Marine Drugs doi: 10.3390/md24040143

Authors: Alexandros Tsoupras

Modern lifestyles expose humans to a dynamic and complex exposome that significantly influences overall health, including skin physiology [...]

Marine Drugs doi: 10.3390/md24040142

Authors: Prasong Srihanam Wilaiwan Simchuer Vanseng Chounlamany Kesiny Phomkeona Phengxay Deevanhxay Yodthong Baimark

Alginate is a biocompatible and biodegradable polymer derived from seaweed. It has been extensively researched and developed for various applications. However, its poor mechanical properties present a significant drawback that limits its use in multiple fields. Furthermore, the fabrication of reinforced alginate films using conventional melt processing has the potential for scaling up production. This study aimed to enhance the mechanical properties of sodium alginate (SA) films by incorporating calcium alginate (CA) powder. The SA/CA biocomposite films were created using a thermo-compression technique, with glycerol acting as a plasticizer for the SA matrix. Various CA contents—2.5, 5, 10, and 20 wt%—were investigated. Scanning electron microscopy and energy dispersive spectroscopy revealed good interfacial adhesion between the SA film matrix and the CA powder. As the CA content increased, the moisture content of SA/CA biocomposite films decreased. The addition of CA powder significantly improved the tensile properties of the SA films. Based on the tensile test, SA/CA biocomposite films with 20 wt% CA powder exhibited a maximum tensile strength of 11.7 MPa and a Young’s modulus of 234.7 MPa. These results indicate a substantial increase of 208% in maximum tensile strength and 907% in Young’s modulus compared to SA films without CA. These findings indicated that the CA powder serves as an effective reinforcing filler for thermo-compressed SA films, which could lead to the development of high-strength alginate-based products for potential use in various applications, including biomedical, agricultural, and packaging applications.

Marine Drugs doi: 10.3390/md24040141

Authors: Monserrat Alemán Marianna Venuleo Juan Luis Gómez-Pinchetti Eduardo Portillo Flavio Guidi

Protein and phycocyanin production is challenged by freshwater scarcity in arid coastal regions. This study assessed and optimized the cultivation of Limnospira platensis BEA 1257B in full seawater. Eight cultivation phases were conducted in 10,000 L raceways under a greenhouse to evaluate the effects of seawater content, nutrient availability, shading, CO2 supply, and medium recycling on biomass productivity and biochemical composition. Freshwater, energy, and fertilizer savings, together with effluent characteristics of the optimized full-seawater recirculation strategy (SWR), were evaluated against a conventional freshwater cultivation process. Lower productivity was associated with high salinity and irradiance. Under long-term optimized conditions (615 days), the strain achieved stable productivities of 4.1 ± 1.4 gDW m−2 day−1 (14.8 ± 5.0 tDW ha−1 year−1). Increasing salinity promoted carbohydrate accumulation in the biomass (26.0% AFWD), while protein (64.4%) and C-phycocyanin (9.9%) moderately decreased. Nevertheless, protein quality, phycocyanin, and essential fatty acids remained high. Spray-dried biomass exhibited nutritionally relevant contents of K, Mg, Ca, Fe, and Mn, and complied with international food safety standards. SWR reduced energy demand by 10.5% and freshwater consumption by 12% on a surface basis, although these advantages were partially offset when expressed per unit of product, while clearly supporting environmentally sustainable and regulatory-compliant Limnospira production.

Marine Drugs doi: 10.3390/md24040140

Authors: Yu-Hui Zeng Yang-Yan Jin Yan Sheng Chang-Feng Chi Bin Wang

Antioxidant peptides show significant activity and can be developed into functional foods for treating chronic diseases. Cigarette smoke components can cause damage or even apoptosis of lung cells, eventually leading to chronic lung diseases. Therefore, this study aimed to investigate the protective effects and mechanisms of Skipjack tuna peptides against in vitro cigarette smoke extract (CSE)-induced chronic obstructive pulmonary disease (COPD). The results demonstrated that tuna peptides DVGRG (S1), PHPR (S5), GRVPR (S6), and SVTEV (S7) significantly enhanced the activities of SOD, CAT, and GSH-Px by upregulating the mRNA transcription levels of Keap1 and Nrf2, consequently reducing ROS and MDA levels in CSE-induced COPD model of MLE-12 cells. Molecular docking analysis revealed that S1, S6, and S7 competitively inhibited the Keap1-Nrf2 interaction by binding to the Kelch domain of Keap1, whereas S5 operated through a non-competitive mechanism. These peptides also downregulated p65 mRNA expression and upregulated IκBα mRNA expression, leading to a significant reduction in inflammatory cytokines of IL-1β, IL-6, and TNF-α, thereby alleviating inflammatory responses. Furthermore, these peptides significantly inhibited CSE-induced apoptosis by restoring mitochondrial membrane potential and upregulating the Bcl-2/Bax ratio. Additionally, S1, S5, S6, and S7 promoted MLE-12 cell migration in a concentration-dependent manner, suggesting a role in lung epithelial repair and regeneration. In conclusion, tuna peptides S1, S5, S6, and S7 exert antioxidant, anti-inflammatory, anti-apoptotic, and cell migration-promoting effects through the regulation of the Keap1/Nrf2 and NF-κB signaling pathways, as well as Bcl-2/Bax apoptotic balance, providing a promising strategy for mitigating CSE-induced lung injury.

