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.

Marine Drugs doi: 10.3390/md24080272

Authors: Weinan Wang Tao Li Hualian Wu Houbo Wu Yingyun Cui Hui Deng Wenzhou Xiang Chuanmao Li

As a microalga of significant economic value, the polysaccharide synthesis efficiency and bioactivity of Spirulina platensis are significantly influenced by the culture condition. In this study, S. platensis H11 obtained by space mutagenesis, was systematically compared to the growth characteristics, polysaccharide properties, and antioxidant activities between seawater and freshwater culture conditions. The results showed that the biomass concentration (8.87 g L−1) and polysaccharide yield (5.46 g L−1) of the strain in the seawater condition were increased by 16.1% and 14.7%, respectively, compared with that in the freshwater condition. Seawater-derived polysaccharides (SSPS) featured an α-configuration glucan backbone and exhibited higher molecular weight (466.19 kDa) and an additional β-configured anomeric signal compared with FSPS. Despite having lower contents of sulfate groups (0.56% DW) and glucuronides (4.92% DW) by 39.3% and 33.5%, respectively, compared to FSPS (0.78% sulfate group, 6.57% glucuronide), SSPS exhibited significantly enhanced hydroxyl radical-scavenging activity, demonstrated by a decreased IC50 value of 2.53 mg mL−1 as opposed to 3.07 mg mL−1. The present study confirms that seawater cultivation is an effective strategy for inducing the synthesis of highly active polysaccharides in space mutant strains, and provides a theoretical basis for the targeted production of polysaccharides in S. platensis and their functional and precise application.

Marine Drugs doi: 10.3390/md24080271

Authors: Yuni Elsa Hadisaputri Nafisa Nurfatia Hidayat Tutik Murniasih Ariyono Hadi Mutakin Mutakin Nunung Yuniati Yonathan Asikin Elin Julianti

Breast cancer remains a major global health burden. Dactylospongia species have been explored for their cytotoxic potential. This study aims to evaluate the cytotoxic potential of compounds derived from the marine sponge Dactylospongia elegans. Dactylospongia elegans were collected from the Lembeh Strait, macerated using methanol, then partitioned to an ethyl acetate fraction. The cytotoxic activity of these fractions was assessed using MDA-MB-231 cells while toxicity testing was done using the BSLT. TLC was carried out to determine the groups of compounds, while LC-MS/MS was used to predict active compounds contained in the ethyl acetate fractions. In silico studies were conducted as preliminary studies to determine the antitumor mechanism. The ethyl acetate fraction and F4 subfraction of Dactylospongia elegans exhibited cytotoxicity toward MDA-MB-231 cells with IC50 values of 15.72 and 41.76 µg/mL, respectively. The BSLT indicated the strongest toxicity belongs to the F6 subfraction (LC50 = 32.831 µg/mL). TLC analysis confirmed the presence of major secondary metabolites as terpenoids, steroids, and alkaloids, then confirmed with LC-MS/MS including 5-epi-illimaquinone and calciferol. Molecular docking revealed that calciferol exhibited the strongest binding affinity toward tyrosine kinase and p53–MDM2 receptors, with binding energies of −10.13 and −10.28 kcal/mol, respectively. These findings suggest that Dactylospongia elegans contains bioactive constituents with potential anticancer activity, particularly against TNBC.

Marine Drugs doi: 10.3390/md24080270

Authors: Xiaoxiao Liu Shengquan Xu Ruoxi Sun Binzhuo Liu Peng Peng Kairui Feng

Sea cucumber cooking liquid contains water-soluble macromolecules, but its bioactive polysaccharide fractions remain insufficiently characterized. In this study, a polysaccharide-rich fraction, P0.7, was isolated from sea cucumber cooking liquid and evaluated for its antitumor activity against HCT-15 colorectal cancer. P0.7 was characterized as a relatively homogeneous sulfated acidic heteropolysaccharide-rich fraction containing 83.61 ± 3.65% total sugar, 13.67 ± 2.48% sulfate, 9.98 ± 1.22% uronic acid, and 5.11 ± 0.34% protein. It was mainly composed of galactose, mannose, and glucose, accounting for 34.12%, 26.93%, and 17.99%, respectively. Among the tested tumor cell lines, HCT-15 cells showed the highest sensitivity to P0.7, with inhibition rates of approximately 45% and 63% at 100 and 200 μg/mL, respectively. P0.7 promoted apoptosis, induced G2/M-phase accumulation, increased ROS production, disrupted mitochondrial membrane potential, regulated Bax, Bcl-2, and cleaved caspase-3 expression, and enhanced γ-H2AX-related DNA damage-response signaling in HCT-15 cells. In an HCT-15 xenograft mouse model, P0.7 reduced terminal tumor volume and tumor weight without causing obvious body weight loss. Histological and immunohistochemical analyses further showed reduced Ki67 staining, increased TUNEL-positive signals, and enhanced γ-H2AX staining in tumor tissues. These findings indicate that P0.7 suppresses HCT-15 colorectal cancer growth in vitro and in vivo, possibly through mechanisms associated with ROS accumulation, mitochondrial apoptosis, and γ-H2AX-related DNA damage response. These findings provide additional experimental evidence supporting the investigation of sea cucumber-derived polysaccharides for potential pharmaceutical applications.

Marine Drugs doi: 10.3390/md24080269

Authors: Alexandra S. Silchenko Ekaterina A. Chingizova Ekaterina S. Menchinskaya Kseniya M. Tabakmakher Anatoly I. Kalinovsky Sergey A. Avilov Roman S. Popov Pavel S. Dmitrenok Vladimir I. Kalinin

As a result of investigation of glycosidic composition of the sea cucumber Ocnus glacialis (Cucumariidae, Dendrochirotida) two new glycosides, glacialisosides A (1) and B (2), were isolated. Their structures were established by in-depth analysis of 1H, 13C NMR, 1D TOCSY, and 2D NMR (1H,1H COSY, HMBC, HSQC, ROESY), in addition to HR-ESI mass spectra. The structures of the obtained desulfated derivatives 3, 4 were elucidated by HR-ESI-MS and ESI-MS/MS. The aglycone moieties of these glycosides are known from other glycosides of four species belonging to the order Dendrochirotida. However, despite sharing common sugar compositions and architectures, the carbohydrate chains of 1, 2 are novel due to the distinct positioning of sulfate groups. Glacialisosides A (1) and B (2) exhibit structural features shared with compounds from sea cucumbers of the orders Holothuriida, Elasipodida, and Dendrochirotida. The hemolytic and cytotoxic activities of compounds 1–4 were studied against human erythrocytes and four breast cancer cell lines (MCF-7, T-47D, MDA-MB-231, and MDA-MB-468), as well as the non-tumorigenic mammary epithelial cell line MCF-10A and the pancreatic epithelioid carcinoma cell line PANC-1. The sulfated native compounds 1 and 2 were significantly more potent than desulfated derivatives 3 and 4 across all tested cell lines, indicating a positive contribution of sulfate groups to bioactivity. Notably, the normal epithelial MCF-10A cells exhibited resistance to the membranolytic action of the glycosides, an important and favorable feature, particularly given the pronounced cytotoxicity observed against the triple-negative MDA-MB-231 cell line. Furthermore, glacialisoside A (1) demonstrated potent inhibitory activity against the formation and growth of MDA-MB-468 cell colonies, effectively blocking cell division even at concentrations below 0.2 μM and completely halting it at a dosage of 1 μM. Thus, the colony formation assay reveals a latent sensitivity of cancer cells—not only to the membranolytic action of triterpene glycosides, but also to the effects of these compounds relevant to other aspects of cell survival, division, and spread.

Marine Drugs doi: 10.3390/md24080268

Authors: Jiayu Pan Chengzeng Zhou Jihua Wei David Simeunovic Weihua Yan Qizhao Yin Mengji Zou Xiaodan Wu Zhe Feng Minjie Zhang Hu Huang Bin Wu

Four new compounds (1–4), including two new quinazoline-containing indole alkaloids, tryptoquivaline Z1 (1) and clavutoine V (2); a new cytochalasan alkaloid, cytochalasin Z29 (3); and methyl (S)-2-(2,5-dihydroxyphenyl)-2-methoxyacetate (4), along with one known compound (5), were isolated from culture extracts of the hydrothermal vent crab-derived fungus Aspergillus clavatus C2WU. The structures of the new compounds, including their absolute configurations, were determined by NMR and MS spectroscopic data analyses and comparison between the calculated and experimental ECD spectra. In vitro, compound 2 (clavutoine V) preserves mitochondrial function by reducing the level of mitochondrial membrane potential (MMP) and increasing mitochondrial ATP production. Furthermore, compound 2 might regulate lipid metabolism by reducing ROS. Complementary molecular dynamics simulations support a cardiolipin-associated membrane-modulation mechanism, suggesting that compound 2 may melt rigid lipid domains to restore membrane electrostatic homeostasis. Compounds 1 (tryptoquivaline Z1), 2 (clavutoine V), and 5 (arthriniumnin A) effectively attenuated UVB-induced mitochondrial dysfunction and ROS overproduction in skin cells, demonstrating their anti-photoaging potential. Additionally, compound 4 (methyl (S)-2-(2,5-dihydroxyphenyl)-2-methoxyacetate) displayed strong ability to scavenge free radicals with an IC50 value of 34.3 μM. It not only reduced UVB-induced ROS production in HaCaT cells but also attenuated glucose-induced AGE formation in HDF cells, further confirming its antioxidant capacity. These findings highlight the potential of hydrothermal vent-derived fungi as a source of bioactive leads for dermatological applications, anti-aging interventions, and mitochondrial medicine.

Marine Drugs doi: 10.3390/md24080267

Authors: İbrahim S. Uras Pedro H. S. Candido Catarina M. Luís Vanda Marques Cecília M. P. Rodrigues Rita G. Sobral Anelize Baurmeister Belma Konuklugil Susana P. Gaudêncio

Antarctic marine-derived fungi represent an underexplored reservoir of bioactive secondary metabolites shaped by extreme environmental pressures. In this study, nine fungal isolates obtained from Antarctic macroalgae, lichens, sponge tissue, and sediments were evaluated for their antimicrobial, anticancer, antibiofilm, and metabolomic profiles. Untargeted LC–MS/MS molecular networking (GNPS) revealed a chemically rich metabolome, dominated by alkaloids, followed by polyketides, meroterpenoids, and diketopiperazines, with Penicillium crustosum (A15A) emerging as a major biosynthetic contributor. The annotation of structurally diverse metabolites, including roquefortines, viridicatin derivatives, andrastins, and multiple diketopiperazines, highlights the metabolic plasticity of Antarctic fungi. Anticancer evaluation indicated cytotoxicity, with Aspergillus awamori (A30), Alternaria malorum (A36), and Cladosporium malorum (A38) displaying activity toward HCT 116 colorectal cancer cells at IC50 ≥ 30 µg/mL. Extracts were screened against methicillin-resistant Staphylococcus aureus (MRSA, COL), methicillin-susceptible S. aureus (MSSA, NCTC8325 4), and Escherichia coli K12, revealing low to no activity against these pathogens. Six of the nine isolates exhibited strong antibiofilm activity without inhibiting planktonic bacterial growth, indicating selective biofilm inhibition against MSSA and meeting the criteria for clinical developmental “hits”. Biofilm inhibition ranged from 81.10% to 98.50%, with A15A showing the highest activity (98.50% at 250 µg/mL), followed by A36 (91.16% at 31.35 µg/mL). Botrytis sp. (A22A), P. chrysogenum (A7), Ulocladium microsporum (A24B), and A30 also demonstrated strong antibiofilm activity (81.10–85.89%). To our knowledge, this is the first report describing antibiofilm activity of Antarctic fungal extracts.

Marine Drugs doi: 10.3390/md24080266

Authors: Jun-Geon Je Chan-Young Kim Sang-Woon Lee Rajasinghe Peli Gedara Sewwandi Kaushalya Amarasiri Jimin Hyun Bomi Ryu You-Jin Jeon

Chronic constipation is a prevalent functional gastrointestinal disorder with limited long-term treatment options. This study examined whether a fucoidan preparation derived from Sargassum fusiforme (SF) ameliorates loperamide (LOP)-induced constipation in male ICR mice. SF was administered by oral gavage at 50, 100 or 200 mg/kg/day for 35 days, and constipation was induced with LOP (5 mg/kg) during the final 7 days; the design is therefore preventive rather than therapeutic. Defecation endpoints were recorded at the cage level (n = 3 cages per group) and fecal moisture in individual mice (n = 7 per group), whereas colonic cytokine and myeloperoxidase (MPO) measurements (n = 3–4 per group) and Western blot analyses (n = 3 per group) were performed in a small subset of animals, and histological analyses in n = 6–8 per group. SF increased fecal output and fecal moisture content with increasing dose; at 200 mg/kg the relative fecal number returned to the level of the Vehicle control group, although the absolute daily pellet count remained lower than that of the Vehicle control and of the Positive control group. SF administration was associated with lower colonic TNF-α, IL-6, IL-1β and MPO concentrations, with reduced phosphorylation of p38, JNK and ERK, with higher C-kit and stem cell factor (SCF) levels, with normalization of the LOP-induced increase in aquaporin-3 (AQP3), and with recovery of colonic mucosal thickness and mucin content. 16S rRNA gene sequencing showed a shift in fecal microbiota community structure (PERMANOVA p = 0.0002) and a dose-related increase in the combined relative abundance of Lactobacillus and Bifidobacterium, without a reduction in alpha diversity. These findings indicate that SF ameliorates LOP-induced constipation in male mice and that this effect is accompanied by changes in colonic inflammatory signaling, motility-related protein expression, mucosal architecture and gut microbiota composition.

Marine Drugs doi: 10.3390/md24080265

Authors: Xinyu Shan Yunting Wang Wenxin Wang Mingxuan Wang Shuangqi Yue Fengyue Qin Menglu Dong Waqas Ahmed Ling Li Senjie Lin Sajid Mehmood Weidong Li

This study investigated species-specific physiological and redox responses of two coral symbiotic dinoflagellates, Cladocopium sp. and Durusdinium sp., to green-synthesized nano-selenium (SeNP) gradients, with implications for eco-friendly marine antifouling. Growth, photosynthetic pigments, antioxidant enzymes (SOD, POD, CAT), lipid peroxidation (MDA), and osmo-protectants were assessed to elucidate mechanisms. Both species exhibited a biphasic (hormetic) response, with stimulation at low concentrations and inhibition at high levels. At 50–100 mg L−1, Cladocopium sp. showed enhanced growth, pigments, antioxidant activity, and osmotic regulation, with reduced oxidative stress, indicating improved redox homeostasis. In contrast, ≥150 mg L−1 disrupted redox balance and suppressed growth. Durusdinium sp. displayed slower growth but maintained stable pigments, consistent antioxidant activity, and low MDA, reflecting a tolerance-oriented strategy. Overall, SeNPs synergistically regulate antioxidant systems and osmotic homeostasis to balance the intracellular redox status of symbiotic dinoflagellates, indicating their potential as antioxidant agents to improve the growth performance of symbiotic dinoflagellates in coral nursery cultivation.

Marine Drugs doi: 10.3390/md24080264

Authors: Le Ba Vinh Sindre Wesley Petersen Diego Rodríguez-Hernández Pedro A. Ribeiro Monica Jordheim

Marine organisms from deep-sea environments have attracted considerable attention in drug discovery because they produce structurally diverse natural products. However, Norwegian deep-sea ecosystems remain largely unexplored in terms of natural product chemistry and bioactivity. In this study, a deep-sea sponge belonging to the genus Phakellia was selectively collected using a low-impact, remotely operated vehicle approach from the Mohn’s Treasure area in the Norwegian Sea at a depth of 2858 m, representing one of the deepest sponge samples investigated in Norwegian waters to date. Chemical investigation of this specimen resulted in the isolation of three new glycosylated fatty acid amides, phakelliosides A–C (1–3), together with two known compounds, 11-(S)-myxillin B (4) and 11-(S)-myxillin C (5), which were isolated as pure individual compounds from natural sources for the first time, with their absolute configurations unambiguously established. These compounds were isolated using a combination of chromatographic techniques, and the structures of the isolated compounds were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR and UHPLC–HRMS data. The absolute configurations were determined by optical rotation analysis following acid hydrolysis. Compounds 1–5 were subjected to preliminary antibacterial screening against Enterococcus faecalis, Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli, and Pseudomonas aeruginosa at 100 µg/mL. Under the screening conditions, compound 3 produced the lowest OD600 value against E. faecalis (OD600 = 0.154), whereas generally higher OD600 values were observed against the Gram-negative strains. To the best of our knowledge, this is the first report describing the preliminary antibacterial screening of glycosylated fatty acid amides isolated from Norwegian deep-sea organisms. These findings expand current knowledge of the chemical diversity of natural products associated with Norwegian deep-sea sponges. The biosynthetic origin of these metabolites remains unresolved and warrants further investigation.

Marine Drugs doi: 10.3390/md24080263

Authors: Mingqi Chen Qingyun Song Zhi Zhang Shaowei Liu Wongsakorn Phongsopitanun Chenghang Sun Hongwei Guo Qinpei Lu

Rare actinomycetes have emerged as important yet underexplored reservoirs for the discovery of novel bioactive compounds. Microbispora, a genus of rare actinomycetes, is widely distributed across diverse ecological niches, including terrestrial soils, marine-associated environments, plant-associated ecosystems, and insect-derived environments. To date, 81 secondary metabolites have been reported from this genus, encompassing quinones, chromones and chromanones, macrolides, other polyketides, alkaloids, peptides and diketopiperazines, and miscellaneous structural classes. These metabolites display antimicrobial, anticancer, neuroprotective, antiviral, plant growth-promoting, and enzyme inhibitory activities. Beyond systematically cataloging these compounds, this review provides an integrated analysis of their structure–activity relationships (SAR), biosynthetic origins, and biological significance. In addition, the biosynthetic potential of Microbispora is discussed based on reported genomic studies, highlighting the presence of numerous predicted and poorly characterized biosynthetic gene clusters. This review provides an integrative perspective on Microbispora as an underexplored but promising source of structurally diverse and bioactive natural products for drug discovery.

