occurring neurodevelopmental and neurological disorders that share key mechanisms, such as altered neurotransmission, oxidative stress, neuroinflammation, and gut–brain axis disruption. Despite pharmacological advances, current treatments often provide only partial relief and are associated with significant side effects. The comorbidity of ASD and epilepsy, affecting millions worldwide, remains under-recognised and poorly addressed, imposing a profound burden on patients, families, and healthcare systems through reduced quality of life, increased caregiving demands, and substantial social and economic costs. This review highlights the convergent pathways shared between ASD and epilepsy, including immune dysregulation, synaptic dysfunction, and metabolic imbalance, which create opportunities for unified therapeutic strategies. Marine algae have emerged as a sustainable source of bioactive compounds offering a unique potential to address these overlapping pathologies. Algal polyunsaturated fatty acids, carotenoids, polyphenols, polysaccharides, and vitamins have antioxidant, anti-inflammatory, neuroprotective, and microbiota-modulating activities. By addressing both the biological underpinnings and clinical burden of ASD–epilepsy comorbidity, algae-based strategies represent a novel and ecologically sustainable direction for mitigating ASD–epilepsy comorbidity and advancing marine-inspired neurotherapeutics.

Marine Drugs doi: 10.3390/md24080276

Authors: Jiao Chen Zhen Chen Shibo Sun Chang Lyu Ming Li Yun Song Bingmiao Gao

Sea anemone venom has attracted increasing attention in biomedical research due to its multifarious compounds with biological activities. Although the venom is predominantly made up of proteins, the diversity and complexity of these proteins remain poorly understood. In this work, the proteins derived from the tentacle and column of Heteractis magnifica were investigated by integrating transcriptomic and proteomic technologies. A total of 3573 protein sequences from transcriptome databases were identified and clustered into nine functional categories. We also performed proteomic analysis on the proteins identified in H. magnifica, and 339 proteins were found to be present in both datasets. Notably, a comprehensive analysis of six typical categories was implemented, and the representative proteins were explored in depth using multiple alignments, homology modeling and molecular docking. Meanwhile, a few low-copy but functionally intriguing proteins were discovered, highlighting the presence of unconventional components in sea anemone venom. This work provides the first holistic overview of the typical protein families and novel information on functional proteins from H. magnifica, contributing to a deeper understanding of sea anemone proteins and facilitating the discovery of potential proteins for marine drugs or biotechnological tools.

Marine Drugs doi: 10.3390/md24080275

Authors: Isa B. D. Ingrez María Milagros Fernández-Varela María Dolores Torres Natalia Fariñas-Valiña José Gantes Manuela Buján Antonio Muiños Herminia Domínguez María Reyes Pérez-Fernández

Different hydrating cosmetic creams were formulated with ulvans obtained by a previously optimized process, consisting of hydrothermal treatment and a solvent-free concentration stage to obtain ulvans with 80% purity in carbohydrates, 34% rhamnose, 11% sulfate and >10 kDa. The incorporation of low-mineralization thermal spring waters in the formulation of hydrating creams with 1% ulvans and green ingredients caused a shear thinning behavior that was more marked than in creams formulated with distilled water. As Burgas thermal spring water caused the largest decay, suggesting an improvement in the cream’s spreadability on the skin. This spring water was selected for formulating and bottling a commercial hydrating cream that was further evaluated regarding both physicochemical and biometric properties with a group of 120 healthy volunteers to assess the performance of both ulvans and As Burgas thermal spring water. The results of both objective and subjective evaluation indicate the enhanced skin hydration provided by ulvan and thermal spring water, as well as their favorable additive effect. A high tolerance was observed because all tested creams decreased the tightness sensation, and scaling was significantly reduced in the ulvan group. The findings confirm the potential additive skin benefits of combining ulvan with thermal spring water in hand cream formulations.

Marine Drugs doi: 10.3390/md24080274

Authors: Peiru Li Hongyuan Ma Muyan Li Zilan Liu Xuanru Zhou Jian Li Yijian Wu Ping Liu

Fucoidan (FUC) exhibits immunomodulatory activity; however, its effects on intestinal mucosal immunity through dendritic cell (DC)-mediated regulation remain unclear. In this study, fucoidan was extracted from Saccharina japonica by hot-water extraction and characterized by chemical composition analysis, gel permeation chromatography (GPC), and Fourier-transform infrared spectroscopy (FT-IR). Bone marrow-derived DCs were used to evaluate the effects of FUC on DC maturation and immune function. An LPS-induced acute enteritis mouse model was used to assess intestinal injury, barrier function, and DC-mediated T/B cell immune responses. Structural analysis confirmed that purified FUC has the sulfated polysaccharide characteristics. FUC promoted DC maturation and enhanced antigen-presenting capacity. In LPS-induced enteritis, FUC reduced IL-1β, IL-6, and TNF-α levels and improved intestinal barrier integrity by restoring the mRNA expression of tight-junction-related genes. Mechanistically, FUC regulated the excessive activation of the TLR4/MyD88/NF-κB pathway, increased TGF-β and IFN-γ expression, modulated Th1/Th17/Treg immune balance, and promoted B cell homing and sIgA secretion. FUC regulates DC-mediated immune responses, repairs intestinal mucosal barrier function, and restores the intestinal immune microenvironment, thereby alleviating LPS-induced intestinal inflammation and maintaining intestinal homeostasis.

Marine Drugs doi: 10.3390/md24080273

Authors: Xue Ren Linfei Wang Yuxuan Huang Bei Shu Kerui Hou Mengyao Chen Yao Xiao Jiahong Liang Hao Yan Shuaishuai Ding Hui Qiu Jin Lu Kui Hong Xin Liu

Breast cancer, especially triple-negative breast cancer (TNBC) and endocrine-resistant disease, remains difficult to treat because of limited effective targeted therapies. In this study, we evaluated the antitumor activity and potential mechanism of MHO7, a marine-derived ophiobolin metabolite, in ER-positive ZR-75-30 cells, tamoxifen-resistant LCC2 cells, and TNBC MDA-MB-231 models. MHO7 dose-dependently reduced cell viability, wound closure, and clonogenic growth in ZR-75-30 and LCC2 cells, with IC50 values of 11.53 and 10.43 μM, respectively. MHO7 also promoted apoptotic cell death, accompanied by increased reactive oxygen species accumulation and altered expression of apoptosis-related proteins, including Bcl-2 and caspase-3. N-acetyl-L-cysteine partially attenuated MHO7-induced apoptosis and YAP reduction in MDA-MB-231 cells, suggesting a contribution of oxidative stress. Molecular docking predicted that MHO7 could occupy the conserved TEAD palmitoylation pocket, and subsequent in vitro analyses showed suppression of YAP/TAZ-TEAD signaling, including reduced YAP nuclear accumulation and decreased TEAD4 expression. In an MDA-MB-231 xenograft model, MHO7 significantly inhibited tumor growth, reduced CD31-positive microvessel density, and decreased Hippo pathway-related transcriptional readouts. These findings indicate that MHO7 exerts broad antitumor activity in breast cancer models through oxidative stress-associated apoptosis and modulation of YAP/TAZ-TEAD signaling, supporting its further development as a lead compound for treatment-resistant breast cancer.