Marine Drugs doi: 10.3390/md24040139

Authors: Maria Dimopoulou Stavroula Savvidi Panagiotis Madesis Aliki Dimopoulou Dimitrios Stagos Olga Gortzi

Long-chain polyunsaturated fatty acids (LC-PUFAs) of omega-3 family, particularly docosahexaenoic acid and eicosapentaenoic acid, are essential nutrients that play a critical role in children’s growth and health. This review examines the evidence on the effects of omega-3 supplements and omega-3-enhanced foods on children’s development, as well as on neurological and metabolic disorders. Research consistently highlights the importance of DHA in brain and visual development, especially during early childhood, when rapid neural growth occurs. PubMed, Web of Science, Scopus and the Cochrane Library databases were searched for relevant articles published up to January 2026. Adequate omega-3 intake has been associated with improvements in cognitive performance, attention, and learning outcomes. In children with neurodevelopmental conditions such as attention-deficit/hyperactivity disorder and autism spectrum disorder, omega-3 supplementation shows modest but potential benefits in reducing behavioral symptoms and supporting executive function, although results remain mixed. Additionally, omega-3 fatty acids exhibit anti-inflammatory properties that may positively influence metabolic health, including lipid profiles, insulin sensitivity, and obesity-related risk factors in children. Omega-3-enhanced foods provide an alternative to supplements and may improve adherence and overall dietary quality. However, variability in dosage, study design, and baseline nutritional status limits definitive conclusions. Overall, omega-3 fatty acids appear to support healthy development and may aid in managing certain neurological and metabolic disorders in children.

Marine Drugs doi: 10.3390/md24040138

Authors: Ricardo Moreno Traspas Zachariah Tman

The liver is a central regulator of systemic metabolism and exhibits exceptional regenerative capacity, yet aging progressively impairs hepatic resilience through metabolic dysregulation, mitochondrial dysfunction, epigenetic instability, and chronic inflammation. Marine ecosystems constitute a vast and underexplored source of structurally diverse bioactive compounds that have evolved to modulate conserved stress response and homeostatic pathways. This review synthesizes current preclinical evidence demonstrating how marine-derived metabolites target key molecular axes implicated in liver aging, including energy sensing, redox balance, mitochondrial quality control, inflammatory signaling, and chromatin-associated regulation. Rather than focusing solely on isolated hepatoprotective effects, we frame marine bioactives within an aging biology perspective, highlighting their ability to modulate pathways associated with cellular plasticity and resilience. We further propose that this mechanistic convergence provides a theoretical framework for exploring marine compounds as potential adjunctive modulators within emerging, experimental liver rejuvenation strategies, including partial cellular reprogramming approaches that require coordinated metabolic and epigenetic control. While acknowledging that direct reversal of liver aging remains to be clinically established, integrating marine chemodiversity with contemporary aging and regenerative biology outlines a conceptual roadmap for developing liver-directed interventions targeting aging-related vulnerability as a fundamental driver of disease.

Marine Drugs doi: 10.3390/md24040137

Authors: Yaoying Lu Xiaojing Chen Yunjiang Feng

Probiotics are known to improve gut microbiota balance, enhance food digestion, and support overall health. Among these, Bacillus species are particularly promising due to their safety, spore-forming ability, environmental resilience, and diverse enzymatic activities. However, most Bacillus probiotics used in industry are of terrestrial origin, leaving marine-derived strains largely unexplored. Utilising the untapped potential of marine microbial biomass, this study presents a multi-stage methodology for identifying and evaluating marine-derived Bacillus strains with probiotic potential. A structured screening pipeline was applied to 67 microbial isolates from the Great Barrier Reef sponges. Initial selection focused on essential probiotic characteristics, including growth, stability, safety, and survival under gastrointestinal conditions. Strains meeting these criteria were then assessed for desirable properties, including digestive enzyme production and pathogen inhibition. Using this workflow, three marine-derived Bacillus strains were identified as potential probiotics, one of which demonstrated strong antimicrobial activity against Salmonella enterica at 5 and 10 mg/mL (p < 0.01). These findings demonstrate the capability of marine-associated Bacillus as novel bioproducts with functional antimicrobial properties.

Marine Drugs doi: 10.3390/md24040136

Authors: Nedeljka Rosic Isidora Skrlin Carol Thornber

Macroalgal species are widely distributed throughout the world’s oceans and are well recognised for their biotechnological, ecological, and pharmacological potentials, containing a wide range of diverse bioactive compounds. In many coastal habitats worldwide, excessive accumulations of algal biomass (including rapidly growing blooms and drift accumulations resulting from dislodgement from benthic habitats) are commonplace and can pose environmental and economic challenges. In this study, we report occurrences of algal blooms and drift accumulations during 2024 and 2025 involving three major macroalgal clades, Chlorophyta, Phaeophyceae, and Rhodophyta, from two distinct marine regions: the North Atlantic Ocean and the South Pacific Ocean. Species identified included Grateloupia turuturu, Polyides rotundus, Ascophyllum nodosum, Ulva spp., Sargassum spp. and Fucus spp., among others. The indicated species are known for their diverse pharmacological properties, including antimicrobial, antioxidant, and anti-inflammatory effects. Specialised bioinformatic tools were employed to assess the potential of identified macroalgae as a source of antimicrobial peptides (AMPs). For selected macroalgal species, in silico screening of publicly available databases was performed to identify previously reported and characterised AMPs associated with these species. This in silico approach presents a promising strategy for discovering novel antimicrobial agents with potential activity, especially against drug-resistant bacteria. Finally, applying proteomics methodologies for in silico evaluation of the selected algal species advances modern technologies for the sustainable use of natural resources.

Marine Drugs doi: 10.3390/md24040135

Authors: Antonia Angou Spyros Didos Konstantina Tsotsouli Ioannis S. Boziaris Anagnostis Argiriou

The growing demand for clean-label food ingredients drives interest in novel marine flavorings. This study evaluated the physicochemical, antioxidant, volatile (GC-MS), and sensory profiles of freeze-dried powders from blue crab roe (Callinectes sapidus), sea urchin roe (Paracentrotus lividus), and beluga caviar (Huso huso) to assess their culinary potential. Results revealed that sensory quality is governed by the synergy between a matrix’s lipid composition and endogenous antioxidant capacity. Sea urchin powder, possessing a low polyunsaturated fatty acid (PUFA) profile and high carotenoid content, exhibited exceptional oxidative stability, yielding a concentrated marine aldehyde signature and top consumer scores. Blue crab roe demonstrated a robust PUFA matrix buffered by high phenolic content, facilitating controlled lipid peroxidation into desirable savory volatiles (ketones and aldehydes). Conversely, the high-fat, monounsaturated-dominant beluga caviar lacked sufficient antioxidants, leading to lipid degradation, oxidized hydrocarbons, earthy off-flavors, and poor texture. Both crab and caviar powders exhibited favorable Atherosclerosis and Thrombogenicity indices. Ultimately, balancing lipid composition and endogenous antioxidants is crucial for flavor stability, highlighting the commercial and environmental potential of transforming underutilized or invasive species like blue crab into stable, nutrient-dense marine flavoring agents.