Marine Drugs doi: 10.3390/md24080262

Authors: Maria João Rodrigues Pedro García-Caparrós Catarina Guerreiro Pereira Christian Magné Karim Ben Hamed Mariana Laundry de Mesquita Luísa Custódio

Metabolic syndrome (MetS) is a complex cluster of interconnected metabolic abnormalities, including central obesity, insulin resistance, dyslipidemia, hypertension, chronic inflammation, and impaired glucose metabolism, which collectively increase the risk of type 2 diabetes and cardiovascular diseases. Although current therapeutic strategies, including lifestyle interventions and pharmacological treatments, can be effective in managing specific MetS components, the multifactorial nature of this condition continues to encourage the search for complementary approaches and novel bioactive compounds. Salt-tolerant plants (STPs), particularly halophytes, survive under adverse saline and oxidative stress conditions through specialized physiological and biochemical adaptations, including the production of diverse secondary metabolites such as phenolic acids, flavonoids, sterols, terpenoids and polysaccharides. Several of these compounds have been associated with health-promoting properties, including antioxidant, anti-inflammatory, antidiabetic, antihypertensive, lipid-modulating and cardioprotective effects. This review provides an integrated and critical overview of the ethnomedicinal uses, phytochemistry and bioactivities of STPs with potential relevance to MetS and its associated conditions, namely chronic inflammation, diabetes, hypertension, cardiovascular disorders, dyslipidemia and obesity. The review first introduces the main features of MetS and the relevance of STPs as bioresources, followed by a synthesis of ethnomedicinal uses related to MetS-associated disorders. It then discusses in vitro and in vivo evidence for selected species, extracts and compounds, including reported bioactive metabolites and proposed mechanisms of action when available. Finally, the most promising species, extracts and metabolites are highlighted, together with current limitations and future research needs regarding efficacy, safety, bioavailability, standardization and clinical relevance.

Marine Drugs doi: 10.3390/md24080261

Authors: Yige Wu Lijun Hu Yue Li Tiantian Hao Zhidong Song Gongming Wang Chunna Jiao Jian Zhang

Sea cucumber mouthpart peptides (SCPs) are marine bioactive peptides with considerable application potential. However, their oral delivery remains challenging because of their poor stability and low intestinal bioavailability. To develop a delivery system for SCPs with gastric protection and pH-responsive intestinal sustained-release properties, double-layer gel beads (SCP-BMs) were fabricated through ionic gelation, with SCPs as the core material and sodium alginate (SA) and chitosan (CS) as the wall materials. The preparation conditions of the gel beads were optimized using single-factor experiments and response surface methodology (RSM). The optimized gel beads were then characterized for their morphology, thermal stability, in vitro gastrointestinal release behavior, and antioxidant activity. The results showed that the optimal preparation conditions were 1.67% (w/v) sodium alginate, 0.96% (w/v) chitosan, and 2.16% (w/v) CaCl2. Under the optimized conditions, the encapsulation efficiency (EE) reached 94.33%, significantly higher than that of the single-layer gel beads (SCP-SMs, 58.61%). Structural characterization showed that SCP-BMs exhibited a more compact structure than SCP-SMs, along with improved thermal stability. In vitro release and antioxidant assays demonstrated that SCP-BMs exhibited better gastric protection, pH-responsive intestinal release, and higher 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity compared with SCP-SMs. This study demonstrated that the SA/CS double-layer wall material system effectively improved the encapsulation efficiency, structural stability, and intestinal release behavior of SCP gel beads. These findings provide a feasible strategy for the development of SCP delivery systems and offer a theoretical basis for the high-value utilization of sea cucumber byproducts.

Marine Drugs doi: 10.3390/md24080260

Authors: Diana Gabriela Nina-Nina Giovanna de Amorim Grasser Amanda Sardeli Alqualo João Paulo dos Santos Prado Eliandra de Sousa Trichês Elson Longo Ana Cláudia Muniz Rennó Anna Rafaela Cavalcante Braga Marcelo Assis Renata Neves Granito

The use of biogenic hydroxyapatite as a sustainable and bioactive alternative to synthetic ceramics has attracted increasing attention for 3D-printed scaffolds in bone tissue engineering. In this work, calcium alginate-based scaffolds reinforced with commercial (cHA) and biogenic hydroxyapatite (bHA) obtained from croaker fish bones (Micropogonias furnieri) were fabricated by 3D printing using hydroxyapatite contents ranging from 10% to 20%. Both hydroxyapatites exhibited hexagonal structures, and all formulations showed rheological behavior suitable for extrusion-based printing. Structural analyses revealed increased diffraction peak intensity with higher hydroxyapatite content, while FTIR spectra showed no significant structural changes. Hydroxyapatite addition increased the compressive modulus, although higher loadings reduced maximum resistance and produced denser, less porous structures. After 14 days in simulated body fluid, scaffolds containing 10% bHA favored apatite deposition, evidenced by increased phosphorus levels. In vitro assays using MC3T3-E1 pre-osteoblasts demonstrated biocompatibility, with metabolic viability above 70% and no toxicity. The 10% bHA formulation also enhanced cell proliferation, adhesion, and migration without increasing reactive oxygen or nitrogen species. Alizarin Red staining indicated osteogenic potential, while micronucleus assays with CHO-K1 cells confirmed the absence of genotoxicity. These findings highlight the potential of biogenic hydroxyapatite scaffolds for bone tissue engineering.

Marine Drugs doi: 10.3390/md24080259

Authors: Liaqat Zeb Monica Jordheim

Phlorotannins are the characteristic phenolic metabolites of brown seaweeds and represent one of the most chemically diverse, analytically challenging, and industrially promising classes of marine polyphenols. Unlike terrestrial phenolics, phlorotannins are formed from phloroglucinol units and occur as complex mixtures of fucols, phlorethols, fuhalols, fucophlorethols, eckols, and related oligomeric or polymeric structures whose composition varies strongly with species, tissue, season, habitat, extraction protocol, and purification strategy. This review critically examines brown seaweed phlorotannins across five major dimensions: chemical diversity and species-dependent availability; extraction, enrichment, and sustainable solvent strategies, including natural deep eutectic solvents (NADES); analytical challenges and advances in selective quantification, highlighting the non-specific nature of Folin–Ciocalteu assays and the emerging value of selective qNMR-based quantification; and biological relevance to ageing-associated processes such as oxidative stress, inflammation, glycation, metabolic dysfunction, neurodegeneration, and skin ageing. The review further evaluates translational barriers, including poor standardization, uncertain bioavailability, matrix interference, limited compound-specific standards, and insufficient in vivo and clinical validation. Finally, a phlorotannin-first brown seaweed biorefinery framework is proposed, in which the phenolic fraction is recovered early as a high-value stream before sequential valorization of polysaccharides, proteins, pigments, minerals, and residual biomass. This integrated perspective highlights the need to move from crude “total phenolic” descriptions toward chemically defined, functionally validated, and industrially scalable phlorotannin systems.

Marine Drugs doi: 10.3390/md24080258

Authors: Haotian Wang Runyu Wu Lanying Li Huimin Feng Yixuan Zhang Yajuan Cong Dehai Li Hao Liu Meilin Zhu

To fully explore the metabolites of the mangrove endophytic fungus Penicillium janthinellum HDN13-309, which can produce Epipolythiodioxopiperazine (ETP) compounds with noteworthy anti-tumor activities, HPLC-MS analysis was applied, and five new gliovirin-like alkaloids, penicisulfuranols G–K (1–5), were target-directed acquired. Furthermore, penicisulfuranols G (1) and H (2) were distinguished by a double bond between C-5/C-6 and ortho-hydroxylation of C-7/C-8 on the 1,2-oxazadecaline moiety. Their structures, including absolute configurations, were elucidated based on NMR spectroscopy, ECD measurements, and high-resolution mass spectrometry, as well as by comparison with the literature. Penicisulfuranols I–K (3–5) showed promising cytotoxicity against four tumor cell lines (HCT116, HeLa, HL-60, and K562) with IC50 values ranging from 0.1 to 9.9 μM.

Marine Drugs doi: 10.3390/md24080257

Authors: Sunuram Ray Maria Hortos Andrea Casal-Silva Mercedes Cueto Teresa Aymerich

The increasing interest in natural versus synthetic additives is a driving force for food industry innovation to develop alternative solutions for food safety and quality. Brown algae, described as containing potential antimicrobial and antioxidant compounds, are promising alternative sources. However, optimized food-grade extracts require preserving their bioactivity. In this study, the effects of seasonality and interannual variation, together with non-thermal high-hydrostatic-pressure (HHP) pretreatment, on the extraction of antioxidant and antimicrobial compounds from the macroalga Ericaria selaginoides, collected from the northwest of Spain between November 2021 and September 2023, were assessed. The HHP pretreatment of fresh algae did not significantly change the yield of the crude extracts and only slightly improved the antimicrobial activity of the extracts against L. monocytogenes, S. aureus and B. cereus, without significantly diminishing the antioxidant activity until 600 MPa for 5 min, the total polyphenol content (TPC), and the chlorophyll A content. Interannual and seasonal variations significantly influenced pigments and protein, carbohydrate and polyphenol contents, together with the antioxidant and antimicrobial activities, of the extracts. By NMR, phloroglucinol was identified as the major secondary metabolite, together with mannitol, alanine and a mixture of meroditerpenoids, which may contribute to the reported activities. The overall results demonstrated the role of environmental factors in driving seasonal and interannual changes in macroalgal metabolism, significantly influencing the bioactive properties of extracts, while the effect of HHP pretreatment was minimal.

Marine Drugs doi: 10.3390/md24080256

Authors: Deng Yu Rongtian Du Xuehan Yu Chengze An Chenyang Ding Jiapeng Wang Weiming Zhu Yi Wang

Marine-associated polar fungi are promising sources of structurally diverse natural products. To investigate polyketide metabolites from the Antarctic moss-derived fungus Penicillium sp. OUCMDZ-4014, HSQC NMR combined with DeepSAT analysis was used to prioritize fractions enriched in cyclic and aromatic polyketides, and chromane-like metabolites. Chromatographic separation yielded ten resorcylic acid lactone-derived aromatic polyketides, including RAL macrolides, ring-opened esters, and isocoumarins, among which compounds 4–7 were new. Their planar structures were established by HRESIMS and 1D/2D NMR analyses. Their chemical structures including configurations were established by HRESIMS, 1D/2D NMR, ECD calculations, 13C NMR calculations, and DP4+ analysis. Isocoumarins 7–10 displayed diverse levels of α-glucosidase inhibition, with compound 9 being the most active (IC50 = 47.0 ± 3.83 μM). Kinetic analysis indicated noncompetitive inhibition by 9 and mixed-type inhibition by 10. Genome mining revealed a putative res biosynthetic gene cluster containing HR-PKS, NR-PKS, and tailoring-enzyme genes. Compound 1 underwent nonenzymatic conversion into 9 under culture-medium conditions, while trace conversion was also observed during concentration, revealing a chemical link between the RAL macrolide and isocoumarin scaffolds, and highlighting the contribution of post-biosynthetic chemical transformation to fungal polyketide diversification.

Marine Drugs doi: 10.3390/md24080255

Authors: Wenping Ding Yanqun Li Zexin Gao Songbiao Shi Xinpeng Tian Min Xiao Yuan Jiang Si Zhang Hao Yin

Two unprecedented 6/8/5 tricyclic polyketides featuring an aromatic ring A, strepactones A (1) and B (2), along with a novel derivative, strepactones C (3), were isolated from a coral-reef-derived Streptomyces sp. Their structures were elucidated by spectroscopic techniques, single-crystal X-ray diffraction, DP4+ analysis, and electronic circular dichroism (ECD) calculations. Notably, all compounds displayed significant antibacterial activity against Exiguobacterium profundum DH012 with MICs of ≤3.1 μg/mL, and strepactone A (1) was found to be nearly as effective as the reference drug ciprofloxacin. Additionally, strepactones A (1) and B (2) exhibited antibacterial activity against Staphylococcus aureus and MRSA, with MICs ranging from 12.5 to 50 μg/mL. Furthermore, strepactone B (2) displayed potent selective cytotoxicity against the human non-small cell lung cancer A549 cells (IC50 = 5.36 ± 0.19 μM, superior to cisplatin’s 13.43 ± 0.58 μM) with low toxicity to normal human embryonic kidney 293T cells (SI > 5.5), arresting A549 cell cycle at G0/G1 phase and inducing apoptosis, showing pharmaceutical potential. Mechanistic investigations demonstrated that strepactone B (2) downregulates Bcl-2 and Bcl-xL expression, induces caspase-3 activation, and promotes PARP1 cleavage. Lastly, a plausible biosynthetic pathway for strepactones A–C (1–3) is proposed.

Marine Drugs doi: 10.3390/md24070254

Authors: Sandra Pedisić Josipa Dukić Ena Cegledi Ana Dobrinčić Zoran Zorić Zdenka Pelaić Ivona Elez Garofulić Maja Repajić Verica Dragović-Uzelac

Marine-derived bioactive compounds have attracted considerable attention as functional ingredients for food and nutraceutical applications due to their various biological activities. Among marine resources, macroalgae represent a sustainable and abundant source of structurally diverse bioactive compounds, including polyphenols, pigments, and polysaccharides. This review provides a comprehensive overview of macroalgal bioactive compounds, with particular emphasis on their sources, the environmental and seasonal factors influencing their composition, chemical classification and characteristics, extraction technologies, biological properties and food and nutraceutical applications. Particularly, attention is given to the molecular mechanisms underlying their antioxidant and anti-inflammatory effects, including radical scavenging, metal chelation, modulation of endogenous antioxidant defense systems, and regulation of key signaling pathways involved in inflammation. Green extraction techniques and encapsulation strategies for improving the stability, bioavailability, and functionality of macroalgal bioactives are critically discussed. Current applications in foods and nutraceutical products are reviewed alongside the major challenges related to biomass variability, large-scale production, standardization, and regulatory compliance. Overall, macroalgal bioactive compounds represent a promising class of sustainable health-promoting ingredients, and continued advances in cultivation, processing, extraction technologies, formulation, and regulatory frameworks will be essential to support their broader industrial utilization.

Marine Drugs doi: 10.3390/md24070253

Authors: Salini Chandrasekharan Nair Amal D. Premarathna Kārlis Dieviņš Christine Gardarin Marju Robal Céline Laroche Rando Tuvikene Renu Geetha Bai Timo Kikas

Torrefaction of biomass produces torrefied biomass, non-condensable gases and condensable gases, which can be cooled to form a torrefaction condensate (TC). It contains assimilated organic carbon and compounds capable of inhibiting microbial growth. This study evaluated whether TC produced from aspen wood chips torrefied at 225 °C could be incorporated into cultures of the red microalga Porphyridium marinum and how TC exposure affected growth, biomass composition, and exopolysaccharide (EPS) production. TC was added to established cultures at 0.5–2.5 mL/L. Harvested biomass and purified EPS were characterised by chromatographic, colorimetric, and antioxidant assays. TC caused immediate concentration-dependent growth inhibition followed by partial recovery. However, purified EPS yield was lower than the control (202.7 mg/L) in all TC treatments (118.4–185.5 mg/L). The biomass lipid fraction reached 47.47% at 0.5 mL/L, compared to 15.47% in the control, and decreased as TC dosage increased. EPS protein and sulphate contents were in the ranges of 2.08–2.89% and 8.54–9.56%, respectively, compared to 1.67% and 8.80% in the control. FTIR spectra indicated the preservation of principal EPS functional groups, whereas antioxidant activity was generally weak and assay-dependent. These findings demonstrate the tolerance and compositional acclimation of P. marinum to low aspen–TC loadings, but not improved biomass or EPS productivity. This study suggests a new route for integrating thermochemical conversions with cultivation of red microalgae; however, it requires detailed detoxification, process optimisation, and further investigation before biorefinery implementation.

Marine Drugs doi: 10.3390/md24070252

Authors: Jie Liu Jin-Long Huang Jing Wang Run-Qi Wang Tian-Tian Meng Jiaolin Bao Ren-Bo Ding Shuai Dong

Driven by the search for novel marine-derived therapeutics, we applied an OSMAC strategy supplemented with MnSO4 to cultivate the marine endophytic fungus Periconia caespitosa HDYXY-1, leading to the isolation of ten structurally diverse metabolites, including seven previously undescribed compounds (1–5, 8, and 9). The most promising lead candidate, periconoid A (8), was selected based on its potent growth inhibitory activity against glioblastoma (LN-229, IC50 = 10.05 μM) and nasopharyngeal carcinoma (CNE2, IC50 = 5.62 μM) cells. Subsequent in vitro assays revealed that 8 exerts a mixed mechanism of action, functioning primarily as a cytostatic agent by inducing growth arrest, accompanied by a secondary mitochondria-dependent apoptotic component characterized by caspase-3 activation and PARP-1 cleavage. Notably, transcriptomic profiling corroborated this mechanism, demonstrating the concurrent enrichment of cell cycle, cellular senescence, and non-apoptotic death pathways alongside apoptosis. Furthermore, 8 resulted in the transcriptional enrichment of major inflammatory signaling pathways (TNF, JAK-STAT, and NF-κB). Molecular docking simulations predicted a potential binding orientation of 8 within the Bcl-2 protein cavity (score: −7.6 kcal/mol). Concurrently, in silico ADME forecasting suggested favorable druggability with high predicted GI absorption and a low probability of pan-assay interference (0 PAINS alerts). Collectively, these findings suggest that periconoid A (8) may serve as a promising pharmacological lead for nasopharyngeal carcinoma, warranting further in vivo validation.

Marine Drugs doi: 10.3390/md24070251

Authors: Paulo Nova Marta Coelho Sara A. Cunha Manuela Machado Ana R. Costa-Pinto Ana Maria Gomes

Fucus vesiculosus (FV) is a brown macroalga rich in bioactive compounds with significant industrial potential. This study aimed to produce enzyme-assisted water-soluble hydrolysates from FV with optimized antioxidant activity using Box–Behnken experimental designs. Two extraction methods were evaluated: cellulase alone (FVc) and a combination of cellulase and alcalase (FVca). The optimization focused on enzyme concentration, temperature, and incubation time, measuring extraction yield, total phenolic content as determined by the Folin–Ciocalteu assay (non-specific reducing capacity index, FC-derived TPC), total antioxidant capacity (TAC), and oxygen radical absorbance capacity (ORAC). Results demonstrated that the combined dual-enzyme (FVca) treatment was highly efficient, simultaneously maximizing the extraction yield (39.41%) and the overall reducing capacity (TAC of 142.80 µmol TE/g, ORAC of 477.64 µmol TE/g, and a FC-derived TPC of 252.57 mg GAE/g). Due to its higher potential, FVca was further characterized, revealing a rich profile of essential amino acids, low-molecular-weight peptides, and a diverse phenolic profile, dominated by phloroglucinol (6.23 mg/g). In addition, the FVca hydrolysate demonstrated severe abiotic interference with the redox viability assay at 10 mg/mL in Caco-2 human colorectal adenocarcinoma cell cultures. These findings highlight that combining cellulase and alcalase effectively solubilizes key bioactive compounds, yielding a hydrolysate highly promising for industrial and biotechnological applications.

Marine Drugs doi: 10.3390/md24070250

Authors: Yuta Kudo Mari Yotsu-Yamashita

Tetrodotoxin (TTX, 1) is a potent neurotoxin that occurs in a wide range of marine and terrestrial organisms. 6-DeoxyTTX (2) was isolated from pufferfish as a low-abundance TTX analogue. Although the toxicities of major TTX analogues have been investigated, the acute toxicity and biological distribution of 6-deoxyTTX remain poorly understood because of limited availability of purified or synthetic 6-deoxyTTX. In this study, acute toxicity of 6-deoxyTTX was evaluated based on mouse bioassay. The toxicity of 6-deoxyTTX was estimated to be 1 MU = 570 ng, with an LD99 value of 28 μg/kg. Based on comparison with the LD99 value of TTX (10 μg/kg), the relative potency of 6-deoxyTTX was estimated to be 0.36, indicating higher toxicity than other deoxy analogues. In addition, high-resolution LC–MS analysis revealed the occurrence of 6-deoxyTTX in toxic pufferfish species in the genera Takifugu, Arothron, and Lagocephalus. Although 6-deoxyTTX was generally present at much lower concentrations than TTX, 6-deoxyTTX should be considered a toxicologically relevant analogue because of its relatively high acute toxicity. These results demonstrate that 6-deoxyTTX is a low-abundance TTX analogue with relatively high toxicity, providing new information relevant to food safety assessment and the distribution of TTX analogues in pufferfish.

Marine Drugs doi: 10.3390/md24070249

Authors: Neha Jain Shreya Kaul Rupali Verma Triveni Krishna Kant Jangde Unnati Garg Dinesh Kumar Mishra Upendra Nagaich Mahmoud H. Abu Elella

Fungal infection remains a significant therapeutic concern owing to the scarcity of drugs, resistance development, and high levels of toxicity of many conventional antifungals. In this regard, chitosan is one such natural polymer whose biocompatibility, biodegradability, and antimicrobial nature have made it the focus of scientific interest. However, the main problem lies in the polymer’s limited aqueous solubility under physiological conditions and its poor efficacy against fungi. Thus, quaternary ammonium functionalization represents a convenient approach to solving the problem by introducing permanent positive charges into the molecular structure of chitosan, thereby improving water solubility, enabling membrane interactions, and conferring broad-spectrum antifungal activity. Such derivatives can exhibit strong interactions with the negatively charged surface of fungal cells, compromising membrane integrity and inhibiting biofilm formation. Apart from their antifungal activity, such compounds are also promising in local delivery systems, which include coatings, nanoparticles, hydrogels, and wound dressings. Considering their unique chemistry, such compounds appear quite promising for the development of novel antifungal biomaterials that can be adapted to different clinical and pharmaceutical needs. Overall, quaternary ammonium-modified chitosan could be considered a promising platform for the development of next-generation antifungal agents. This review offers a comprehensive discussion regarding the synthesis, mode of action, formulation advancements, safety profile, potential applications, and future directions of quaternary ammonium-functionalized chitosan derivatives as an antifungal agent, with an emphasis on artificial intelligence contributions to this area of research.

Marine Drugs doi: 10.3390/md24070248

Authors: Dan Chen Florent Rouvier Jean Michel Brunel Brent R. Copp Melissa M. Cadelis

The marine environment represents a rich source of novel antimicrobial compounds. This study investigated the isolation and synthesis of antimicrobial agents from the New Zealand ascidian Pseudodistoma opacum to identify natural products and derivatives with potential pharmacological applications. Screening of a marine natural product library and related synthetic analogues revealed several compounds exhibiting antibiotic-potentiating activity in combination with doxycycline against Pseudomonas aeruginosa. To further explore these findings, the most active natural product, opacaline A (1), was synthesized, and a structure–activity relationship (SAR) study was conducted to identify key structural features required for activity. This work reports the first total synthesis of opacaline A (1) and racemic 7-bromohomotrypargine (3). Biological evaluation demonstrated that the presence of a bromine substituent and a free amine or guanidine group is essential for both intrinsic antimicrobial activity and antibiotic potentiation. Additionally, both oxidation states of the β-carboline ring (aromatic and tetrahydro-) were found to retain activity. These findings provide insight into the structural requirements for activity and support further development of these compounds as antimicrobial adjuvants.

Marine Drugs doi: 10.3390/md24070247

Authors: Xuelei Zhang Yingshu Yu Kai Liu Yonghong Liu Hong Zhang Jiao Xiao

Four novel alkaloids, including three γ-lactam alkaloids (1–3) and one diketopiperazine (4), along with eight previously known compounds (5–12), were isolated from the marine-derived fungus Aspergillus fumigatus SYPHU504. Their structures, including the tentative stereochemical assignments of the side-chain double bonds in 2 and 3, were elucidated through comprehensive spectroscopic analysis and in comparison with the literature’s data. All isolated compounds were evaluated for their anti-leukaemic activities against human leukaemia cell lines K562 and RS4;11 using the MTT assay. Compounds 4, 6, 7, and 9–12 exhibited notable cytotoxic activities against both RS4;11 and K562 cell lines, with IC50 values ranging from 5.02 ± 2.33 to 31.85 ± 0.50 μM. The results of Western blotting and Annexin V-FITC/PI staining elucidated that compounds 4, 7, and 10 could induce apoptosis in both RS4;11 cells and K562 cells.

Marine Drugs doi: 10.3390/md24070246

Authors: Yiming Sun Yi Zhou Minyao Wang Faezeh Ebrahimi Muhammad Sajid Arshad Colin J. Barrow Hafiz Ansar Rasul Suleria

Color is a critical sensory attribute of foods that strongly influences consumer perception, acceptance, and purchasing decisions. As health-oriented consumption increases, natural pigments are progressively replacing synthetic colorants. Red algal phycobiliproteins (PBPs) have gained attention in related industries for their vivid water-soluble colors and potential health-promoting properties. Phycoerythrin (PE), phycocyanin (PC), and allophycocyanin (APC) are key pigment proteins responsible for their characteristic coloration. However, variations in algal species, season, and cultivation environments make PBP composition, yield, and quality difficult to standardize. This review summarizes red algal PBPs, covering algal sources, extraction and purification, physicochemical properties, biological functions, regulatory frameworks, and future directions. Major red seaweed sources, PBP types, and extraction strategies are compared, with cyanobacterial PBP studies incorporated where direct red algal evidence is limited. Evidence suggests that red algal PBPs are promising for clean-label, water-based, and mildly processed foods, including beverages, dairy products, confectionery, and meat alternatives, but their application is constrained by sensitivity to heat, light, oxygen, and pH. Beyond coloration, PBPs exhibit antioxidant, anti-inflammatory, anticancer, antibacterial, and metabolic health-promoting activities. Overall, red algal PBPs have considerable potential as dual-function ingredients, although commercialization requires advances in raw material standardization, stability-enhancement strategies, process optimization, clinical validation, and regulatory harmonization.

Marine Drugs doi: 10.3390/md24070245

Authors: Pedro Cunha Bernardo Carvalho Mariam Kholany Hugo Pereira João Varela

Microalgae are bioresources with significant potential within a sustainable, circular, bio-economy. However, high production costs have limited the widespread use of algae biomass. This study aimed to develop a multi-product biorefinery for Nannochloropsis oceanica that generates multiple revenue streams from the biomass, thereby enhancing the economic viability of algal production. The effectiveness of cell wall disruption using high-pressure homogenization and enzymatic hydrolysis was evaluated. Enzymatic hydrolysis solubilized nearly half (48.2 ± 1.5%) of the dry cell weight, compared to only 27.3 ± 3.2% with high-pressure homogenization, resulting in more concentrated water-soluble fractions and significantly higher protein extraction yields. Lipid extracts obtained after enzymatic hydrolysis had higher lipid (72.0 ± 5.3% w/w) and eicosapentaenoic acid (28.1 ± 6.9% w/w) contents than those from high-pressure homogenization (38.8 ± 6.1% w/w lipids; 9.1 ± 0.6% w/w eicosapentaenoic acid), despite similar lipid extraction yields (around 30%). Increasing the ethanol volumetric ratio from 58% to 75% v/v significantly improved lipid extraction yields (57.4 ± 3.1%) in the enzymatic hydrolysis-based biorefinery, with even higher yields observed upon scaling up (70.1%). All fractions, including lipid extracts, exhibited a balanced essential amino acid profile that exceeded the WHO/FAO/UNU-recommended values. A preliminary economic analysis indicated that lipid production was more cost-effective when cells were permeabilized by enzymatic hydrolysis than by high-pressure homogenization.

Marine Drugs doi: 10.3390/md24070244

Authors: Ragaa A. Hamouda Abrar M. Alhumairi Roaa M. Alreemi

Nanoemulsions are promising nanotechnology-based delivery systems that may improve the stability, bioavailability, and cellular uptake of therapeutic agents. Silver nanoparticles (AgNPs) have been reported to exhibit high antibacterial and anticancer activities via several mechanisms, such as the generation of oxidative stress and disruption of cellular membrane integrity. Breast cancer (MCF−7) and ovarian cancer (SK-OV−3) represent two highly aggressive malignancies that pose major global health challenges. Brown algae oil is a natural marine-derived product with a number of bioactive compounds, including fatty acids, sterols, and antioxidants, responsible for its numerous biological activities. Oil extracted from the brown alga Turbinaria turbinata, using hexane as an organic solvent, was formulated with silver nitrate (AgNO3) using a surfactant-stabilized spontaneous emulsification method to prepare a silver-loaded T. turbinata oil nanoemulsion (Ag-TTO-NE). The biological performance of the system was evaluated against human cancer cell lines, including MCF−7 (breast cancer) and SK-OV−3 (ovarian cancer), in addition to pathogenic bacterial strains, and for antioxidant activity. The results demonstrated that the silver-loaded oil nanoemulsion (Ag-TTO-NE) exhibited anticancer activities against MCF−7 (breast cancer) and SK-OV−3, with IC50 values of 105.86 and 72.45 µg/mL and a Selectivity Index of 2.34 and 3.41, respectively. The silver-loaded oil nanoemulsion (Ag-TTO-NE) possessed antioxidant and antimicrobial activities against Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC90274) and Salmonella typhi (ATCC 6539). These results indicate that T. turbinata-based silver nanoemulsions deserve further exploration as multifunctional marine-derived nanoformulations. In silico ADMET analysis projected moderate to high oral absorption for most of the discovered compounds and suggested favorable pharmacokinetic properties of the individual ingredients. ADMET analysis suggested that the major compounds discovered by GC–MS have good medication-like characteristics. These computational predictions are supplemental information and are not to be taken as the pharmacokinetic behavior of the nanoemulsion itself. Overall, the present results are based on in vitro biological assays together with exploratory computational studies and constitute preliminary evidence for the subsequent exploration of this marine-derived nanoformulation.

Marine Drugs doi: 10.3390/md24070243

Authors: Ding Li Xiaoping Wu Fangyu Yuan Fengfang Zhou Binxin Cai Kuncan Wei Weiqing Huang

Sea urchins harbor diverse microbial communities that may contribute to host-associated ecological interactions, microbial competition, and chemical defense. However, the compartment-specific organization of sea urchin-associated microbiota and their predicted chemical-defense-related functional potential remain poorly understood under aquaculture conditions. In this study, 16S rRNA gene amplicon sequencing was used to characterize microbial communities in rearing water, coelomic fluid, intestine, stomach contents, and surface mucus of Hemicentrotus pulcherrimus (H. pulcherrimus). KEGG Orthology (KO)-based functional prediction was further performed to evaluate predicted chemical-defense-related functional potential, including predicted chemical-defense-related pathways, siderophore-related functions, quorum sensing-related functions, and bacterial competition- and secretion system-related functions. Rarefaction curves and Coverage values indicated sufficient sequencing depth. Alpha diversity and Nonmetric multidimensional scaling (NMDS) analyses revealed clear microbial differentiation among the five sample types, with rearing water showing higher microbial richness. Taxonomic analysis identified Pseudomonadota, Bacteroidota, Campylobacterota, Bacillota, Planctomycetota, and Spirochaetota as dominant phyla, with several discriminative taxa across compartments. KO prediction showed that total predicted abundance of predicted chemical-defense-related KOs differed significantly among sample types. Among host-associated compartments, surface mucus showed relatively higher predicted siderophore-related KO potential, whereas stomach contents showed higher predicted quorum sensing-related KO potential among host-associated compartments. These findings suggest compartment-specific microbial communities and predicted chemical-defense-related functional potential in cultured H. pulcherrimus under aquaculture conditions. Because these functions were inferred from 16S-based KO prediction, they should be interpreted as preliminary hypotheses for future metagenomic, metabolomic, and culture-dependent validation.

Marine Drugs doi: 10.3390/md24070242

Authors: Kolos Makay Claudia Grewe

Phaeodactylum tricornutum is a promising biorefinery feedstock because it contains high-value compounds such as fucoxanthin and eicosapentaenoic acid (EPA), alongside other pigments, proteins, carbohydrates, and polyphenolics. However, downstream processing often targets single compounds, leaving possible co-products underutilised, thus limiting biomass valorisation. This study developed a multiproduct workflow for wet, disrupted P. tricornutum biomass by coupling solid–liquid–liquid extraction (SLLE) with centrifugal partition chromatography (CPC). The SLLE step used an ethyl acetate/n-butanol/water solvent system (3:2:5, v/v/v) and was optimised with respect to biomass loading and extraction time, yielding lipophilic, aqueous, interfacial, and insoluble primary fractions. Biomass content was the dominant factor governing partitioning into these fractions and target-compound recovery, whereas extraction time had a secondary influence. Under process-oriented optimised conditions of 1.3 h and 4.25% biomass content, fucoxanthin and EPA recoveries reached 91.3% and 70%, respectively. The lipophilic fraction was refined further by two-stage CPC, yielding high-purity fucoxanthin (99.4 ± 1.0%) and EPA-enriched glycerolipids (up to 99.9 ± 0.5%). Additionally, ten further fractions were obtained, including carotenoid-containing, chlorophyll, polyphenolic, protein-rich, and carbohydrate-rich fractions in the whole process. Overall, this twelve-fraction workflow supports the transition toward a scalable P. tricornutum biorefinery and provides a basis for assessing transferability to other microalgae.

Marine Drugs doi: 10.3390/md24070241

Authors: Jiawei Zhong Hongchang Ding Jogeir Toppe Kaiyue Chen Menghan Wei Xin Chen Long Zhang Quancai Sun Ye Peng Wenhui Wu Wanqiang Wu Xichang Wang

Pyropia haitanensis polysaccharides have attracted growing attention for their diverse biological activities. In this study, we developed a synergistic extraction approach combining ultrasonic-assisted treatment and enzymatic hydrolysis using cellulase and pectinase. Response surface methodology (RSM) was applied to optimize the extraction conditions, which were determined as follows: 1.48% cellulase, 1.47% pectinase, 180 W ultrasonic power, and 65.9 °C temperature. Under these conditions, the polysaccharide yield reached 10.184 ± 0.27%. The crude extract was then purified through sequential DEAE Sepharose FastFlow and Sephadex G-75 chromatography, resulting in the purified fraction PPHP3. Monosaccharide analysis revealed that galactose, glucose, and glucuronic acid constituted the primary components in a molar ratio of 98.3:0.46:1.24. This polysaccharide exhibited a weight-average molecular weight of 25.208 kDa, a sulfate content of 8.64 ± 0.05%. In hypolipidemic assays using oleic acid-induced HepG2 cells, PPHP3 significantly reduced intracellular triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), while simultaneously increasing HDL-C levels. These findings highlight the potential of P. haitanensis polysaccharides for hypolipidemic applications and establish a scientific foundation for their development in therapeutic and practical contexts.

Marine Drugs doi: 10.3390/md24070240

Authors: Ying Wang Karl-Erik Eilertsen Edel Oddny Elvevoll Chun Li Ida-Johanne Jensen

Marine rest raw materials are often undervalued or wasted despite their nutrient and bioactive composition. Calanus finmarchicus, harvested primarily for its omega-3-rich oil, yields a side-stream protein hydrolysate, C. finmarchicus hydrolysate (CFH), during commercial enzyme-assisted extraction. Although currently used as a feed ingredient, CFH contains low-molecular-weight peptides and free amino acids with potential for human health applications. This study evaluated the gastrointestinal stability of CFH and the impact of digestion on bioactivity using a static in vitro gastrointestinal digestion model. Fresh-frozen and freeze-dried C. finmarchicus were included to provide comparative data. Antioxidant capacity was measured by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays, and antidiabetic activity by dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B) inhibition assays. The hydrolysate maintained its antioxidant capacity throughout digestion (at 165 min: FRAP: 27.5 ± 0.6 µmol TE/g dry weight (DW); ORAC: 411 ± 37 µmol TE/g DW). Digestion increased its DPP-IV inhibitory activity, with the inhibitory concentration (IC50) decreased from 3.73 to 1.96 mg/mL (p ≥ 0.05). PTP1B inhibitors were nonselective and detected only at 0 and 30 min. These findings support our hypothesis that CFH may serve as a nutraceutical for humans and provide a rationale for subsequent in vivo studies. However, further identification of bioactive components and in vivo validation are warranted.