Marine Drugs doi: 10.3390/md24040134

Authors: Svetlana V. Guryanova Oksana Yu. Belogurova-Ovchinnikova Tatiana V. Ovchinnikova

The skin serves as the first line barrier of innate immunity, protecting the body from external influences and maintaining its homeostasis. Exogenous and endogenous stress factors alter the structure and functional properties of the skin. The search for compounds capable of counteracting these processes has allowed the identification of peptides as promising ingredients of products for medicinal and cosmetic applications. This review comprehensively examines the mechanisms of action and dermatological applications of two distinct classes of natural products—endogenous human peptides and those derived from marine organisms. Human peptides exhibit numerous biological functions, including antimicrobial and immunomodulatory ones, as well as promoting antioxidant protection and wound healing. Microbiome-associated peptides are an underestimated but powerful regulator of skin aging through immunomodulation, inflammation control, barrier function maintenance, and selection of the proper microbial community. Peptides from marine organisms exhibit significant structural diversity and a broad spectrum of biological activity, including regenerative effects and effects on antibiotic-resistant microorganisms. This review summarizes current data obtained from in vitro, ex vivo, and clinical studies demonstrating a broad potential of peptides for maintaining skin health. Both peptide classes represent powerful, targeted strategies for innovative dermatological interventions aimed at promoting skin rejuvenation, protection, and overall homeostasis.

Marine Drugs doi: 10.3390/md24040133

Authors: Alejandro M. S. Mayer Veronica A. Mayer Michelle Swanson-Mungerson Marsha L. Pierce Cai M. Roberts Abimael D. Rodríguez Fumiaki Nakamura Orazio Taglialatela-Scafati

During 2022–2023, research groups from 40 nations contributed to the preclinical pharmacology of 173 structurally defined marine-derived compounds, unveiling innovative mechanisms of action. Peer-reviewed publications in the field of marine natural product pharmacology during 2022–2023 included mechanism-of-action studies with 43 compounds showing antibacterial, antifungal, antiprotozoal, antitubercular, and antiviral activity. Additional mechanism-of-action studies were reported for 74 marine compounds that exhibited antidiabetic and anti-inflammatory properties, as well as significant effects on both the immune and nervous systems. Finally, while 65 marine compounds revealed unique and diverse pharmacological mechanisms, further investigation will be required to determine whether they will contribute to a particular therapeutic category. Collectively, the pharmacology of 2022–2023 preclinical marine natural products demonstrated robust activity, offering both novel mechanistic insights and promising chemical scaffolds to enrich the 2026 marine pharmaceutical development pipeline (https://www.marinepharmacology.org/) which currently consists of 17 marine-derived pharmaceuticals approved for clinical use and 29 compounds in either Phase I, II or III of clinical pharmaceutical development.

Marine Drugs doi: 10.3390/md24040132

Authors: Dele Abdissa Keneni Tarryn Swart Alyson Bennett Michelle Isaacs Rosemary Dorrington

This review paper covers publications from 2013 to July 2025, and describes brominated and non-brominated indole alkaloids, ircinianins, terpenoids, and polyketide compound classes from the marine sponge of the genus Psammocinia. It provides an overview of the reported secondary metabolites, their source organisms, geographic origins, and associated biological activities. Also, the structure-activity relationship study and biosynthetic pathways of the reported compounds are illustrated. Herein, 15 new secondary metabolites, including 11 terpenoids and four akaloids, were identified in the Psammocinia sponge species during this period. Briefly, the biological activities of these secondary metabolites involve molecular, cellular, and microbial targets.

Marine Drugs doi: 10.3390/md24040131

Authors: N. M. Liyanage D. S. Dissanayake Yiqiao Li Kyung Yuk Ko D. P. Nagahawatta You-Jin Jeon

Sulfated polysaccharides (SPs), biologically active macromolecules from marine and terrestrial organisms, hold significant potential in revolutionizing cancer therapy. Characterized by their unique sulfate ester groups and structural diversity, SPs exhibit a broad spectrum of bioactivities, including immunomodulation, apoptosis induction, metastasis suppression, and angiogenesis inhibition. Prominent SPs, such as fucoidan from brown algae and carrageenan from red algae, have shown remarkable anticancer properties, either as standalone agents or in synergy with conventional therapies like chemotherapy and radiotherapy. Their mechanisms of action involve targeting critical pathways such as NF-kB, VEGF, and PI3K/Akt, disrupting cancer cell proliferation, invasion, and tumor microenvironment dynamics. SPs also enhance immune system responses, reduce chemotherapy-induced side effects, and exhibit antioxidant properties, making them versatile candidates in cancer treatment. Innovations like SP-based nanoparticles are addressing bioavailability and drug delivery challenges, providing targeted and sustained therapeutic effects while minimizing off-target toxicity. Despite their promise, challenges such as structural complexity, scalability, and clinical validation hinder their widespread adoption. This review provides a comprehensive analysis of SPs’ therapeutic potential, mechanisms, and emerging applications in oncology. It emphasizes the need for advanced extraction, characterization techniques, and clinical research to unlock their full potential, paving the way for novel, efficient, and safer cancer therapies.