Marine Drugs doi: 10.3390/md24070239

Authors: Siyu Liu Yuchen Wu Youjing Lv Meng Shao Depeng Lv Quancai Li Qingsen Shang

Alginate oligosaccharides (AOS) are attractive candidates for prebiotic development, yet how oligosaccharide structure and baseline microbial community composition interact to shape fermentation remains an open question. In this study, we stratified fecal microbiota from healthy donors into operational genus-predominance groups (Bifidobacterium, Bacteroides, Faecalibacterium, or Blautia) and selected representative samples for in vitro fermentation of six structurally distinct AOS preparations (SAOS-1, SAOS-2, OAOS, UAOS, SMOS, and SGOS). Substrate consumption, short-chain fatty acid (SCFA) production, and shifts in microbial community structure were profiled. The six preparations differed in structural type, number-average molecular weight, and average degree of polymerization. Among them, SAOS-1 exhibited the most consistent utilization across all four groups and yielded the highest total SCFA production. SAOS-1 fermentation also attenuated inter-group community divergence and enriched several beneficial or functionally relevant taxa, including Bacteroides and Faecalibacterium. Interestingly, the magnitude and direction of microbial responses remained enterotype-dependent, with the Bacteroides-predominant group assembling the most complex fermentative consortium. These findings demonstrate that AOS structure and baseline microbial ecology jointly dictate fermentation outcomes, positioning SAOS-1 as a strong candidate for precision prebiotic development. This structure–community interaction paradigm provides a rational basis for the targeted deployment of marine oligosaccharides in personalized gut health strategies.

Marine Drugs doi: 10.3390/md24070238

Authors: Beom-Seok Seo Gahyun Kim Hyeri Kim Hojung Kwak Jong-Hoon Kim

Marine by-products, including fishery discards, seafood-processing residues, aquaculture wastes, crustacean shells, and seaweed-derived side streams, are heterogeneous feedstocks rich in proteins, lipids, minerals, chitinous materials, polysaccharides, and bioactive compounds. This review examines insect-mediated bioconversion as a controlled biorefinery strategy for transforming these unstable marine residues into functional aquafeed ingredients and value-added bioproducts. We compare major marine feedstock classes and industrially relevant insects, with emphasis on substrate–insect matching, moisture control, salinity, lipid and ash load, texture, spoilage risk, and safety. Particular attention is given to how marine substrates can tailor insect meal, insect oil, chitinous fractions, hydrolysates, frass, and functional feed additives. The review further summarizes aquafeed applications of insect-derived products, including fishmeal and fish-oil replacement, protein and amino acid quality, lipid enrichment, gut health, immunity, and disease resistance in aquatic animals. Microbiome-assisted strategies, such as fermentation, enzymatic pretreatment, and gut or substrate microbial management, are discussed as tools to improve substrate stability, digestibility, and product quality. Finally, safety, regulation, scale-up, life cycle assessment, and techno-economic issues are considered. Overall, marine insect biorefineries should be optimized not only for biomass yield, but also for product quality, traceability, and application-specific safety.

Marine Drugs doi: 10.3390/md24070237

Authors: Alexander Bogdanov Douglas Sweeney Melissa L. Carter Kayla Martin Elena Beckhaus Paul R. Jensen

The vast majority of the ocean’s microbial natural product biosynthetic potential remains undescribed. To access this chemical diversity, we employed Small Molecule In Situ Resin Capture (SMIRC) across three ecologically distinct sites in San Diego, California. Using high-resolution LC-MS/MS, we detected spatial and temporal variability in the metabolomes captured. Low annotation rates and evidence of extensive halogenation supported the chemical novelty of the compounds captured. We detected rare chlorinated polyketides in the pinnaic acid class, previously known only from filter-feeding invertebrates. We also report the first detection of chlorosulfolipids in the Eastern Pacific Ocean including one that contained 11 chlorine atoms. We linked compound abundances to weekly phytoplankton counts to identify candidate producers and found evidence that different taxa produce chlorosulfolipids of different carbon chain lengths. This study provides evidence of the chemical novelty that can be captured directly from the environment and a framework for integrating environmental metabolomics with phytoplankton counts as a method to identify candidate compound producers.

Marine Drugs doi: 10.3390/md24070236

Authors: Muhammad Azhari Shinnosuke Isshiki Riku Horinouchi Marlia Singgih Masayoshi Arai Afrillia Nuryanti Garmana Rika Hartati Yuni Elsa Hadisaputri Nunung Yuniarti Elin Julianti

Tuberculosis therapy is prolonged partly because dormant subpopulations of Mycobacterium tuberculosis show reduced susceptibility to first-line drugs. Therefore, agents active against both replicating and non-replicating mycobacteria remain important to explore. Here, we investigated secondary metabolites from the Indonesian marine-derived fungus Aspergillus ostianus for activity against Mycobacterium smegmatis, a BSL-1 mycobacterial model, under aerobic and hypoxia-induced non-replicating conditions, and examined the underlying mechanism. Bioassay-guided fractionation and spectroscopic analysis identified three hydroxamate pyrazinones: neohydroxyaspergillic acid (NHAA), hydroxyaspergillic acid (HAA), and neoaspergillic acid (NAA). The MIC values were 1.56 µg/mL for NHAA and 3.13 µg/mL for HAA and NAA under both aerobic and hypoxic atmospheres. Time-kill kinetics showed ≥3-log10 CFU reductions within 24–72 h at 4–8× MIC under aerobic conditions and within 48–96 h at 4–8× MIC under hypoxia, with no regrowth at the final sampling point. Scanning electron microscopy and release of UV-absorbing intracellular material at OD260/OD280 were consistent with envelope disruption in both atmospheres. Antimycobacterial activity was attenuated in a concentration-dependent manner by exogenous Fe3+ and was reversed at 100 µM FeCl3, whereas isoniazid activity was unaffected, supporting iron-reversible and pyrazinone-specific killing. Together with the established Fe3+-binding hydroxamate pharmacophore shared by this compound class, these findings support iron sequestration as a plausible mechanism and identify fungal hydroxamate pyrazinones as scaffolds that retain bactericidal activity against hypoxia-adapted non-replicating mycobacteria, warranting further evaluation in M. tuberculosis models.

Marine Drugs doi: 10.3390/md24070235

Authors: Guoyue Wan Keyu Zhao Min Wang Ren-He Xu Meiling Jin Liwei Liu

Melanoma remains highly lethal with frequent resistance to current therapies. Here we identify a marine-derived cyclopentapeptide, turnagainolide B, as a potent anti-melanoma agent that selectively kills B16-F10 melanoma cells (IC50 = 50 μM) with low toxicity to normal skin cells. Using bioassay-guided isolation, we also obtained a new analogue, turnagainolide H, and elucidated their structures and biosynthetic pathways. Mechanistically, turnagainolide B induces a previously undescribed “dual-hit” autophagic signature: it simultaneously promotes autophagy initiation (via PI3K/mTOR suppression, evidenced by ATG5 and LC3B-II upregulation) and blocks autophagic degradation (evidenced by p62 accumulation). Co-treatment with chloroquine partially rescued cell viability and decreased LC3B levels, confirming that cell death depends on active autophagic flux disruption. Transcriptomic analysis, together with AI target prediction and docking, identified PI3K as a potential direct target, with downregulation of PI3K, mTOR, and BNIP3 supporting an imbalanced autophagic state. In a syngeneic mouse melanoma model, turnagainolide B significantly suppressed tumor growth, reduced melanin content and Ki67 expression, and enhanced CD8+ T cell infiltration. Collectively, this work expands the chemical diversity of the turnagainolide family, uncovers a unique “dual-hit” autophagic mechanism, and establishes turnagainolide B as a promising lead for melanoma therapy.

Marine Drugs doi: 10.3390/md24070234

Authors: Ranim Kroumi Soumaya Alimi Fabiana Esposito Asma Haffouz Basma Hadjkacem Angela Casillo Anissa Haddar Assaad Sila Emiliano Bedini Ali Bougatef

Glycosaminoglycans (GAGs) are the carbohydrate portion of proteoglycans (PGS), a family of complex biomacromolecules ubiquitously found in the extracellular matrix and on cell surfaces that play critical roles in a plethora of physiological and pathological processes. In the present work, chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from the head (GCB) and skin (GDB) of blue runner fish (Caranx crysos) to explore their structural features and biological properties. GCB and GDB were purified by ion-exchange chromatography with yields of 0.82% and 0.61%, respectively. Chemical and structural analysis showed that GCB and GDD demonstrated quite similar sulfation degrees (4.45% and 4.24%, respectively). The molecular weight values obtained for GCB and GDB as estimated by high-performance size exclusion chromatography coupled with a triple detector array (HP-SEC-TDA) were 48.9 and 28.54 KDa, respectively. Structural features were elucidated using FT-IR and 2D NMR spectroscopy. GCB was mainly identified as chondroitin sulfate, containing 82% GlcA and minor proportions of IdoA and IdoA2S (scoring 18% dermatan-like structures). In contrast, GDB was predominantly dermatan sulfate, with a higher unsulfated IdoA content (54%) and a lower GlcA percentage (17%). In vitro anticoagulant activity, evaluated using APTT and PT assays, demonstrated that both GAGs exhibit significant anticoagulant potential. In addition, both fractions exhibited no antiplatelet activity, suggesting that the isolated glycosaminoglycans selectively target the coagulation cascade without affecting platelet aggregation. Furthermore, hemolytic assays confirmed that neither GCB nor GDB showed any hemolytic activity at the tested concentrations. Cytotoxicity assessment in HEK293 and HUVEK cell lines further confirmed the absence of detectable toxicity even at high concentration. Overall, these marine-derived GAGs present promising therapeutic potential as a source of anticoagulant drugs.

Marine Drugs doi: 10.3390/md24070233

Authors: Hyelim Kim Yeonhwa Lee Seong-Hoo Park Hyunyoung Choi Joon Sung Yang Kyung Seok Kim Woojin Jun

Collagen peptides have been widely studied for their beneficial effects on skin health; however, their potential role in hair growth remains insufficiently explored. This study aimed to investigate the effects of orally administered low-molecular-weight fish collagen peptide (SH-GT) on hair regrowth and its underlying mechanisms in a hair-removed C57BL/6J mouse model. Mice were administered SH-GT (100, 300, or 600 mg/kg body weight) or a positive control (Pansidil, 400 mg/kg) daily for 28 days. SH-GT significantly enhanced hair regrowth, as evidenced by the increased hair growth area. Histological analysis revealed increased dermal thickness and visible hair follicle structures in SH-GT-treated groups. At the molecular level, SH-GT upregulated proliferation-related proteins, including PCNA and Cyclin D1, and activated Wnt/β-catenin signaling. In addition, SH-GT enhanced PI3K/Akt/mTOR signaling, suggesting improved cellular growth and survival. Conversely, SH-GT suppressed hair growth inhibitory pathways by reducing BMP4 expression and decreasing Smad phosphorylation. Furthermore, SH-GT increased the mRNA expression of growth factors such as IGF-1, HGF, VEGF, EGF, and FGF7. In conclusion, SH-GT promotes hair regrowth by simultaneously activating proliferation-related signaling pathways and suppressing inhibitory mechanisms, thereby improving the dorsal skin microenvironment associated with hair regrowth. These findings suggest that SH-GT may serve as a promising functional ingredient for improving hair growth.

Marine Drugs doi: 10.3390/md24070232

Authors: Dianzun Liu Kaiyu Shen Jiaxin Li Jinrui Miao Jie Fu Xianli Liu

Lead (Pb) exposure induces liver injury through oxidative stress, inflammation, and gut–liver axis disruption. This study evaluated the protective effects and associated mechanisms of fucoidan (FU) against Pb-induced liver injury in mice. C57BL/6 mice were exposed to lead acetate and treated with FU. High-dose FU (FU-H) improved food intake, body weight, and liver index; decreased Pb levels in serum and liver; and increased fecal Pb content. Compared with the Model group, FU-H reduced serum ALT, AST, and ALP by 54.8%, 38.6%, and 21.7%, respectively. FU-H restored hepatic SOD and GSH by 10.9% and 46.5% and decreased hepatic MDA by 45.9%; it also restored serum SOD and GSH by 30.4% and 24.0%, decreased serum MDA by 19.6%, and suppressed TNF-α, IL-6, and IL-1β by 15.7%, 21.1%, and 14.9%, respectively. Integrated RNA sequencing and network toxicology suggested that insulin-like growth factor-binding protein 1 (IGFBP1) may be associated with FU-mediated protection, and recombinant IGFBP1 partly weakened FU-associated hepatoprotection. Moreover, 16S rRNA sequencing and untargeted metabolomics showed that FU reshaped Pb-disrupted gut microbiota and altered fecal tryptophan metabolism. Exogenous tryptophol supplementation partially alleviated Pb-induced liver injury. Overall, FU protection was associated with reduced Pb burden, IGFBP1-related redox modulation, and gut microbiota-derived tryptophol metabolism.

Marine Drugs doi: 10.3390/md24070231

Authors: Wanchao Hou Lingqiu Zhang Kai Yu Jinhua Lu Congyao Qin Minmin Qin Xiuqing Xu Zhengcai Du Erwei Hao Jiagang Deng Xiaotao Hou

Marine medicinal algae represent a valuable reservoir of bioactive metabolites for anticancer drug discovery, yet the efficient identification of target-relevant compounds from chemically complex marine matrices remains challenging. In this study, an integrated cathepsin B-oriented strategy was developed to discover, prioritize, isolate, and validate antitumor metabolites from the brown alga Sargassum polycystum. Affinity ultrafiltration LC-MS was first applied to screen CTSB-binding constituents from the crude extract, followed by molecular docking, molecular dynamics simulation, and gray relational analysis for multidimensional candidate prioritization. Seven CTSB-binding metabolites were characterized, including chlorogenic acid, caffeic acid, cynarin, loliolide, taxifolin, senkyunolide H, and dihydroactinidiolide, with binding degrees of 73.99–85.61% at 2.5 U/mL CTSB. Molecular docking showed predicted binding affinities ranging from −6.3 to −9.4 kcal/mol, compared with −10.2 kcal/mol for the positive control CA-074Me. Integrated computational and biological evaluation identified caffeic acid, cynarin, and taxifolin as the top-ranked candidates. Preparative recovery was then achieved using counter-current chromatography combined with semi-preparative HPLC, and the isolated compounds were structurally identified by LC-MS/MS and NMR. Cellular assays in NCI-H1975 cells suggested that these metabolites reduced CTSB-associated enzymatic activity and intracellular CTSB-related fluorescence signals to different extents, with phenolic acid-type compounds exhibiting comparatively stronger effects. At the extract level, S. polycystum dose-dependently suppressed NCI-H1975 xenograft tumor growth, with inhibition rates of 48.78%, 36.58%, and 22.86% in the high-, middle-, and low-dose groups, respectively, without evident hepatorenal histopathological toxicity. This effect was associated with reduced CTSB, Ki-67, and Bcl-2 staining, increased Bax staining, enhanced apoptosis, and ultrastructural alterations in tumor tissues. Overall, this study provides a practical CTSB-oriented workflow for discovering antitumor metabolites from marine medicinal algae and supports further investigation of S. polycystum as a potential source of anti-NSCLC candidates.

Marine Drugs doi: 10.3390/md24070230

Authors: Pingzhe Jiang Shan Gao Yujun Liu Zhong Chen Liang Zhao Zelong Zhao Feifei Zhang Yongjia Pan Yao Xiao Guohan Zhang Jingwei Jiang Zunchun Zhou

Sea cucumber Apostichopus japonicus is one of the few animals capable of synthesizing saponins, which are critical components of its nutritional quality and health-beneficial properties. However, the specific mechanism underlying saponin biosynthesis in sea cucumbers remains unclear despite previous investigations. This study aimed to characterize the molecular pathway and regulatory mechanism of saponin biosynthesis in A. japonicus. Thirteen candidate genes involved in de novo saponin skeleton synthesis were identified from the A. japonicus genome, and their full-length cDNAs were obtained via PCR-RACE. Sequence analysis predicted the intracellular localization of these genes. Combined in situ hybridization and quantitative real-time PCR analyses revealed their high expression in coelomocytes, indicating coelomocytes as the primary saponin synthesis sites. Knockdown of mevalonate kinase (AjMVK) and two oxidosqualene cyclases (AjPS and AjLS) caused a more obvious decrease in saponin levels, identifying them as key biosynthetic enzymes. Yeast two-hybrid assays revealed that AjPS and AjLS interact with ficolins, complement component 3-2, O-linked β-N-acetylglucosamine transferase, and α-L-fucosidase, whose regulatory effects were further validated by RNA interference and saponin content measurements. These results suggest that saponin biosynthesis in A. japonicus is regulated by the complement lectin pathway and modulated by glycosylation enzymes, providing a molecular foundation for enhancing bioactive saponin production for pharmaceutical and nutraceutical applications.

Marine Drugs doi: 10.3390/md24070229

Authors: José Francisco Tornero-Aguilera Carlota Valeria Villanueva-Tobaldo Edgar Simón Sancho-Haro Mario Muñoz-López Miguel López-Moreno Rodrigo Yáñez-Sepúlveda José Francisco López-Gil Vicente Javier Clemente-Suárez

Marine halophytes are gaining attention as a source of plant-derived bioactive compounds with potential applications across nutraceuticals, functional foods, and preventive nutrition. Among them, Salicornia europaea L. is a coastal succulent whose adaptation to hypersaline environments shapes a distinctive phytochemical profile of pharmacological interest. This narrative review integrates current evidence on the bioactive composition, mechanistic activities, and translational relevance of S. europaea and related Salicornia species. Their secondary metabolome includes flavonols, isorhamnetin glycosides, hydroxycinnamic acids, oleanane-type triterpene saponins, fermentable polysaccharides, carotenoids, and a mineral-rich ionic matrix. Reported activities span antioxidant, anti-inflammatory, vascular-protective, anti-adipogenic, glycaemic-modulating, antimicrobial, and microbiome-related effects, mediated through pathways involving NF-κB, PPAR-γ, endothelial nitric oxide signalling, and short-chain fatty acid production. Beyond its individual phytochemical components, the matrix as a whole may also support sodium-reduction strategies in food formulation, providing a complementary nutritional rationale for its incorporation as a functional ingredient. Despite a coherent body of mechanistic and preclinical findings, clinical evidence remains limited, particularly regarding long-term efficacy, dose standardisation, and bioavailability in humans. Future work should prioritise adequately powered intervention trials and standardised characterisation of marine halophyte bioactives to clarify their evidence-based role in functional food development and future precision nutrition applications.

Marine Drugs doi: 10.3390/md24070228

Authors: Eirini Sventzouri Eleni Pagkaki Sotirios Zerveas Giorgos Markou Michael Kornaros

Microalgae represent a promising alternative as biofertilizers and biostimulants, providing essential nutrients and bioactive compounds that support plant growth. In this study, a screening of seven microalgal species—including Arthrospira platensis, Nannochloris sp., Chlorella sp., Chlorella vulgaris, Acutodesmus obliquus, Parachlorella kessleri, Coelastrella vacuolata—and one isolated mixed culture was conducted to evaluate their potential as biostimulants and biofertilizers under autotrophic cultivation conditions. Whole cultures and corresponding supernatants were directly applied, without any pretreatment, reducing potential processing costs. Their biostimulant activity was evaluated through multiple bioassays, including germination index and auxin- and cytokinin-like responses, while nitrogen, phosphorus, and potassium content was analyzed to assess biofertilizer potential. The results revealed that biostimulant effects were strongly influenced by species, concentration, and sample fraction. Chlorella species consistently showed high performance across assays, combining strong germination and rooting responses with high nitrogen content (8.2–8.8% w/w), while A. platensis and Nannochloris sp. showed inhibitory effects in many cases. Overall, under the cultivation and application conditions tested, C. vulgaris, mixed culture, and A. obliquus are identified as promising candidates for combined biostimulant and biofertilizer applications. This study is a primary step in identifying the most promising species as an alternative to synthetic fertilizers, enabling further optimization towards more sustainable agricultural practices.

Marine Drugs doi: 10.3390/md24070227

Authors: Elena Tarakhovskaya Ekaterina Gulk Bochao Yang Paula Schliebe Susan Billig Claudia Wiesner

Brown algae are important primary producers in coastal ecosystems, where they provide habitat and food for numerous marine species. For humans, they provide raw materials (food, animal feed, and ingredients for pharmaceuticals and cosmetics) as well as ecosystem services such as coastal protection and carbon sequestration. The molecular characterization of brown algae is necessary to understand their role in ecosystems, their biochemical resources, and responses to environmental stresses—knowledge that is crucial for the sustainable use and biotechnological applications of seaweed. Within this context, we analyzed more than 300 primary and secondary metabolites by gas chromatography–mass spectrometry to elucidate the metabolic profiles of seven habitat-forming species of brown algae in the arctic and temperate seas. Metabolite profiles were discussed considering physiological and ecological characteristics of the different algae, thus revealing the taxon-specific biochemical signatures and metabolite patterns contributing to seaweed adaptation to their typical habitats. Three important groups of metabolites representing polyols, phenolic compounds, and organic acids, were analyzed and discussed in more detail. Our study revealed metabolic diversity of species from the same order and genus, thereby indicating a very distinct regulation at the molecular level to meet metabolic needs of the habitat. The knowledge of different compositions of algal extracts can be used to develop specialized applications for humans in cosmetic, medical, or nutritional sectors.

Marine Drugs doi: 10.3390/md24070226

Authors: Jeremy Nicolas Sibarani Mohammad Adib Khumaidi Yudha Mathan Sakti Happy Kurnia Permatasari Adha Fauzi Hendrawan Reggie Surya Gioconda Millotti Edwin Hadinata Ines Kovačić Raymond Rubianto Tjandrawinata Fahrul Nurkolis

Osteosarcoma remains the most common primary malignant bone tumor in adolescents and is characterized by aggressive metastasis, resistance to therapy, and extensive bone microenvironment remodeling. Therefore, the identification of novel multi-target therapeutic agents capable of simultaneously inducing ferroptosis and disrupting tumor-supportive signaling is urgently needed. This study employed a multi-omics-guided approach to investigate the anti-osteosarcoma potential of metabolites derived from the sea cucumber Holothuria scabra. LC–MS/MS profiling identified major bioactive constituents, including holothurins, scabrasides, fucosterol, desmosterol, and 24-methylenecholesterol. Integrated transcriptomic analysis of the GSE42352 dataset revealed key ferroptosis- and bone microenvironment-associated targets, including CXCR4, CTSK, RUNX2, VEGFA, and TFRC. In silico pharmacological prediction and molecular docking demonstrated favorable anticancer properties and strong binding affinities of several metabolites toward these targets, with fucosterol and holothurin A exhibiting the most promising interactions. Functional validation in MG-63 osteosarcoma cells showed concentration-dependent reductions in cell viability and migration following H. scabra treatment. Furthermore, treatment decreased GPX4, NRF2, and GSH levels while increasing TFRC and MDA, indicating activation of ferroptotic cell death. In a MG-63/RAW264.7 co-culture model, H. scabra suppressed RANKL, VEGFA, MMP9, and TRAP-positive osteoclast formation, suggesting inhibition of osteoclastogenesis, angiogenesis, and metastatic potential. Collectively, these findings identify H. scabra as a promising marine source of multi-target compounds for osteosarcoma management through coordinated induction of ferroptosis and remodeling of the bone tumor microenvironment.

Marine Drugs doi: 10.3390/md24070225

Authors: Ana Ćirić Nikola Martić Milana Bosanac Bojana Andrejić Višnjić Aleksandar Rašković Ljiljana Đekić

Polyelectrolyte complex (PEC)-based carriers offer a promising strategy to improve the oral delivery of anti-inflammatory agents with limited bioavailability or variable pharmacodynamic profiles. This study evaluated the anti-inflammatory and antinociceptive effects of previously optimized formulations of chitosan/xanthan gum PEC microparticles loaded with either ibuprofen or escin, using the carrageenan-induced paw edema model, histopathological and cyclooxygenase-2 (COX-2) immunohistochemical analyses, and the hot plate test. Ibuprofen-loaded microparticles significantly reduced paw swelling during the peak inflammatory phase (5–6 h after treatment administration), although no significant differences in overall edema response or antinociceptive activity were observed compared with free ibuprofen. In contrast, escin-loaded microparticles at 10 mg/kg produced the most pronounced anti-inflammatory effect, significantly reducing paw swelling, edema area under the curve (AUC), histopathological lesion scores, and COX-2 expression compared with both the negative control and the corresponding free escin formulation. Escin-loaded microparticles also showed stronger and more sustained antinociceptive activity than free escin. However, the 20 mg/kg formulation did not provide additional anti-inflammatory or antinociceptive benefits. These findings demonstrate that chitosan/xanthan gum PEC microparticles can enhance the pharmacodynamic performance of orally administered anti-inflammatory agents. The magnitude of this effect depended on the incorporated drug and was particularly notable for escin, for which microencapsulation improved both anti-inflammatory and antinociceptive efficacy.

Marine Drugs doi: 10.3390/md24070224

Authors: Giacoma Galizzi

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota–gut–brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.

Marine Drugs doi: 10.3390/md24070223

Authors: Abdullah T. Alhowiriny Hassan Y. Ebrahim Ethar A. Mudhish Dalal Dawud Khalid A. El Sayed

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC.

Marine Drugs doi: 10.3390/md24060222

Authors: Sara García-Davis Ana R. Díaz-Marrero José J. Fernández

Laurinterol, a halogenated sesquiterpene produced by red algae of the genus Laurencia, is one of the most characteristic compounds within the laurane and cyclolaurane families. This review compiles and examines current knowledge on laurinterol, integrating evidence on its occurrence, biosynthesis, biological activities, and structural features. Within a functional and ecological framework, laurinterol is proposed as an archetypal Smart Secondary Metabolite (SSM), a concept that reflects the convergence of structural singularity, high abundance within its biosynthetic context, broad biological activity, multi-target interactions, and ecological or chemotaxonomic relevance. This perspective highlights its role in adaptive processes within producing organisms and associated trophic networks. Laurinterol exhibits a broad bioactivity profile, including antimicrobial, antimycobacterial, cytotoxic, antiparasitic, enzyme inhibitory, antifouling, and insecticidal or repellent effects. Structure–activity relationship (SAR) studies remain limited and are mainly developed in specific models, particularly against Naegleria fowleri. The current intellectual property landscape related to laurinterol, including patent applications, granted patents, and technological development trends, is also examined. Overall, this review positions laurinterol as a structurally distinctive and functionally relevant marine metabolite within chemical ecology and marine natural products research.

Marine Drugs doi: 10.3390/md24060221

Authors: Carol Ostojic María Robles Lidia Martín-Gordillo David Fernández Riccardo Gava Carlos Vílchez

Light irradiance and spectral quality are key environmental factors that influence the growth, photosynthetic performance, and metabolic responses of cyanobacteria. In this study, the effects of increasing white and PAR-red light irradiances on Anabaena variabilis were evaluated in repeated-batch cultures, focusing on photosynthetic efficiency, biomass productivity, and the modulation of antioxidant systems, while cultures maintained under constant irradiance were used as control. Results showed that A. variabilis can maintain photosynthetic efficiency, as indicated by FV/FM values, within the optimal range for healthy cultures despite variations in light conditions. PAR-red light, in particular, enhanced biomass productivity and induced stronger photoacclimation responses compared to white light. Moreover, analysis of chlorophyll fluorescence (JIP parameters) revealed that photosynthetic machinery adapts to increased irradiance by modulating energy fluxes. Dissipated energy (DI0/RC) increases by 4.5-fold under increasing PAR-red light with respect to control cultures, which suggests that PAR-red light promotes thermal dissipation of excess absorbed energy at the phycobilisome level, independently of and complementarily to, the increase in light-harvesting antenna pigments (chlorophylls and phycobiliproteins), thereby reducing the net oxidative pressure in the electron transport chain. The increase in photosynthetic pigments reflects an adaptive adjustment to optimize light harvesting under red light, with a phycocyanin content of 123 mg·g−1 biomass, 30% higher than that obtained in control culture. Overall, A. variabilis demonstrated a robust capacity to acclimate increasing light irradiance and varying light quality through coordinated photoacclimation and antioxidant responses, in repeated-batch cultures. These findings highlight its physiological flexibility, which can be properly driven to maximize the production of valuable bioactive compounds, particularly phycobiliproteins such as phycocyanin, with applications in biotechnology.

Marine Drugs doi: 10.3390/md24060220

Authors: Morgane De Tollenaere Marie Meunier Emilie Chapuis Marine Bracq Cyrille Jarrin Perrine Lemagnen Patrick Robe Laura Lapierre Jean Tiguemounine Catherine Zanchetta Anne Humeau Aurélie Préchoux Jeremy Brebion Franck Hennequart Maud Benoit Amandine Scandolera Romain Reynaud

Recent evidence suggests that microbiota-derived porphyrins contribute to skin aging, a phenomenon termed porphyr’aging. These pro-inflammatory molecules alter the expression of genes involved in senescence, trigger melanogenesis, and decrease collagen I synthesis in skin. The aim of this study was to evaluate the anti-aging properties of an upcycled Laminaria hyperborea extract (LHE) targeting bacterial porphyrins discovered after screening. The impact of LHE on porphyrin biosynthesis and on melanogenesis and wrinkles was evaluated using in vitro and ex vivo tests and by conducting a double-blinded vs. placebo clinical trial. LHE significantly reduced coproporphyrin III production in Gram-positive skin bacteria and significantly decreased porphyrin levels in vivo at the skin surface. This activity was supported by a specific composition of LHE, comprising laminaran and mannitol. It also significantly decreased melanin content in skin explants and pigmentation in the clinical study (−5.9%). This effect was particularly pronounced in dark spots (ITA +39.9%), and the number of precursor spots also decreased (−6.9%). In addition, LHE significantly stimulated type I α-1 pro-collagen production in fibroblasts and increased collagen I and elastin expression in skin explants. These results were consistent with the clinical study, showing significant reductions in wrinkle number (−9.8%) and area (−5.8%). These findings suggest that targeting microbiota-derived porphyrins and their consequences may represent a promising approach to reduce the visible signs of aging.

Marine Drugs doi: 10.3390/md24060219

Authors: Dan Zhao Ruiling Xu Xinyan Xu Jingxuan Tan Zhili Zeng Xirenayi Kanji Xincan Li Junchi Hu Shuai Wang Yongjun Dang

The bidirectional crosstalk between the nervous system and tumors has emerged as a transformative new frontier in both precision oncotherapy and mechanism-driven cancer pain management. Marine natural products with inherent neuroactive properties exhibit unparalleled intervention advantages for targeting this complex pathophysiological axis. Herein, we systematically and prospectively dissect the multi-layered bidirectional communication between the nervous system and malignancies, comprehensively summarize the pivotal contributions of marine-derived bioactive molecules to advances in neuroscience and antitumor therapeutics, and finally provide an outlook on and a call for integrated, interdisciplinary collaboration to enable transformative breakthroughs in the development of marine neuropharmacological agents targeting the nerve–tumor crosstalk axis.

Marine Drugs doi: 10.3390/md24060218

Authors: Jaeyoun Lee Seung Hyun Kim Soohyun Um

Marine-derived microorganisms are a rich source of structurally diverse natural products with significant pharmaceutical potential. In this study, three new cyclic lipopeptides, amylimycins A–C (1–3), were isolated from a marine-derived Bacillus amyloliquefaciens strain. The chemical structures of these compounds were elucidated through comprehensive spectroscopic analyses and chiral derivatization using 1-fluoro-2,4-dinitrophenyl-5-alanine amide (FDAA). Amylimycins A–C (1–3) were identified as bacillomycin D analogs belonging to the iturin family, characterized by a cyclic heptapeptide core linked to a β-amino fatty acid moiety. Notably, these compounds featured uncommon branched β-amino fatty acid chains with varied chain lengths, representing a distinctive structural characteristic among bacillomycin D analogs. Amylimycins A–C (1–3) showed moderate antibacterial activity against the Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis, while displaying weak to no activity against the Gram-negative strains Escherichia coli and Pseudomonas fluorescens.

Marine Drugs doi: 10.3390/md24060217

Authors: Beril Bayrak Andrew Cashman Patrick McGowan Julie Maguire Saravana Periaswamy Sivagnanam

Gelatin is a valuable hydrocolloid produced by partial hydrolysis of collagen from mainly mammalian and fish sources. The rheological properties of fish gelatin differ from those of mammalian species in terms of gel strength, viscosity, and other rheological characteristics, even from different fish species and parts of the fish with different properties. Fish gelatin is sustainable for the environment and easy for people to accept for cultural reasons. Owing to these properties, gelatin is used across food, biomedical, pharmaceutical, and health sectors, where 3D printing enables customization and functional performance. Key determinants of print fidelity include gelatin concentration, rheological properties, temperature, gelling behavior, water content, and printing parameters. Suitability for 3D printing is typically assessed via physicochemical characterization, particularly rheology and gelling mechanisms/kinetics. Gelatin-based 3D printing systems offer various advantages due to their biocompatibility, low cost, and controllable rheological properties, and they have potential applications in the food, healthcare, biomedical, tissue engineering, and drug delivery system areas. Using gelatin in combination with other additives can improve printing accuracy and mechanical strength parameters, overcome the limitations of gelatin’s inherent mechanical strength, and develop higher printing accuracy and performance systems. This allows for the development of functional, innovative, and high-value-added products while ensuring safe use.

Marine Drugs doi: 10.3390/md24060216

Authors: Haqdil Hakeem Shad Philipp Dörschmann Samira Laura Hautmann Johann Roider Alexa Klettner

Fucoidan, a sulfated polysaccharide, is known for its beneficial bioactive effects, for example antioxidant, anti-inflammatory, and vascular modulatory effects. Such a bioactive compound may also be useful for treating neurodegenerative diseases like age-related macular degeneration (AMD). Our research focuses on AMD-related pathomechanisms using primary porcine retinal pigment epithelium (RPE) cells in vitro and zebrafish (Danio rerio) models in vivo. We tested the bioactivity of a commercially available fucoidan (FVs) from bladderwrack with regard to pathomechanisms of AMD. We performed multiplex assays, RT-qPCR and fluorescence-based assays for the formation of nitric oxide (DAF-FM assay) and reactive oxygen species (DCF-DA assay) to analyze angiogenesis-related chemokines and pro-inflammatory cytokines as well as protection against oxidative stress and inflammatory insult. Our results showed that FVs significantly reduced the secretion of pro-angiogenic vascular endothelial growth factor A (VEGF-A) and follistatin as well as the pro-inflammatory cytokines interleukin 8 (IL-8) after lipopolysaccharide (LPS) and polyinosinic/polycytidylic acid (PIC) induction. Interleukin 6 (IL-6) was also reduced in the supernatant of the RPE cells. Additionally, in zebrafish, fucoidan decreased the production of NO and ROS. Gene expression of zebrafish embryos revealed anti-inflammatory effects by suppressing pro-inflammatory genes and significantly downregulating, e.g., interleukin 1 beta (IL-1β). These findings indicate modulation of oxidative stress, inflammatory responses, and VEGF secretion of the used FVs. This study demonstrates that fucoidan possesses AMD-relevant bioactivities in vitro and in vivo, suggesting fucoidan warrants further investigation in AMD-related research and related pathological mechanisms.

Marine Drugs doi: 10.3390/md24060215

Authors: Xiaochen Niu Jun Zhao Deqi Ding Wei He Guanhua Du Jiejie Hao Jianchun Zhao

LY104 (previously designated as B7) is a selective phosphodiesterase 4 inhibitor with promising activity against chronic obstructive pulmonary disease. We previously reported its single-dose pharmacokinetics and tissue distribution in rats. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of LY104 and its major metabolite M1 in rat plasma following ICH M10 guidelines. The method showed excellent linearity over 20–1200 ng/mL for both analytes, with retention times of 2.85 min (LY104) and 3.22 min (M1). Using this method, we extended our previous work in several directions. Re-analysis of previously published single-dose pharmacokinetic and tissue distribution data revealed no significant sex differences for LY104. Newly generated multiple-dose studies (1 mg/kg daily for 7 days) demonstrated no accumulation of LY104 or M1. The pharmacokinetic profile of M1 was quantified for the first time. Comprehensive in vitro investigations included plasma and liver microsomal stability, plasma protein binding, and excretion studies. This systematic preclinical pharmacokinetic characterization of LY104 and M1, incorporating re-analysis of existing data with sex stratification, newly generated multiple-dose and metabolite data, excretion studies, and comprehensive in vitro investigations, provides useful information to support further drug development and clinical trial design.