Marine Drugs doi: 10.3390/md24040130

Authors: Yuanjie Chen Ting Feng Xiaojing Li Jing Xu Juren Cen

Phaseolorin J (TT-55), a chromone compound isolated and purified from the fermentation products of Phomopsis asparagi DHS-48, is an endophytic fungus obtained from mangrove forests. Preliminary experimental studies have revealed its potent antioxidant and anti-inflammatory activities, though its mechanism of action remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antioxidant and anti-inflammatory effects of TT-55, following initial evidence of its potency, by employing an LPS-induced RAW264.7 macrophage model in vitro. The results revealed that in the LPS-induced inflammatory model of RAW264.7 cells, the TT-55 dose dependently inhibited the expression of LPS-induced inflammatory cytokines (TNF-α, IL-18, IL-1β, IL-6) and the production of oxidative stress markers (reactive oxygen species, SOD, MDA). Following combined treatment with the Nrf2 pathway inhibitor ML385 and TT-55, the inhibitory effects of TT-55 on inflammatory cytokines and oxidative stress markers were reversed by ML385. Meanwhile, ML385 also attenuated the ability of TT-55 to suppress LPS-induced upregulation of NLRP3 inflammasome-related genes. In conclusion, TT-55 may exert its antioxidant and anti-inflammatory effects by activating the Nrf2/HO-1 signaling pathway and suppressing the upregulation of NLRP3 inflammasome-related genes.

Marine Drugs doi: 10.3390/md24040128

Authors: Juan Gao Jieyi Long Xiaoyan Pang Xuefeng Zhou Yonghong Liu Bin Yang

Microorganisms provide critical lead compounds for drug development, yet most biosynthetic gene clusters remain silent under standard culture conditions. The OSMAC strategy activates these clusters by adjusting cultivation parameters, thereby enabling the discovery of novel compounds from a single strain. Here, we applied OSMAC to explore the metabolic potential of the soft coral-derived fungus Aspergillus sclerotiorum SCSIO 41031. Three different culture media were employed for the large-scale fermentation process. After isolation by chromatography, the compounds were structurally characterized using NMR, MS, and X-ray single-crystal diffraction, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. In total, three new compounds, named 6,6′-diacetyl-1,1′-dihydroxy-3,3′-dimethoxydibenzyl ether (1), esterwortmannolol (17) and pestalpolyol I (20), along with 19 known compounds (2–16, 18–19 and 21–22) were obtained. This study validates the efficacy of the OSMAC strategy and underscores that A. sclerotiorum SCSIO 41031 serves as a valuable resource for producing structurally diverse natural products with potent biological activities.

Marine Drugs doi: 10.3390/md24040129

Authors: Yuchen Wang Jingyi Luo Chao Xu Dongyu Hu Yimeng Li Yanzuo Ye Jun Yang Xianxiang Chen Chuan Li Kexue Zhu

Inflammation is pivotal to the pathogenesis of chronic disorders, including diabetes and cardiovascular disorders. Conventional pharmaceuticals used in the treatment of inflammation and related diseases face several challenges. In recent years, polysaccharides isolated from marine organisms have attracted extensive research attention due to their good safety profile, easy availability, and powerful anti-inflammatory properties. However, there is still a lack of systematic elucidation of their anti-inflammatory mechanisms and functional effects. In this review, the sources and structural characteristics of marine polysaccharides were reviewed. Moreover, the anti-inflammatory mechanisms of marine polysaccharides and their advanced applications were discussed. Finally, the current challenges of marine polysaccharides in anti-inflammatory research and food industry applications, as well as future research directions, were proposed. This review deepens the understanding of the anti-inflammatory effects of marine polysaccharides and provides feasible guidance for the development and clinical application of novel anti-inflammatory drugs.

Marine Drugs doi: 10.3390/md24040127

Authors: Feiyu Niu Ziqiang Gu Zihan Yu Zhi Bao Jichao Li Peng Yang Dongyu Li Haijin Mou Changliang Zhu

The enzymatic method is the primary focus for alginate oligosaccharide (AOS) production. However, the high viscosity of sodium alginate (SA) substrate often limits enzymatic efficiency. Pretreatment strategies aimed at reducing SA viscosity offer a promising and innovative solution to enhance process efficiency. This study compared the effects of three pretreatment methods—high-pressure vapor (HP-v), high-pressure solution (HP-s), and atmospheric-pressure air (AP-a)—on the physicochemical properties of SA. These pretreatments reduced SA viscosity and induced visible color changes in the order HP-v > HP-s > AP-a. Additionally, the effects of high-pressure treatments on molecular weight, M/G ratio, and chemical structure of SA were analyzed, confirming the feasibility of pretreatment-assisted enzymolysis. Molecular weight distribution and ESI-MS analysis of AOS after enzymolysis demonstrated that brief HP-v treatment maximizes the catalytic potential of alginate lyase, facilitating efficient AOS production without altering its structural characteristics.

Marine Drugs doi: 10.3390/md24040126

Authors: Keiichi Hiramoto Masashi Imai Masahiro Terasawa Koji Suzuki

Tumor metastasis is closely associated with coagulation and inflammation, particularly via thrombin–PAR1 signaling. However, the potential of natural polysaccharides such as rhamnan sulfate (RS) to modulate these pathways and suppress metastasis remains unclear. We aimed to investigate the effects of orally administered RS derived from Monostroma nitidum on melanoma metastasis and its underlying mechanisms. Male C57BL/6J mice were orally administered water or RS daily. On day 8, saline or B16 melanoma cells were injected intravenously. Mice were treated for 21 days and divided into four groups (control, RS-only, M + W, and M + RS; n = 5/group). Metastasis and related molecular factors were analyzed in plasma, lung, and aortic tissues. Significant lung and aortic metastases were observed in the M + W group but were markedly suppressed in the M + RS group. RS reduced the expression of inflammatory factors (e.g., IL-6, PAR1), proteases, leukocyte activation markers, complement factors, angiogenic factors, and EMT-related factors. Conversely, thrombin, thrombomodulin, plasmin, TAFIa, and tight junction proteins were increased in RS-treated mice. RS suppresses melanoma metastasis by modulating thrombin–PAR1-mediated inflammation and associated pathways. These findings suggest RS as a potential therapeutic agent, although further mechanistic and clinical studies are required.