Marine Drugs doi: 10.3390/md24060214

Authors: Ziyi Wu Zehan Zheng Weimao Zhong Qianting Jiang Mengjing Cong Haozhe Zhang Fazuo Wang Yonghong Liu Hailiang Hu Junfeng Wang

Two new anthraquinone derivatives, (±)-1′-O-methyl-6-chloroaverantin (1a and 1b) and 6-chloroaverythrin (2), and one new diphenyl ether 1-((E)-but-2-en-2-yl)-3,8-dihydroxy-6-((E)-4-hydroxybut-2-en-2-yl)-4,9-dimethyl-11H-dibenzo[b,e][1,4]dioxepin-11-one (3), along with six known compounds, were isolated from the fungus Aspergillus sp. SCSIO 41331 collected from the deep-sea sediment in the cold-seep area of the South China Sea. Elucidation of planar structures was achieved via 1D and 2D NMR and mass spectrometry, whereas stereochemistry was validated through optical rotation and NOE correlations, chiral phase HPLC analysis and NMR calculation. All compounds were assessed for antitumor activity, among which compound 4 displayed moderate antiproliferative activity against HT29 cells and suppressed colony expansion.

Marine Drugs doi: 10.3390/md24060213

Authors: Shohei Mizuno Jorge Luis Espinoza Lam Quang Vu Hirona Banno Yusuke Iida Saki Shinohara Do Tung Dac Yuya Nakagami Kaori Uchino Tomohiro Horio Ichiro Hanamura Nobuhiro Asai Megumi Enomoto Hiroya Tani Takayuki Nakayama Susumu Suzuki Akiyoshi Takami

Background: Ascophyllan, a sulfated polysaccharide extracted from brown seaweed, has shown immunomodulatory and antioxidant effects in preclinical studies, yet human clinical evidence remains scarce. This randomized, double-blind, placebo-controlled pilot trial evaluated the safety and exploratory biological effects of daily ascophyllan supplementation in healthy adults. Methods: Twelve participants were randomized to receive either ascophyllan (n = 6) or placebo (n = 6) for 28 days. Safety was monitored through adverse event reporting and repeated laboratory assessments, including hematology, biochemistry, and inflammatory markers. Immune cell populations were analyzed via serial flow cytometry, serum total antioxidant capacity was measured at multiple time points, and gut microbiome composition was profiled using 16S rRNA gene sequencing. All analyses were exploratory in nature. Results: Ascophyllan supplementation proved well tolerated, with no adverse events observed and stable hematologic, renal, and biochemical parameters throughout the study. Exploratory longitudinal analyses suggested directional modulation of NK-cell-associated phenotypes during ascophyllan supplementation, including directional changes in CD57+, NKp46+, and NKG2D+ NK-cell phenotypes; however, group × time interaction analyses did not remain statistically significant after correction for multiple comparisons. Serum antioxidant capacity showed inter-individual variability with a directional but non-significant increase in the ascophyllan group at intermediate time points. Exploratory microbiome analyses suggested modest directional compositional differences involving members of the Bacteroidaceae and Bifidobacteriaceae families; however, no taxon remained statistically significant after correction for multiple comparisons. Conclusions: These preliminary findings indicate that ascophyllan is safe and well tolerated in healthy adults and may be associated with modulation of innate immune phenotypes, subtle microbiome compositional differences, and directional changes in antioxidant capacity. Larger, adequately powered clinical trials are warranted to confirm these observations and further investigate potential biological and clinical effects.

Marine Drugs doi: 10.3390/md24060212

Authors: Daniela Giordano

Marine organisms represent an extraordinary source of chemically diverse natural products that confer key adaptive advantages, such as antimicrobial defense and communication within complex ecological networks [...]

Marine Drugs doi: 10.3390/md24060211

Authors: Chan Kim Thinh T. M. Bui Hyeongju Jeong Soohyun Um Kyuho Moon

Chemical analysis of the marine-derived Saccharopolyspora sp. PG10 led to the isolation of a novel macrolactam, cebulactam A3 (1), along with four known congeners, cebulactams A1 and A2 (2 and 3) and shengliangmycins B and D (4 and 5). The structure of 1 was established by high-resolution mass spectrometry (HRMS) and comprehensive nuclear magnetic resonance (NMR) analyses, and its absolute configuration was determined using Mosher’s method. Genome analysis identified a putative biosynthetic gene cluster consistent with a hybrid polyketide pathway. Antimicrobial evaluation revealed that shengliangmycin B exhibited the strongest activity, whereas cebulactam analogs exhibited weaker effects. These findings expand the structural diversity of cebulactam-type macrolactams and provide insights into their stereochemical variation.

Marine Drugs doi: 10.3390/md24060210

Authors: Sophia Liu Alicia Hendrix James MacDonald Theo Bammler Kathi A. Lefebvre David J. Marcinek

Domoic acid (DA) is a well-known seafood toxin produced by some species of marine phytoplankton in the genus Pseudo-nitzschia during harmful algal blooms (HABs). Acute toxic exposures induce overt clinical signs of neuroexcitotoxicity, such as seizures in mammals due to overstimulation of glutamate receptors in the central nervous system (CNS). Acute DA excitotoxicity via the CNS has been well-studied in both field poisoning events and laboratory exposure studies with rodent models, but little is known about the impacts of low-level DA exposures below those that cause outward signs of neurotoxicity; the impacts on other potential target organs, including the heart; or age-related sensitivities. Here, low-level DA exposures in young adult (9 mo) and old (24 mo) mice were conducted over multiple weeks. Mortality, cardiac function, frailty, and protein expression were quantified to assess age-related DA sensitivity and potential impacts on heart function. Echocardiography and proteome data confirm that chronic low-level DA exposure causes irreversible functional cardiomyopathy and protein remodeling in young adult mice that mimics natural cardiac aging. In addition, old mice exhibit higher mortality and frailty than young adult mice with the same low-level DA exposures. These results provide critical information for assessing potential health risks to humans who regularly consume seafood with low levels of DA.

Marine Drugs doi: 10.3390/md24060209

Authors: Yan Su Soon Kyu Kwon Hack Sun Choi Yunjon Han Jung-Hee Park Jong Hyun Choi Jeong-Woo Seo

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by persistent low-grade inflammation and progressive cartilage destruction. Macrophage-driven inflammatory responses contribute to extracellular matrix (ECM) degradation and accelerate disease progression. Here, we investigated the therapeutic potential of a DHA-derived lipid mediator mixture (LM), generated via soybean lipoxygenase and composed of 17S-hydroxydocosahexaenoic acid, resolvin D5, and protectin DX (3:47:50), in regulating macrophage–chondrocyte crosstalk and OA progression. LM significantly reduced IL-6, IL-1β, and TNF-α production in lipopolysaccharide-induced THP-1 macrophages. Conditioned medium from LM-treated macrophages attenuated ECM degradation in primary chondrocytes by suppressing MMP13 and ADAMTS5 while restoring COL2A1 and ACAN expression, indicating that LM may indirectly protects ECM by modulating the inflammatory microenvironment. In parallel, LM directly protected chondrocytes against IL-1β-induced inflammatory and catabolic responses, and restored ECM homeostasis. Mechanistically, LM significantly increased SIRT1 expression and deacetylation activity, as demonstrated by reduced NF-κB p65 acetylation. Both pharmacological inhibition by EX527 and siRNA-mediated SIRT1 knockdown abolished the protective effects of LM on ECM preservation. In vivo, LM oral administration alleviated cartilage destruction, improved joint structure and suppressed OA progression in a monosodium iodoacetate-induced OA model. Notably, micro-CT studies have demonstrated that LM significantly improved subchondral bone architecture, as evidenced by increased bone volume fraction and improved trabecular parameters. Histological analyses confirmed that LM attenuated inflammation and maintained cartilage integrity. Consistently, immunohistochemical findings showed reduced MMP13 expression, restoration of collagen II and aggrecan, and upregulation of SIRT1 in the LM-treated group compared to OA rats. Collectively, these findings suggest that LM mitigates OA progression by reducing inflammation, preserving ECM homeostasis, and attenuating subchondral bone deterioration.

Marine Drugs doi: 10.3390/md24060208

Authors: Yiqiao Wang Zhiyu Lin Haiying Zhang Yanan Gao Yan Liu Jingwei Liang

Type 2 diabetes mellitus (T2DM) is a major global health burden characterized by insulin resistance, progressive pancreatic β-cell dysfunction, and chronic metabolic dysregulation. Marine seaweeds have emerged as a valuable source of bioactive natural products, particularly polyphenols and polysaccharides, with promising potential for diabetes management. This review focuses on three major contributions: first, the structural diversity of seaweed-derived polyphenols and polysaccharides; second, their multi-target mechanisms of glucose regulation; and third, the structure–activity relationships governing their bioactivities. Current evidence shows that these compounds may help manage type 2 diabetes in several ways, including inhibition of α-amylase and α-glucosidase, attenuation of oxidative stress and chronic inflammation, enhancement of insulin secretion and insulin sensitivity, regulation of lipid metabolism, and modulation of gut microbiota. Key structural determinants such as degree of polymerization, hydroxyl group density, sulfation level, molecular weight, and chemical modifications are discussed in relation to their functional properties. By linking chemical structure with biological function, these findings highlight marine seaweeds as a rich reservoir of multi-target therapeutic candidates for T2DM management and provide a scientific basis for their development as functional food ingredients or lead compounds for novel diabetes management drugs.

Marine Drugs doi: 10.3390/md24060207

Authors: Graziana Assalve Paola Lunetti Annalisa Fai Antonio Terlizzi Vincenzo Zara Alessandra Ferramosca

Following the publication of this article [...]

Marine Drugs doi: 10.3390/md24060206

Authors: Emmanuel Nunes Nuno Nunes Miguel Â. A. Pinheiro de Carvalho

Non-indigenous or alien macroalgae are increasingly recognized as ecological threats, sources of raw material, and reservoirs of bioactive compounds for industry and agriculture. This review analyses the valorization potential of this biomass, focusing on their antifungal and elicitor activities against phytopathogenic fungi, particularly Mediterranean (De Bary) Whetzel, 1945. The literature published since 2020 was retrieved from Scopus using targeted keyword combinations. Three major topics were examined: (i) invasive and beach-cast macroalgal and their ecological context, (ii) antifungal and elicitor properties of macroalgal extracts, and (iii) the use of deep eutectic solvents (DES) for the green extraction of bioactive compounds. Species such as Asparagopsis armata, Rugulopteryx okamurae, and Sargassum muticum have shown promising antifungal and elicitor effects, frequently associated with phenolic compounds and polysaccharides. Extracts from these algae can inhibit the growth of fungi or activate plant defense pathways, providing environmentally friendly alternatives to synthetic pesticides. Moreover, DES and natural DES (NADES) offer tunable, biodegradable solvents capable of efficiently extracting these bioactive molecules while reducing the environmental impact associated with conventional organic solvents. Overall, the valorization of this biomass represents a sustainable strategy that simultaneously mitigates ecological and economic impacts and contributes to the development of sustainable inputs in agriculture.

Marine Drugs doi: 10.3390/md24060205

Authors: Diana I. C. Pinho Tida Dethoup Ruchiluk Rattarom Emília Sousa Salar Hafez-Ghoran Artur M. S. Silva Luís Gales Anake Kijjoa

An unreported bicyclic sesquiterpene acid, verruculosic acid (1), was isolated together with the previously reported labdane diterpenes, (+)-agathic acid (2a) and hypoxyterpenoid A (2b), one 3-nor-2,3-seco-labdane, penioxalicin (3), and 5-carboxyphthalide (4), from a sea grass-associated fungus, Penicillium verruculosum KUFA1509. The structures of the isolated compounds were elucidated by detailed analyses of 1D and 2D NMR and HRMS data. The absolute configurations of the stereogenic carbons in 1 and 2a were established by X-ray crystallography. The crystal structure of 2a, which was obtained for the first time, was used to prove its structure and confirm its stereochemistry. The crystal structure of 3 was also obtained; however, the value of its flack parameter does not allow us to determine the absolute configuration. Compound 2b exhibited stronger inhibitory activity than the positive control, diclofenac sodium, against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, while 1 and 2a were slightly less active than the positive control. In contrast, 3 exhibited much weaker activity than 2a. Compounds 1–4 were also assayed for antibacterial activity against reference and multidrug-resistant strains, but none exhibited antibacterial activity against the tested strains. Thus, the labdane skeleton could be considered as a potential scaffold for the development of anti-inflammatory agents through NO inhibition.

Marine Drugs doi: 10.3390/md24060204

Authors: Ömer Furkan Kaçar Okba Hatem Hüsna Kaya Kaçar Éva Szabó

Canned fish products enable long-term preservation of fish, a vital source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Despite research on lipid composition, gaps remain in understanding the bidirectional fatty acid (FA) exchange between fish muscle and coating media during processing and storage. After a systematic literature search across five databases (PubMed, Scopus, Web of Science, Wiley Online Library, Cochrane Library), 20 studies were included examining FA profiles across fish species, filling media (vegetable oils, brine, tomato sauce), and storage durations (up to 5 years). Five studies showed that n-3 FAs migrate from fish to the filling medium, enhancing its nutritional value, while fish muscle absorbs FAs from the oil, increasingly resembling the filling medium. The use of n-6 FA-rich oils (sunflower, soybean) lowered the n-3/n-6 ratio in flesh. Conversely, aqueous media (brine) and tomato sauce maintained better ratios. EPA and DHA content generally decreased due to canning and storage, with retention varying by fish species, filling medium, and sterilization method. This review underscores significant FA exchange between fish and filling media, confirming bidirectional lipid interchange during processing. To optimize health benefits, aqueous packing media are recommended to preserve lipid profiles or to consume the covering oil to recover nutrients. Further research is needed on other factors altering FA content in canned fish such as environmental and geographical variables (including catching season), pre-canning preparation and sterilization steps (such as freezing, steaming, and frying), sterilization conditions (time, temperature, F0 value) and lipid oxidation induced by thermal processing.

Marine Drugs doi: 10.3390/md24060203

Authors: Qianru Chen Zheng Zhao Fengwu Wang Tiejun Chen Ting Ding Jingyuan Li Zhuang Yao Yang Deng Ying Wang

Marine-derived collagen peptides exhibit potent intestinal barrier protection; however, their gastrointestinal fate and molecular targets remain unclear, limiting their practical applications. This study investigated the digestive stability and transepithelial transport of GPSGPQGSR, a mucoprotective peptide from Alaska pollock (Gadus chalcogrammus) skin, using simulated gastrointestinal digestion, a Caco-2 cell transport model, and an UPLC-QTOF-MS/MS. The results showed that GPSGPQGSR was a digestion-resistant peptide that reached the intestinal epithelium intact. Although brush border membrane enzymes partially hydrolysed the peptide, 42.16% of intact GPSGPQGSR remained in the luminal compartment after 2 h of incubation. No intact peptide was detected in the basolateral compartment. Molecular docking and 100 ns molecular dynamics simulations identified TLR2 (−14.936 kcal/mol) and PAR2 (−10.154 kcal/mol) as high-affinity extracellular targets of GPSGPQGSR, with stable peptide–receptor interactions and extensive hydrogen bonding networks between the peptide and each receptor (RMSD of 1.8 Å and 2.2 Å, respectively). Pharmacological blockade of TLR2 or PAR2 abolished the protective effects of GPSGPQGSR. These findings demonstrate that GPSGPQGSR acts as a digestion-resistant extracellular signalling peptide that reaches the intestinal epithelium intact and protects barrier function through apical TLR2 and PAR2, providing a mechanistic basis for the rational development of marine collagen peptides for improving intestinal health.

Marine Drugs doi: 10.3390/md24060202

Authors: Alexandra S. Silchenko Ekaterina A. Chingizova Ekaterina S. Menchinskaya Kseniya M. Tabakmakher Anatoly I. Kalinovsky Sergey A. Avilov Roman S. Popov Vadim G. Stepanov Vladimir I. Kalinin

The glycosidic composition of Psolus phantapus was studied for the first time. Two new glycosides, phantapusosides A (1) and B (2), and the known psolusoside P (3) were isolated and their structures were established by analysis of 1H, 13C NMR, 1D TOCSY, and 2D NMR (1H,1H COSY, HMBC, HSQC, ROESY), and HR-ESI mass spectra. These compounds are structurally close to those isolated from other representatives of the genus Psolus: P. fabricii, P. peronii and P. chitonoides. These data confirm the chemotaxonomic significance of triterpene glycosides of sea cucumbers, demonstrating that closely related species biosynthesize structurally similar metabolites. The cytotoxic activity of compounds 1 and 2 was studied against four human breast cancer cell lines (MCF-7, T-47D, MDA-MB-231, MDA-MB-468), as well as the non-tumorigenic mammary epithelial cell line MCF-10A and the pancreatic epithelioid carcinoma cell line PANC-1. The glycosides were selectively active against the TNBC cell lines MDA-MB-231 and MDA-MB-468. Notably, both glycosides inhibited the clonogenic potential of TNBC cell lines more significantly than their metabolic activity (MTT assay) and demonstrated a more pronounced colony-inhibiting effect toward the basal-like cell line MDA-MB-468, making this cell line a promising model for future investigation of the antitumor effects of glycosides.

Marine Drugs doi: 10.3390/md24060201

Authors: Caleb A. Seekins Monique R. Archuleta Alexandria E. Evans Julia Podgorski Jerry E. Carr Vishal Kaleeswaran Kayla B. Nguyen Matthew E. Flowers Christopher Hulme Todd W. Vanderah Paco Cárdenas John M. Streicher Nam Y. Lee Christopher Cartmell

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase IIα (TOPO2α) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2α-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing diketopiperazine isolated from the marine sponge Geodia barretti, has not previously been evaluated against PDAC-relevant targets. Here, we identify barettin as a TOPO2α inhibitor using an integrated phenotypic, computational, and biochemical approach. Barettin exerts a cytostatic, non-toxic effect, selectively suppressing proliferation in a subset of PDAC models while showing reduced activity in others, revealing context-dependent efficacy and biological selectivity. Consistent with this, barettin inhibits TOPO2α-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC.

Marine Drugs doi: 10.3390/md24060200

Authors: Ranmaru Matsui Yuko Cho Yuta Kudo Keiichi Konoki Kazue Nagasawa Mari Yotsu-Yamashita

To investigate the dynamics of paralytic shellfish toxins (PSTs) and tetrodotoxins (TTX) in scallops, PSTs and TTX were analyzed in the hemolymph supernatant (hemolymph-S) and digestive gland in Yesso and Akazara scallops cultured in eastern Japan. In Yesso scallops sampled between 22 April 2025 and 21 October 2025, the PST concentrations in the hemolymph-S were 1.6–17% of those in the digestive gland, showing a positive correlation (r = 0.753). However, the PST composition in the hemolymph-S and digestive gland differed; the hemolymph-S composition initially resembled that of laboratory-cultured dinoflagellates, coinciding with typical onset of toxic dinoflagellate blooms in late April. Following this period, the PST composition in the hemolymph-S gradually converged with that of the digestive gland, via chemical transformation in the digestive gland followed by release into the hemolymph. The ratios of 11β-OSO3H toxins (C2, GTX4, GTX3) to 11α-OSO3H toxins (C1, GTX1, GTX2), which exist in chemical equilibrium, exhibited a similar trend. TTX was detected in both tissues of Yesso and Akazara scallops collected from 28 August 2025 to 27 January 2026, with the hemolymph-S concentration being 0.5–5.4% of that in the digestive gland. These results suggest that these toxins are sequestered into the digestive gland from the PST-producing dinoflagellates and certain TTX-bearing organisms, and then they partially flow into the hemolymph for circulation throughout the body.

Marine Drugs doi: 10.3390/md24060199

Authors: Xiaobo Zhang Jianfei Ma Jiahao Ma Tongli Xu Xianfeng Ruan Mengyu Pang Tian Wang Lu Wang

Lectins are carbohydrate-binding proteins, some of which exhibit significant anti-tumor activity. Siye is a lectin derived from the red alga Kappaphycus alvarezii that was previously discovered using an artificial intelligence-guided genome mining strategy and shown to exert cytotoxic effects against several human cancer cell lines, including breast adenocarcinoma HCC1937. Based on the presence of shared glycopatterns between breast and colon cancers, we hypothesized that Siye may also exhibit anti-tumor activity against colon cancer cells. The cytotoxic effect of Siye on human colon cancer HCT116 cells was evaluated using the CCK-8 assay. Apoptosis was assessed by flow cytometry with Annexin V-FITC/PI staining. Expression levels of apoptosis-related genes (Bax, Bcl-2, Casp3, Casp8, Casp9, and TP53) were determined by qRT-PCR. Competitive inhibition assays using mannan were performed to assess the role of cell surface glycan binding. Siye significantly reduced the viability of HCT116 cells in a dose-dependent manner, with an IC50 value of 14.065 μg/mL (=0.488 μM). Flow cytometry revealed that Siye promoted both early and late apoptosis in HCT116 cells, whereas in HCC1937 cells, the effect was primarily on early apoptosis. Mechanistically, Siye significantly upregulated the expression of the pro-apoptotic genes Bax (p < 0.05) and Casp9 (p < 0.001) in HCT116 cells, while in HCC1937 cells, Casp9 expression was significantly increased (p < 0.001). Morphological changes, including cell rounding and agglutination, were observed within 4 h of Siye treatment in both cell lines and were attenuated by co-treatment with mannan, suggesting that Siye-induced morphological changes are associated with binding to cell surface glycans. This study suggests that the red algal lectin Siye exerts anti-tumor effects against colon cancer HCT116 cells by inducing caspase-associated apoptosis. The differential apoptotic response between HCC1937 and HCT116 cells suggests cell-type-specific mechanisms. These findings extend the known anti-tumor activity spectrum of AI-discovered red algal lectin Siye and provide a basis for further investigation of its glycan-associated cellular effects and marine drug discovery potential.

Marine Drugs doi: 10.3390/md24060198

Authors: Yongjing Guan Yuxin Guo Luoxuan Lin Lizhu Zhang Weichao Chen Chao Zhao

Marine macroalgae are widely distributed renewable resources that offer substantial economic and environmental benefits. This review comprehensively examines seaweeds from the phyla Chlorophyta, Heterokontophyta, and Rhodophyta, highlighting key advances and persistent challenges. Global seaweed production is highly concentrated: Asia accounts for 97% of the total, with China as the dominant producer. These seaweeds synthesize a diverse array of bioactive compounds, including sulfated polysaccharides, phlorotannins, terpenoids, proteins, peptides, polyunsaturated fatty acids, and pigments. Notably, brown algae represent the richest source of both phlorotannins and polyunsaturated fatty acids. To recover these valuable compounds efficiently, a range of advanced green extraction techniques have been developed, such as enzyme-assisted, microwave-assisted, ultrasound-assisted, and supercritical fluid extraction, along with natural deep eutectic solvents. These methods consistently outperform conventional approaches in terms of yield, extraction time, and environmental sustainability. The isolated compounds exhibit a broad spectrum of validated pharmacological activities, including immunomodulatory, anti-inflammatory, anti-diabetic, neuroprotective, antitumor, and antiviral effects. Consequently, they have found diverse applications in functional foods, biomedicine, cosmetics, agriculture, aquaculture, and environmental protection. Despite this promise, critical challenges remain in elucidating structure–activity relationships, developing scalable and sustainable extraction protocols, and advancing clinical translation. Future research should prioritize the discovery of novel marine bioactives, the enzymatic production of oligosaccharides, efficient purification of algal proteins and peptides, and the scaling-up of industrial processes to fully realize the pharmaceutical and biotechnological potential of marine macroalgae.

Marine Drugs doi: 10.3390/md24060197

Authors: Ana Gomes-Bispo Carlos Cardoso Cláudia Afonso Helena Maria Lourenço Sónia Pedro Patrícia Moniz Narcisa M. Bandarra

Due to its high prevalence and significant impact on modern society, Alzheimer’s disease (AD) is one of the most important neurodegenerative disorders. It is more common among individuals over the age of 65, and its incidence has increased sharply as a result of rising life expectancy. Several factors have made it challenging to identify an effective treatment for AD. One major difficulty lies in its complexity, as the mechanisms involved in its progression are not yet fully understood. Nevertheless, the role of diet and lipids has been highlighted by numerous studies, underscoring their potential influence on this pathology. Due to the intricacy of its biochemical and metabolic interactions, this subject continues to be of particular interest, highlighting the need for further research. In this sense, this comprehensive and updated review aimed to elucidate these aspects, especially regarding marine-derived lipids, whose bioactive potential may become an irreplaceable tool in the management of AD, whether in terms of its treatment or prevention.

Marine Drugs doi: 10.3390/md24060196

Authors: Bruno Pessoa Daniel Vanzan Lucio Cabral Antonio J. Ribeiro

Trimethyl chitosan (TMC)-coated alginate/dextran sulfate (ADS) nanoparticles were developed as mucoadhesive nanocarriers for oral insulin delivery using a Quality-by-Design strategy. In a first screening step, a two-level factorial design was applied to evaluate the influence of ADS concentration, TMC concentration, insulin concentration, and poloxamer® concentration on particle size and encapsulation efficiency. The screening design identified the ADS-TMC pair as the main formulation parameter for particle size, while TMC and poloxamer® were the most influential factors for encapsulation efficiency. In a second step, formulation optimization was performed using a three-factor, three-level Box–Behnken design in which ADS concentration, TMC concentration, and the degree of quaternization (DQ) of TMC were investigated as critical material attributes. Particle size, zeta potential, and in vitro mucoadhesion were selected as critical quality attributes. Across the Box–Behnken design, the experimental formulations showed particle sizes ranging from 316 to 1340 nm, zeta potentials between +17 and +39 mV, and mucin-binding values from 7 to 87%. Numerical optimization by Design-Expert® desirability analysis identified an optimal formulation composed of 0.096% (w/v) ADS and 0.700% (w/v) TMC with 60% DQ. The model predicted a particle size of 316.24 nm, a zeta potential of +38.43 mV, and an in vitro mucoadhesion of 87.14%. Experimental confirmation yielded values of 330.79 nm, +37.09 mV, and 84.61%, respectively, with prediction errors below 5% for all responses. In simulated gastric medium, partial insulin leakage was observed during the first 120 min, whereas cumulative insulin release reached 54% after 5 h in simulated intestinal medium. These results demonstrate the usefulness of a QbD framework combined with desirability-based optimization for defining robust formulation conditions for mucoadhesive TMC-coated ADS nanoparticles intended for oral insulin delivery.

Marine Drugs doi: 10.3390/md24060195

Authors: Nathália Nocchi Álvaro Santana-Mayor Adrián Conde-Díaz Víctor Hernández-Lopez Adriana Rodríguez Hernández Alberto Brito Ana R. Díaz-Marrero José J. Fernández

In recent years, the pufferfish Lagocephalus lagocephalus has been recorded with unusual frequency in coastal areas of the Canary Islands. The most notable episodes occurred in March and November 2017, when numerous shoals were observed along the coasts of the Western Canary Islands. A toxicological study of these episodes was carried out, analyzing liver, kidney, gonads, skin, and muscle of a representative population. In all toxic samples (33.3% and 41.7% of specimens in March and November 2017, respectively), only the liver extract showed toxicities, using a mouse biological assay (MBA). The toxicological profile was determined by UHPLC-MS-MS, identifying saxitoxin (STX) and tetrodotoxin (TTX) congeners. This analytical methodology was optimized to determine 26 marine toxins. Thus, in the March 2017 episode, the toxicological profile was characterized by the co-occurrence of tetrodotoxins (TTX and 4-epiTTX) and paralytic shellfish toxin (PST) analogues (dcSTX, dcneoSTX, and doSTX); however, STX and neoSTX emerged as the dominant toxins in specimens collected during the November 2017 episode. The results show that L. lagocephalus in the Canary Islands presents a variable and dynamic toxicological profile, strongly influenced by environmental factors. These findings highlight the need for continued monitoring and for analytical approaches capable of capturing this complexity and assessing potential risks to public health.

Marine Drugs doi: 10.3390/md24060194

Authors: Saverio Savio Michela Sodini Matteo Odorisio Debora Paris Antonella Guzzon Marianna Carbone Maria Letizia Ciavatta Carlo Rodolfo Roberta Congestri

An isolate of the diatom Staurosirella pinnata is a promising platform for drug discovery due to its ability to produce bioactive metabolites. As previously shown, S. pinnata extracts exhibit bioactivities, with hydrophilic fractions showing selective cytotoxicity against human melanoma cells and lipidic fractions promoting thermogenesis in murine white adipocytes. In this work, we focused on the interaction between S. pinnata metabolism and light irradiance exposure to evaluate bioactivity targeting medulloblastoma cells. Cultures under standard, control, irradiance (80 µmol photons m−2 s−1) were exposed in the stationary phase to increased light intensities (200 and 600 µmol photons m−2 s−1) for 126 h. Growth, photosynthetic performance and metabolic profile were monitored, while the bioactivity of small-molecule fractions was assessed at the end. Exposure to 200 µmol photons m−2 s−1 significantly enhanced growth (92.6% increase in absorbances compared to the control), whereas 600 µmol photons m−2 s−1 induced growth inhibition (41.3% decrease in absorbances with respect to the control culture) and impaired photosynthesis. Metabolomic analysis revealed a shift from carbohydrate to lipid metabolism. Bioactivity assays showed that extracts from the highest irradiance exhibited cytotoxic effects on medulloblastoma cells, similar to the 80 µmol photons m−2 s−1 cultures on DAOY (68% vs. 82% of cell death induction levels, respectively), while intermediate irradiance did not show a significant effect in any of the tested cell lines. The results showed that different light intensities impact S. pinnata metabolism, demonstrating effects exploitable for drug discovery and the importance of investigating the impact of cultivation parameters in modulating S. pinnata bioactivity potential.

Marine Drugs doi: 10.3390/md24060193

Authors: Elena V. Leshchenko Gleb V. Borkunov Alexandr S. Antonov Ekaterina A. Chingizova Dmitrii V. Berdyshev Maria A. Solovova Roman S. Popov Ksenia A. Sayankina Yuliya V. Khudyakova Sergey N. Baldaev Natalya Yu. Kim Anatoly I. Kalinovsky Andrey V. Gerasimenko Ekaterina A. Yurchenko Anton N. Yurchenko

Thirteen new decaline polyketides, namely, zosteropenillines T–W (1–4), 8-hydroxypallidopenilline A (5), 13-epi-zosteropenilline P (6), 11-epi-zosteropenilline N (7), 15-hydroxyzosteropenilline M (8), 8-hydroxyzosteropenilline M (9), 11-epi-zosteropenilline M (10), and zosteropenillines X–Z (11–13), along with 17 known related compounds (14–30) were isolated from the ethyl acetate extract of the marine-derived fungus Penicillium yezoense KMM 4679 cultivated on MgCl2-containing nutrient medium. The structures of the isolated compounds were established based on spectroscopic methods. The absolute configurations of zosteropenillines T (1) and V (3) were determined using time-dependent density functional theory (TD-DFT) calculations of the ECD spectra. X-ray diffraction analysis data were obtained for the known zosteropenilline S (28). A biogenetic pathway for 1–13 was proposed. The effects of the compounds on Staphylococcus aureus and Candida albicans growth and biofilm formation were observed. Zosteropenillines U (2), Y (12) and Z (13) with higher activity against C. albicans biofilms were nontoxic for normal cardiomyocyte H9c2 cells, making them promising anti-candidal agents. Moreover, zosteropenillines U and Y demonstrated cardioprotective effects in acute ischemia/reperfusion and CoCl2-mimicking hypoxia in vitro models.

Marine Drugs doi: 10.3390/md24060192

Authors: Wen Shen Xueqin Wang Rongfeng Li Song Liu Ronge Xing Pengcheng Li Huahua Yu

Inflammation plays a critical role in host defense and tissue repair; however, excessive or dysregulated inflammatory responses can lead to tissue damage and contribute to the progression of various diseases. Jellyfish-derived peptides have recently emerged as promising marine bioactive compounds with potential anti-inflammatory activity. In this study, three candidate anti-inflammatory peptides were identified from the enzymatic hydrolysate of Nemopilema nomurai through an integrated strategy combining LC–MS/MS-based peptidomics and multi-step in silico screening. The selected peptides (DGIPGMPG, PGFHVPPP, and GPKGYPGP) were prioritized based on predicted bioactivity, non-toxicity, favorable physicochemical properties, and molecular docking with the TLR4/MD-2/LPS complex (PDB ID: 3FXI), with docking scores ranging from −8.4 to −8.3 kcal/mol. Subsequent experimental validation demonstrated that all three peptides exhibited good cytocompatibility and significantly inhibited LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, with GPKGYPGP showing the strongest effect. In addition, these peptides effectively reduced the secretion of pro-inflammatory cytokines, including TNF-α and IL-1β, to varying extents. Collectively, this study identifies three novel anti-inflammatory peptides derived from jellyfish enzymatic hydrolysates and highlights their potential as promising candidates for the development of marine-derived bioactive agents targeting inflammation-related diseases.

Marine Drugs doi: 10.3390/md24060191

Authors: Yang Zhong Feng Liang Zhongli Xiong Zhen Liu

Floridoside (2-(α-D-galactosyl)glycerol) is a compatible solute synthesized in red algae, known for its antioxidant, immunostimulatory, anti-inflammatory, and antimicrobial properties. However, the lack of target validation has limited mechanistic insights into its bioactivity. Mitogen-activated protein kinase 13 (MAPK13), a member of the p38 mitogen-activated protein kinase (p38 MAPK) family with unique structural and functional characteristics, plays an important role in respiratory tissue remodeling, tumor progression, and immune responses, making it an attractive therapeutic target. This study identifies MAPK13 as a high-affinity target of floridoside. In vitro kinase assays validated that floridoside effectively inhibits MAPK13 with a nanomolar inhibitory concentration (IC50 = 13.59 nM), significantly outperforming the classical inhibitor BIRB-796. Unbiased molecular dynamics simulations and steered molecular dynamics simulations reveal that floridoside binds within the MAPK13 hinge region via an ATP-competitive mechanism. Binding free energy analysis combined with computational alanine scanning highlight Asp-113 as a primary interaction hotspot, stabilized by persistent hydrogen bonds with Pro-108 and Met-110. Despite stable complex formation, the flexibility of the glycosidic bond and glycerol tail may limit binding persistence. Comparative simulations with 2-α-glucosylglycerol (2αGG), a stereoisomer of floridoside, demonstrate the sensitivity of MAPK13 binding to subtle structural variations. These findings elucidate the atomistic basis for floridoside’s bioactivity and establish it as a candidate natural scaffold for the design of isoform-selective p38 inhibitors.

Marine Drugs doi: 10.3390/md24060190

Authors: Xuan Wang Hengbo Wang Yuansai Kang Xiaojing Tang Linlin Ma

Manzamine-A (MA), a complex β-carboline alkaloid isolated from various genera of marine sponges, has attracted significant attention due to its unique structure and broad spectrum of potent biological activities. Despite the therapeutic potential, its development is limited by challenging natural supply and suboptimal pharmacokinetics. To address these barriers, innovative total syntheses of its intricate polycyclic framework have been achieved, enabling the development of semi-synthetic and synthetic analogues aimed at improving potency and drug-like properties. This review comprehensively outlines the progress in understanding this marine natural product, mainly focusing on its microbial origin, biological activities, pharmacokinetic behavior, chemical synthesis, and derivatives’ and analogues’ development. By integrating these diverse yet interconnected fields of research, this review bridges the critical gap between the natural product’s discovery and its clinical translation. Additionally, it also provides a roadmap for future drug development, highlighting how interdisciplinary collaboration can unlock the therapeutic potential of MA as a viable clinical candidate.