Marine Drugs doi: 10.3390/md24040125

Authors: Zi-Han Xu Zheng-Biao Zou Chun-Xiu Wang Chen Li Xian-Wen Yang Jun-Song Wang

Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho-γ-pyrone (aS)-fonsecinones B and D (1 and 2) and 14 known compounds (3–16) from the deep-sea-derived fungus Aspergillus niger 3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 (10) as the most potent candidate. Compound 10 significantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed that 10 targets NOS2 to modulate Alzheimer’s disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated that 10 occupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally, 10 ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compound 10 as a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD.

Marine Drugs doi: 10.3390/md24040124

Authors: Ana S. Pinto Joana Oliveira Ana F. Esteves Susana Casal Gustavo Mil-Homens Francisco X. Malcata José C. M. Pires Tânia G. Tavares

Interest in microalgae-based technologies has emerged in recent years as a response to environmental challenges and the global food crisis, for providing alternative and sustainable food products. This study used temperature variations between 18 and 32 °C and nitrogen-to-phosphorus (N:P) ratios between 1.9 and 42.6 to model and optimize growth and composition of Chlorella vulgaris, a nutritionally interesting species. Lower temperatures appear ideal for this strain. An increase in average biomass productivity was observed with decreasing temperature, leading to a maximum of 122.27 mgdw L−1 d−1 at 18 °C on the fourth day of cultivation. The maximum productivities for total proteins, fatty acids, carbohydrates, and pigments were, respectively, 26.9 mg L−1 d−1, 26.4 mg L−1 d−1, 16.0 mg L−1 d−1, and 2.41 mg L−1 d−1, all referring to 18 °C. The fatty acid, carotenoid, and amino acid profiles were also ascertained; several indicators suggested that cultivation of these microalgae under the aforementioned optimal conditions holds potential for the food industry. The high proportion of polyunsaturated fatty acids—including two essential fatty acids; the high production of lutein, and the presence of several essential amino acids are among the favorable indicators. Overall, the information generated by this study is helpful to support future pilot studies aimed at the commercial production of microalgae-derived products.

Marine Drugs doi: 10.3390/md24040123

Authors: Jiang Li Xinning Pan Long Chen Qian Zhang Zhiyan Wang Dewi Seswita Zilda Zhou Zheng

The enzymatic valorization of agarose, a major polysaccharide in red algae, is critical for its application in the food, pharmaceutical, and biotechnology industries. In this study, a gene encoding a thermostable α-neoagarobiose hydrolase, aga2457, was cloned from an epiphytic bacterium associated with Indonesian macroalgae. Unlike typical mesophilic GH117 enzymes, recombinant Aga2457 displayed a higher optimal temperature at 50 °C and retained 55% activity after 12 days of incubation at 50 °C. The enzyme specifically hydrolyzes neoagarobiose into D-galactose and 3,6-anhydro-L-galactose, thereby facilitating the complete depolymerization of agarose. Combined molecular dynamics (MD) simulations and site-directed mutagenesis revealed that residues P253, N256, and Q285 are pivotal for substrate recognition and active site stability. These findings highlight Aga2457 as a robust biocatalyst for industrial agar processing and provide structural insights for the rational design of thermostable agarolytic enzymes.

Marine Drugs doi: 10.3390/md24040122

Authors: David Mauricio Cañedo-Figueroa Blanca Azucena Márquez-Reyna Alan Orlando Santos-Mena Daniela Nahomi Calderón-Sandate Flor Itzel Lira-Hernández Julio E. Castañeda-Delgado Ana Cristina García-Herrera Rosa María del Ángel Moisés León-Juárez Marco Antonio Valdez-Flores Gabriela López-Angulo Claudia Desireé Norzagaray-Valenzuela Loranda Calderón-Zamora Evelin Cervantes-Bobadilla Juan Fidel Osuna-Ramos Luis Adrián De Jesús-González

The continuous emergence of SARS-CoV-2 variants highlights the need for novel antiviral agents with favorable safety profiles. Marine microalgae constitute a valuable source of bioactive compounds, including antiviral peptides. Building on previous in silico identification of peptides derived from the marine microalga Phaeodactylum tricornutum with predicted activity against SARS-CoV-2, this study evaluated the antiviral capacity of peptide fractions generated by enzymatic hydrolysis and separated by molecular weight (10–30, 5–10, 3–5, and <3 kDa) in human alveolar epithelial A549 cells infected with the SARS-CoV-2. Cytotoxicity analyses, assessed using MTT and resazurin assays, revealed a moderate, concentration-dependent reduction in metabolic activity while maintaining overall cell viability within an acceptable range for antiviral evaluation, with higher-molecular-weight fractions (10–30 and 5–10 kDa) displaying the most stable profiles. Antiviral activity was assessed by flow cytometry following post-infection treatment. Lower-molecular-weight fractions (3–5 and <3 kDa) showed early reductions in infection at low concentrations but exhibited variable responses. In contrast, the 10–30 and 5–10 kDa fractions showed more robust, dose-dependent inhibition at medium and high concentrations, reducing infection levels to levels close to those observed in uninfected controls. Comparative analysis with the reference antiviral drug lopinavir demonstrated that peptide fractions exhibit lower cytotoxicity while retaining antiviral activity under equivalent experimental conditions. Overall, these results indicate that antiviral efficacy is strongly influenced by peptide molecular weight and consistency of response. This work provides experimental in vitro validation of P. tricornutum–derived peptide fractions as marine antiviral candidates and supports the integration of in silico and functional approaches for marine drug discovery.