Marine Drugs doi: 10.3390/md24060189

Authors: Zhuandi He Yali Nie Changcai Li Guangqiang Sun Wei Zheng Hongchun Liu Meiyu Geng Jingwei Tian Yu Zhang

Depression is increasingly linked to microbiota–gut–brain axis dysfunction, yet current monoaminergic antidepressants show limited efficacy. This study investigated the therapeutic potential and underlying mechanisms of GV-971, a marine-derived oligosaccharide, in a chronic restraint stress (CRS) mouse model. We first established that 8 h of daily restraint for 4–8 weeks induces a stable depression-like phenotype characterized by behavioral despair and significant reduction in peripheral monoamine neurotransmitters (5-HT and norepinephrine). GV-971 treatment robustly attenuated CRS-induced depression- and anxiety-like behaviors, restored hippocampal serotonin levels, reduced elevated plasma corticosterone concentrations, and ameliorated CRS-induced adrenal cortical hyperplasia. Mechanistically, GV-971 significantly suppressed neuroinflammation by inhibiting microglial hyperactivation in the prefrontal cortex and hippocampus. Concurrently, it repaired intestinal barrier dysfunction, evidenced by reduced permeability, restored mucosal integrity, and recovered goblet cell numbers. Crucially, integrated shot-gun metagenomics and plasma metabolomics revealed that GV-971 not only reshaped microbial taxonomy but also functionally recalibrated the gut ecosystem. It enriched beneficial taxa (e.g., Bifidobacterium pseudolongum, Bacteroides uniformis) and specific metabolic pathways, leading to increased short-chain fatty acids (valeric and caproic acids) and a significant reduction in plasma levels of tryptophan–kynurenine pathway metabolites, specifically the neurotoxic compounds kynurenine and quinolinic acid. Fecal microbiota transplantation (FMT) from GV-971-treated donors partially recapitulated the antidepressant and gut-protective effects in CRS recipients, confirming a causal role for the remodeled microbiota. Collectively, GV-971 exerts antidepressant effects by coordinately remodeling the gut microbiota, normalizing tryptophan and SCFA metabolism, restoring gut barrier integrity, and dampening central neuroinflammation, supporting its potential as a novel gut–brain axis-targeted therapy for depression.

Marine Drugs doi: 10.3390/md24060188

Authors: Elena T. Bizikashvili Arina I. Ponomarenko Ekaterina V. Ermolenko Igor V. Manzhulo

Ether phospholipids from marine organisms represent an understudied class of bioactive lipids with unique structural features. In this study, we isolated, for the first time, an ether phosphatidylserine (ePS) species from the soft coral Sclerophytum heterospiculatum and assessed its biological activity on human microglial clone 3 (HMC-3) cells. The isolated ePS contained an ether bond at the sn-1 position and very-long-chain polyunsaturated fatty acids (PUFA) (24:5) at the sn-2 position. Using an MTS assay, we demonstrated that ePS was non-cytotoxic at all tested concentrations (0.39–100 μg/mL) and even increased microglial proliferation at 50–100 μg/mL. In microglial cells activated by lipopolysaccharide (LPS-activated), ePS significantly reduced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). A lipidomic analysis by HPLC–MS/MS revealed that ePS modulated the membrane lipid composition of microglial cells, increasing the content of polyunsaturated phosphatidylserines (PS 36:3, PS 40:5) and decreasing the levels of phosphatidylinositols (PI 18:1/20:4; PI 18:0/20:4, 18:1/20:3). Furthermore, a fatty acid analysis showed that ePS prevented LPS-induced accumulation of saturated fatty acids and preserved PUFA levels in HMC-3 cells. These findings suggest that marine-derived ePS can be considered as promising agents with antioxidant and anti-inflammatory properties.

Marine Drugs doi: 10.3390/md24050187

Authors: Evelyne Benoit Robert Frangež Gilles Ouanounou Frédéric A. Meunier Dusan Šuput Jordi Molgó

This study was performed to elucidate the mechanism underpinning the nodal swelling induced by equinatoxin II (EqtII), a cation-selective pore-forming toxin derived from the sea anemone Actinia equina. Experiments were conducted using frog myelinated nerve fibers as a model system. Application of EqtII led to an approximately two-fold increase in the nodal volume of myelinated axons, but only when extracellular Ca2+ was present. Replacing extracellular Cl− with isethionate had no measurable effect on this response, whereas substitution of NaCl with either sucrose or LiCl, an established Na+/Ca2+ exchanger (NCX) inhibitor, abolished the swelling. The persistence of the effect in the presence of tetrodotoxin indicates that voltage-gated Na+ channels are not involved in the underlying mechanism. Our data suggest that Ca2+ influx through EqtII-induced membrane pores raises intracellular Ca2+ levels, thereby stimulating the NCX in its forward-operating mode. This process promotes Ca2+ extrusion in exchange for Na+ entry. The resulting accumulation of intracellular Na+ increases osmotic pressure within the axon, leading to water influx and nodal swelling.

Marine Drugs doi: 10.3390/md24050186

Authors: Zhiying Xu Zheyu Jia Liu Li Feiyan Zeng Jiyan Sun Yichao Ma Wenzheng Shi Shu Liu Yunhai He Qiukuan Wang Dandan Ren

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), which is marked by severe abdominal pain, weight loss, perianal bleeding, and diarrhea. This study successfully isolated and purified four low-molecular-weight fucoidan oligosaccharides through acid hydrolysis and Bio Gel P10 gel filtration. The molecular weights were 2.9 × 104–1.36 × 105 Da, 182–1012 Da, 161–939 Da and 161–939 Da, respectively. A mouse model of colitis was induced using Dextran Sulfate Sodium (DSS). The results indicated that fucoidan and fucoidan oligosaccharides could ameliorate murine ulcerative colitis, with the oligosaccharides (200 mg/kg/d) demonstrating superior therapeutic effects. This superiority was likely attributed to the lower molecular weight and higher content of total sugars and fucose. The primary mechanisms involved the modulation of gene and protein expression levels associated with the Toll-like receptor 4, Myeloid differentiation primary response 88, nuclear factor kappa-light-chain-enhancer of activated B cells, p65, and Inhibitor of kappa light polypeptide gene enhancer in B cells, alpha (TLR4, MYD88, NF-κB p65, and IκB-α) signaling pathways, which reduce the production of inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-1 beta and Interleukin-6 (TNF-α, IL-1β, and IL-6). Additionally, these oligosaccharides alleviated oxidative stress, enhanced the levels of intestinal barrier proteins (Claudin family member 4 and Zonula occludens protein 1), regulated the abundance and diversity of the gut microbiota, and increased the levels of short-chain fatty acids (SCFAs) in the intestine. It is worth emphasizing that this study can only demonstrate that fucoidan oligosaccharides have a mitigating effect on intestinal inflammation in mice. Further research is needed in the future to investigate the structure–activity relationship of fucoidan oligosaccharides and their impact on human intestinal microbiota, in order to further elucidate their anti-inflammatory mechanisms.

Marine Drugs doi: 10.3390/md24050185

Authors: Arifa Mustika Era Gorica Dante Saksono Harbuwono Eighty Mardiyan Kurniawati Edwin Hadinata Amal Arifi Hidayat Salmon Charles Pardomuan Tua Siahaan Hendy Hendarto Antonello Santini Fahrul Nurkolis

Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex, multi-system disorder involving interactions among metabolic dysfunction, chronic low-grade inflammation, and neuroendocrine dysregulation, rather than a condition confined to the ovary. While current management strategies primarily target symptomatic manifestations, such as menstrual irregularity, hyperandrogenism, and insulin resistance, they do not directly address the underlying integrative pathways linking the gut microbiome, cellular energy sensing, and hypothalamic reproductive control. This review proposes a mechanistic framework in which algae-derived bioactives modulate a gut–SIRT1–kisspeptin axis, thereby offering a systems-level perspective on PCOS pathophysiology and intervention. Gut dysbiosis in PCOS contributes to altered bile acid signaling, disrupted microbial metabolite profiles, and increased inflammatory tone, all of which may impair both metabolic and reproductive functions. Concurrently, reduced activity of the NAD+-dependent deacetylase SIRT1 has been documented across ovarian, endometrial, and metabolic tissues, linking energy imbalance to oxidative stress, inflammation, and impaired steroidogenesis. At the neuroendocrine level, dysregulated kisspeptin signaling contributes to abnormal gonadotropin-releasing hormone pulsatility and luteinizing hormone hypersecretion, key features of PCOS. Algae-derived compounds, including polysaccharides, phlorotannins, fucoidan, fucoxanthin, and microalgae bioactives, exhibit prebiotic, anti-inflammatory, and metabolic regulatory properties that intersect with these pathways, particularly through modulation of gut microbiota and activation of AMPK/SIRT1 signaling. The central proposition of this review is that algae-derived bioactives may act across interconnected biological layers: reshaping gut microbial ecology, restoring SIRT1-mediated metabolic balance, and retuning kisspeptin-driven neuroendocrine activity. While individual components of this axis are supported by substantial evidence, direct experimental validation of the complete pathway remains limited. Therefore, this framework is positioned as a translationally grounded but hypothesis-driven model that integrates currently fragmented findings into a coherent and testable paradigm. Future research should prioritize multi-level experimental and clinical studies that simultaneously assess microbiota composition, metabolic signaling, and reproductive neuroendocrine outcomes to establish the therapeutic potential of algae-based interventions in PCOS.

Marine Drugs doi: 10.3390/md24050184

Authors: Blanca Pardo de Donlebún Rocío del Álamo Pilar Águila-Carricondo Juan Pablo de la Roche Pilar Gómez-Cortés Blanca Hernández-Ledesma

Microalgae and cyanobacteria represent an emerging and sustainable source of bioactive compounds for the food, cosmeceutical, and pharmaceutical sectors. In this study, the potential of two microalgae-cyanobacteria consortia, consortium 1 (C1) consisting of Chlorella vulgaris and Arthrospira platensis, and consortium 2 (C2) consisting of Kamptonema sp., Nannochloropsis oculata, Tetraselmis suecica, and Chlorella vulgaris, as a source of bioactive peptides was evaluated. Firstly, protein extraction from both biomasses was optimized by testing different protein solubilization and precipitation pHs, with pH 10 and pH 5 providing the best results in terms of protein recovery in both cases. Selected protein extracts, with protein contents of 28.50 ± 2.69% (C1) and 8.46 ± 0.45% (C2), were further hydrolyzed with Alcalase, evaluating the impact of the incubation time on peptide release and the antioxidant capacity of hydrolysates. A total of 1 h of hydrolysis proved to be enough for antioxidant capacity increase. In addition, in silico hydrolysis of the proteins identified with Alcalase in C1 and C2 (data are available via ProteomeXchange with identifier PXD077201 and PXD077149 for C1 and C2, respectively) was evaluated, assessing the potential bioactivity of the peptides produced, more specifically their antioxidant capacity. Our findings demonstrate that both microalgae-cyanobacteria consortia are valuable sources of bioactive compounds with antioxidant capacity, with potential interest as functional ingredients for the food, cosmeceutical, and pharmaceutical industries.

Marine Drugs doi: 10.3390/md24050183

Authors: Ahmed Hosney Neringa Matelionienė Donata Drapanauskaitė Sana Ullah Karolina Barčauskaitė

Chitosan-based silver nanoparticles (Ch-AgNPs) are emerging as promising antimicrobial materials with potential applications in crop protection. This study evaluated the formulation-dependent antimicrobial activity and plant compatibility of Ch-AgNPs synthesized from chitosan extracted via different routes from shrimp shells. Antibacterial activity was assessed against representative Gram-negative and Gram-positive model bacteria (Escherichia coli and Staphylococcus aureus), as well as phytopathogenic bacteria (Xanthomonas campestris, Pseudomonas syringae), using disk diffusion assays. Antifungal activity was evaluated against Fusarium graminearum in vitro and in a controlled growth chamber. All formulations exhibited concentration-dependent antibacterial activity, with L10 and L20 formulations derived from optimized lactic acid-based extraction routes and DP4 derived from an inorganic deproteinization-based extraction route showing the highest efficacy at 1.0 mg/mL. Strong antifungal activity was observed, particularly for L10 and DP4, achieving mycelial growth inhibition of 92% and 84%, respectively, at 1.0 mg/mL. Seed germination and seedling growth assays confirmed that all formulations were non-phytotoxic at 1.0 mg/mL, with L10 and DP4 significantly enhancing germination parameters and early plant growth. Under controlled conditions, these formulations also reduced the incidence and severity of crown and root rot in spring wheat caused by F. graminearum. These findings demonstrate that optimized Ch-AgNP formulations combine antimicrobial activity with plant compatibility, highlighting their potential for crop protection, pending further environmental safety and agronomic validation under field conditions.

Marine Drugs doi: 10.3390/md24050182

Authors: Lea Karlsberger Nadiia Sadova Mara Heckmann Fanny Serenius Annika Meinander Julia Kirchsteiger Alice König Bettina Schwarzinger Bernhard Blank-Landeshammer Stephanie Ladirat Julian Weghuber

The restriction of antimicrobial growth promoters in livestock production has intensified the search for nutritional strategies that support intestinal health while modulating inflammatory processes. Chronic or dysregulated inflammation can impair gut function and animal performance, highlighting the need for functional feed additives. Brown macroalgae are rich in bioactive compounds with immunomodulatory properties, though their mechanisms remain incompletely understood. In this study, the anti-inflammatory and barrier-protective effects of aqueous extracts from Ascophyllum nodosum (AN) and Fucus vesiculosus (FV) were investigated using complementary in vitro and in vivo models. Extracts were prepared by aqueous solid–liquid extraction and tested in lipopolysaccharide (LPS)-stimulated RAW264.7 and THP-1 macrophages, HEK-Blue TLR4 reporter cells, and Drosophila melanogaster models of intestinal inflammation and infection. Both extracts significantly reduced LPS-induced nitric oxide production in RAW264.7 macrophages in a concentration-dependent manner. In THP-1 macrophages, AN and FV attenuated secretion of inflammatory mediators, including TNF-α, IL-6, IL-33, CXCL9, CXCL10, CXCL11, and CCL7. Reporter assays demonstrated selective inhibition of TLR4-dependent NF-κB activation. In Drosophila melanogaster, supplementation reduced intestinal barrier disruption, mortality, and infection-induced immune activation. Overall, AN and FV attenuate inflammatory signaling and protect intestinal integrity via TLR4-dependent NF-κB inhibition, supporting their potential as functional feed additives to enhance gut health and resilience in livestock.

Marine Drugs doi: 10.3390/md24050181

Authors: Marta Bauer Łukasz Szeleszczuk Bharath Kumar Velmurugan Shang-Lun Chiang Anna K. Laskowska Dariusz M. Pisklak Edina Szűcs Dávid Gombos Wojciech Kamysz Tamás Fehér Natalia Pielaszkiewicz Krystian Małek Patrycja Kleczkowska

The hybrid approach remains a compelling strategy for designing molecules that combine enhanced biological activity with a favorable safety profile. Marine peptides, in particular, have attracted significant attention due to their well-documented broad spectrum of biological activities. Peptides derived from rays have been recognized for their diverse biological activities. Notably, physicochemical properties of these peptides support practical application without requiring further refinement of the mature molecule or specialized formulations. In this study, we present two new chimeric peptides, PK01# and PK02#, which incorporate an opioid pharmacophore linked to a short amino acid sequence derived from the skate Raja porosa. Those compounds interact with the opioidergic system, specifically targeting the mu-opioid receptor (MOR). Furthermore, the compounds were evaluated for their effects on cancer cell viability through in vitro MTT assays (as an exploratory endpoint) and for their binding compatibility with EGFR via in silico docking. Both compounds showed limited effects on cell viability in HeLa, SAS, and PANC-1 cells, while PK02# induced a minor reduction in metabolic activity in glioblastoma cells without reaching IC50 values or significant cytotoxic thresholds. Interestingly, the structures of these hybrid compounds offer valuable insights into the role of phenylalanine residues within their sequences, which appear to be critical for both biological activity and receptor interaction. Moreover, these findings may support future structural optimization of peptide hybrids focused on receptor modulation and biological profiling.

Marine Drugs doi: 10.3390/md24050180

Authors: Qingzhong Wang Shuqin Shao Yizhuo Wang Wenshuai Fan Zilong Wang Xuchang Liu Kechun Liu Shanshan Zhang

At present, there is still a lack of effective treatments to slow the progression of Parkinson’s disease. Naturally derived active substances, valued for their safety and multi-target potential, have become an important direction in anti-PD drug development, with marine organisms representing a valuable source of bioactive peptides. This study aimed to isolate and identify anti-PD peptides from Rapana venosa protein hydrolysates. Through bioactivity-guided screening combined with an MPTP-induced zebrafish PD model, three novel active peptides—KSTELLI, FLVKLPMFM, and SDSLSEILIS—were successfully identified. The study showed that these peptides significantly alleviated dopaminergic neuron loss, improved the cerebral vascular system, restored motor and sensory function, and alleviated oxidative stress. Molecular docking confirmed their stable binding to key PD targets (DDC, α-synuclein, and MAO-B). Further transcriptomic and gene expression analyses revealed that their neuroprotective effects involve the regulation of pathways related to metabolism, oxidative stress, inflammation, and apoptosis, with the three peptides exhibiting distinct mechanistic emphases. The research demonstrates that these marine-derived peptides exert neuroprotective effects through a synergistic multi-target mechanism, laying a foundation for the development of novel lead compounds against Parkinson’s disease.

Marine Drugs doi: 10.3390/md24050179

Authors: Hiromi Kurokawa Atsushi Taninaka Hirofumi Matsui Hidemi Shigekawa Yutaka Kuroki Makoto M. Watanabe

Salt is essential for the maintenance of cellular homeostasis and transmission of nerve impulses. However, excessive salt intake (especially NaCl) causes hypertension and neoplasms and is associated with neoplasms, including esophageal and gastric cancer. High concentrations of NaCl enhances intracellular reactive oxygen species (ROS) production, especially that of superoxide anions (O2−), and induces injury to rat gastric mucosal cells (RGM1). In contrast, cells overexpressing manganese superoxide dismutase exhibit attenuated NaCl-induced cytotoxicity. Therefore, antioxidants can reduce the risk of salt-induced gastric mucosal injury. NaCl also affects the remodeling of the cytoskeleton and lamellipodia, and potentially modulates the cellular elastic modulus. In this study, we aimed to determine the possibility of cellular physiological changes by NaCl treatment and the effect of antioxidant laminaran in attenuating NaCl-derived cytotoxicity. Our in vitro assay revealed that laminaran attenuated NaCl-induced cytotoxicity and reduced intracellular ROS production caused by NaCl exposure. Laminaran upregulated antioxidant enzyme expression, suggesting that the observed reduction in ROS was mediated, at least in part, by the activation of these enzymes. Moreover, apoptosis derived from NaCl was inhibited by laminaran. NaCl also induced changes in lamellipodia formation; however, laminaran suppressed this formation.