Marine Drugs doi: 10.3390/md24030121

Authors: Zeqing Li Lei Chen Yuan Wang Mengjiao Jiang Siyu Fang Rong Chao Taizong Wu Tianhua Zhong

Five previously undescribed steroids, chrysogenones A–E (1–5), were isolated from the deep-sea-derived Penicillium sp. MCCC 3A00121. Their chemical structures were unambiguously established through comprehensive spectroscopic analyses, density functional theory (DFT)-based electronic circular dichroism (ECD) calculations, and X-ray crystallography. Chrysogenones represent a class of oxidatively modified ergosterone-type derivatives, with 1, 2, and 5 featuring an uncommon malonyl substitution at C-12 of the ergosterone skeleton. Biologically, 1–5 exhibited varying degrees of inhibitory activity against renal fibrosis, as evidenced by the downregulation of the key fibrotic markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1). Among them, chrysogenone B (2) emerged as the most promising candidate, demonstrating superior potency and pronounced inhibition of activated NRK-49F cell proliferation. Integrated network pharmacology analysis and molecular docking studies further suggested that the anti-renal fibrotic effects of compound 2 may be mediated through its interaction with putative molecular targets, including AKT1, HSP90AA1, and MDM2.

Marine Drugs doi: 10.3390/md24030120

Authors: Naveen Kumar Vate Elahe Sharifi Alessandro Coppola Eleonora Montuori Ingrid Undeland Donatella de Pascale Daniela Coppola Mehdi Abdollahi

Enzymatic hydrolysis is one of the effective methods used to obtain the bioactive peptides from marine resources. This study aimed to evaluate effect of the enzyme type (Food Pro PNL (FP), Corolase8000 (C8), and Corolase7089 (C7)) and biomass pretreatment level (whole starfish (SF), deproteinized (DPSF) as well as deproteinized and demineralized starfish (DPDMSF)) on the hydrolysate yield, degree of hydrolysis (DH), generated peptides’ molecular weight (MW), and in vitro radical scavenging and antiproliferative effects. Regardless of the enzyme used, deproteinization reduced the hydrolysate yield (<8% dw/ww) and DH (<5%), but also adding demineralization, in combination with C8, resulted in an equal yield (15%) and DH (>40%) to SF. However, the protein content of hydrolysates from DPSF and DPDMSF was higher than that prepared from SF. C8 was not effective in hydrolyzing SF but was the only effective enzyme in hydrolyzing DPDMSF. The peptides’ MW distribution strongly depended on the pretreatment and enzyme type, mostly ranging from 17 to 70 kDa. Glycine content was higher in hydrolysates from DPSF and DMDPSF, indicating their collagenous nature. Hydrolysates from DPSF, rich in collagenous peptides, showed medium MW but the highest radical scavenging activity. Only SF-FP hydrolysate, rich in non-collagenous peptides, showed antiproliferative activity against melanoma cancer cells. Overall, the findings demonstrate that upstream biomass pretreatment and enzyme selection directly govern the yield and bioactivity of starfish protein hydrolysates, providing a rational basis for designing starfish protein hydrolysates with targeted functional properties.

Marine Drugs doi: 10.3390/md24030119

Authors: Kexin Du Shuo Liang Zijing Wu Yujing Wang Pengcheng Gao Wei Han Youjing Lv Guangli Yu Guoyun Li

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease driven by immune dysregulation and epidermal barrier dysfunction. Current therapeutic options are often limited by safety concerns or suboptimal tolerability. In this study, we isolated and structurally characterized GRB-H—a λ-carrageenan-enriched sulfated hybrid galactan from the marine red alga Gigartina radula—as a complex polysaccharide containing κ-, ι-, μ-, ν-, and λ-carrageenan structural units, and systematically evaluated its anti-AD potential using both in vitro and in vivo models. In vitro, GRB-H significantly suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in RAW 264.7 macrophages, and reduced 2,4-dinitrochlorobenzene (DNCB)-evoked TNF-α and IL-1β expression in HaCaT keratinocytes. In a DNCB-induced murine model of AD, topical application of GRB-H markedly ameliorated skin inflammation, epidermal hyperplasia, and dermal immune cell infiltration. GRB-H treatment lowered total serum immunoglobulin E (IgE) levels, restored the imbalanced Th1/Th2 cell ratio in the spleen, and downregulated the mRNA expression of key inflammatory cytokines—including TNF-α, IL-4, IL-5, IL-31, and interferon-γ (IFN-γ)—in lesional skin. Collectively, these findings demonstrate that GRB-H alleviates AD symptoms through coordinated local anti-inflammatory and systemic immunomodulatory actions, highlighting its promise as a marine-derived candidate for the topical management of AD.

Marine Drugs doi: 10.3390/md24030118

Authors: Philippe Lima Duarte Paulo Anderson Paiva Martins Jéssica de Assis Duarte Manoel Ferreira da Costa Filho Ellen Araújo Malveira Celso Shiniti Nagano Alexandre Holanda Sampaio Edson Holanda Teixeira Rômulo Farias Carneiro Mayron Alves de Vasconcelos

Carotenoproteins from marine sponges represent an underexplored class of pigment–protein complexes with distinctive structural and functional properties. Here, we report the isolation and biophysical characterization of a blue carotenoprotein from the sponge Tedania ignis, termed Ti-CP. The protein was purified and shown to consist of two closely related isoforms with molecular masses of approximately 27–29 kDa. Reverse-phase chromatography enabled separation of the apoprotein (ApoTi-CP) and its associated carotenoids, which were identified as oxygenated carotenoids consistent with astaxanthin and mytiloxanthin. Circular dichroism analysis revealed that both Ti-CP and ApoTi-CP are dominated by β-sheet secondary structure and display highly similar conformational profiles. In contrast, dynamic light scattering demonstrated that carotenoid binding is critical for protein stability, as the native form exhibited a compact and monodisperse organization, whereas ApoTi-CP showed pronounced aggregation. Isothermal titration calorimetry revealed that Ti-CP, but not ApoTi-CP, interacts with tetracycline, oxacillin, and streptomycin, indicating that pigment-mediated stabilization modulates ligand binding. Both Ti-CP and ApoTi-CP reduced bacterial viability and biofilm formation in a strain-dependent manner and enhanced antibiotic activity, including synergistic effects against resistant bacteria. Together, these results provide a comprehensive description of a previously uncharacterized sponge carotenoprotein and highlight the dual role of carotenoids in structural stabilization and antimicrobial modulation, reinforcing the biotechnological relevance of marine pigment–protein complexes.

Marine Drugs doi: 10.3390/md24030117

Authors: Min Ah Lee Jong Soon Kang Joo-Hee Kwon Jeong-Wook Yang Hwa-Sun Lee Chang-Su Heo Hee Jae Shin

Chemical investigation of the marine sponge-derived Streptomyces xiamenensis 1310KO-148 afforded six polycyclic tetramate macrolactams (PTMs), including three known compounds (1–3) and three previously undescribed chlorohydrin-containing analogues, chlokamycins B–D (4–6). Their planar structures were elucidated by extensive analysis of 1D and 2D NMR spectra and HR-ESIMS data, while the relative configurations were assigned using NOESY correlations. The absolute configurations were further confirmed by electronic circular dichroism (ECD) calculations. Compounds 3–6 exhibited significant cytotoxic activity against 14 human cancer cell lines (GI50 = 2.68–24.92 μM) and antibacterial activity against Staphylococcus aureus (MIC = 16.00–32.00 μg/mL) and Micrococcus luteus (MIC = 4.00–32.00 μg/mL) among six tested bacterial strains.

Marine Drugs doi: 10.3390/md24030116

Authors: Sena Davran Bulut Naciye Yaktubay Döndaş Senanur Koçhan Beyza Nur Arslan Mehmet Ali Tamer Mirsade Osmani Safa Baraketi Khaoula Khwaldia Ziye Zhang Hacı Ali Döndaş Tuba Esatbeyoglu Panagiota Katikou Fatih Ozogul

Functional seafoods derived from marine organisms, including fish, shellfish and algae, are gaining increasing attention due to their high content of bioactive compounds, such as omega-3 fatty acids, peptides, polysaccharides and antioxidants, which provide health benefits beyond basic nutrition. These marine-derived compounds exhibit a wide range of biological activities and have been investigated for their potential roles in the prevention and management of chronic diseases, including cardiovascular, neurodegenerative, cancer and gastrointestinal disorders. Their effects are largely mediated through anti-inflammatory, antioxidant and immunomodulatory mechanisms. Advances in biotechnology, including genetic engineering and improved extraction of bioactive compounds, have enhanced the nutritional quality and pharmacological relevance of functional seafoods. At the same time, sustainable aquaculture practices are being developed to reduce environmental impacts. Nevertheless, challenges such as regulatory inconsistencies, scalability issues and limited understanding of bioavailability and long-term effects still persist. These constraints should be considered when interpreting mechanistic and efficacy findings presented across different study designs and exposure conditions. Future perspectives highlight innovations in precision aquaculture, waste valorisation and traceability as key strategies to improve sustainability and strengthen consumer trust. This review summarizes current knowledge on functional seafoods, with emphasis on pharmacological mechanisms, clinical applications and the need for interdisciplinary research to optimize their health benefits and commercial potential.

Marine Drugs doi: 10.3390/md24030115

Authors: Zheng Fu Defang Wu Shunqin You Kai Tang Runying Zeng Zhuhua Chan

Glycosaminoglycans (GAGs) and their degrading enzymes have extensive applications and biotechnology and medicine, and play a crucial role in the recycling of organic matter in oceans. In this study, a potential GAG utilization gene cluster was identified in the genome of a novel marine Bacteroidetes, Roseihalotalea indica gen. nov. sp. nov. TK19036T, through sole carbon source cultivation and differential proteomic analysis. Multiple GAG-lyases within this locus were purified and characterized. RiPL8 comprises a functionally unknown N-terminal domain and a catalytic C-terminal domain, exhibiting specificity for degrading hyaluronic acid (HA). The activity of RiPL35 is sensitive to Ca2+ ion concentration with an optimum at 10 mM. RiPL38 is the first reported member of the PL38 family capable of degrading HA and chondroitin sulfate (CS). In summary, our study reveals Roseihalotalea indica gen. nov. sp. nov. TK19036T harbors an unpredicted GAG degradation gene cluster, and the encoded GAG-lyases exhibit distinct substrate specificities compared to the host organism.

Marine Drugs doi: 10.3390/md24030114

Authors: Tao Li Bingqi Xu Yiyang Wu Liang Wei Hualian Wu Houbo Wu Wenzhou Xiang Jin Xu

The arachidonic acid (C20:4 ω6, ARA) and eicosapentaenoic acid (C20:5 ω3, EPA) from Porphyridium purpureum endow this microalga with potential utilization value, but their distribution patterns remain poorly understood. In this study, a nitrogen concentration, a phosphorus concentration, light intensity and salinity were applied to investigate the synthesis and distribution patterns of EPA and ARA in P. purpureum by measuring growth, lipid content, lipid fractions, fatty acid composition, and the levels of EPA and ARA in storage lipids and membrane lipids. The results show that the optimal conditions for biomass accumulation were a nitrogen concentration of 0.75 g L−1, a phosphorus concentration of 240 mg L−1, a light intensity of 250–300 μmol photons m−2 s−1 and a salinity of 50 ppt. Reducing the phosphorus concentration and increasing salinity enhanced the total lipid content, whereas changes in nitrogen concentration and light intensity had minimal effects on total lipid content. Low nitrogen concentration, low phosphorus concentration and high light intensity favored ARA synthesis, whereas the opposite conditions promoted EPA synthesis. Culture conditions could alter the distribution of ARA and EPA between storage lipids and membrane lipids. Increasing the nitrogen concentration, phosphorus concentration and salinity, as well as reducing light intensity, promoted the distribution of ARA and EPA in membrane lipids. Conversely, the opposite conditions enhanced their distribution in storage lipids. In conclusion, the synthesis and distribution of EPA and ARA in P. purpureum are influenced by culture conditions. To improve the yield of ARA and EPA, P. purpureum should be cultivated under nutrient-sufficient conditions.

Marine Drugs doi: 10.3390/md24030113

Authors: Valery M. Dembitsky Alexander O. Terent’ev Sergey V. Baranin Romulus I. Scorei

Marine invertebrates produce a remarkable diversity of polyhydroxylated steroids and secosteroids whose structural features—particularly vicinal (1,2-)diols, 1,3-diols, and clustered hydroxyl arrays—make them well suited for coordination with boron species. In the marine environment, where boron is abundant, chemically stable, and predominantly present as borate under mildly alkaline conditions, such interactions are not only plausible but may be widespread. This review examines the chemistry of boron–steroid complexation in marine systems, emphasizing how rigid steroidal frameworks preorganize diol motifs to form reversible yet stable borate esters under environmentally relevant conditions. We discuss how polyhydroxy steroids may exist in dynamic equilibria between free and boron-bound forms, with speciation governed by pH, boron concentration, and local microenvironmental factors rather than enzymatic control. Boron complexation can modulate key physicochemical properties, including solubility, conformation, and membrane affinity, thereby influencing the biological activity of marine steroids without covalent modification of the carbon framework. By integrating examples from sponges, echinoderms, and corals together with well-characterized model polyols, this review highlights boron complexation as an underrecognized but potentially important factor influencing the structure, function, and bioactivity of marine steroid metabolites.

Marine Drugs doi: 10.3390/md24030112

Authors: Yaosheng Liu Weizhen Li Zeen Yang Hui Long Sufen Cai Changjie Sun Yu Xiong Yunqi Zhang Yumei Liu Guangpu Luo Senhua Chen Tie Zhao

Mitochondrial dysfunction is a major contributor to skin photoaging. Activation of the Wnt/β-catenin pathway, a key regulator of developmental processes, can improve mitochondrial abnormalities associated with pathology. Therefore, the Wnt/β-catenin pathway emerges as a key therapeutic target in the context of photoaging. Isaridin E (ISE), a marine-derived natural product with a novel structure, exhibits potent antiplatelet and anti-inflammatory activities. We sought to examine the anti-senescence effects of ISE on fibroblasts in photoaged skin. In vitro, ISE improved UVB-induced fibroblast damage in a dose-dependent manner, restoring cell viability, reducing β-galactosidase accumulation, and suppressing SASP factor production. In a photoaging mouse model, ISE markedly decreased skin thickness, increased dermal collagen expression, and reduced SASP levels in skin tissues. ISE significantly improved fibroblast energy production deficits and mitochondrial dysfunction. RNA sequencing and Western blotting demonstrated that UVB irradiation significantly suppressed Wnt/β-catenin signaling activity, whereas ISE dose-dependently restored pathway activation. Using GSK-3β-targeted siRNA, we showed that the anti-photoaging effects of ISE are mediated via the Wnt/β-catenin pathway. ISE appears to counteract photoaging by enhancing Wnt/β-catenin activity and improving mitochondrial function.

Marine Drugs doi: 10.3390/md24030111

Authors: Fei-Hua Yao Jie Yang Xiao-Yan Li Shu-Fen Xu Kai Liu Zhen-Zhou Tang Wei-Hui Li Yong-Hong Liu Xiang-Xi Yi Cheng-Hai Gao

Three new cyclic tetrapeptides (nectriatidels A-C, 1–3), two new curvularin analogs (6 and 7), and four known compounds (4 and 5, 8 and 9) were isolated from the marine-derived fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532, which was obtained from Mauritia arabica in shallow coastal waters. Their structures were elucidated through NMR spectroscopy and HRESIMS, and their absolute configurations were determined by Marfey’s method and quantum chemical calculations. Compounds 1–5 showed moderate amphotericin B (AmB)-potentiating activity against Candida albicans. Compounds 7 and 8 exhibited significant activities against Mycobacterium tuberculosis, with MIC values of 32 and 16 μg/mL, respectively. Additionally, compounds 7 and 8 exhibited moderate cytotoxicity against human colorectal cancer cell lines DLD-1 and SW480, with IC50 values of 25~36 μM. Whole-genome sequencing of A. spelaeus revealed a 35.91 Mb assembly encoding 106 biosynthetic gene clusters (BGCs). antiSMASH analysis revealed that 79 of these BGCs (74.5%) displayed no significant similarity to known pathways in the MIBiG database, which is dominated by hybrid clusters, terpene, T1PKS, NRPS, and NRPS-like types. Genomic analysis identified the putative biosynthetic gene clusters for these metabolites and confirmed the fungal host as the predominant producer.

Marine Drugs doi: 10.3390/md24030110

Authors: Christian Bailly

The cold-water siliceous sponge Geodia barretti, largely present in the North Atlantic Ocean, notably around Scandinavian costs, plays important roles in carbon and silicon cycling in the deep-sea. The demosponge provides a reservoir for numerous microorganisms. Bioactive natural products have been isolated from this sponge, in particular the indole alkaloid barettin discovered forty years ago. Barettin and analogues, notably 8,9-dihydrobarettin, 8,9-dihydro-8-hydroxybarrettin, bromobenzisoxalone barettin, and geobarrettins A-B, contribute to the maintenance of the sponge stability and security (anti-fouling) and the regulation of its microbial environment. The four indole alkaloids 6-bromo-8-hydroxyconicamin, 6-bromoconicamin, and geobarrettin C-D are also implicated in the defense of the sponge against physical and biochemical aggressions. Altogether, these ten natural products are essential to the sponge life. The present review presents a survey of the chemistry and biology associated with Geodia barretti. The pharmacological properties of (dihydro)barettin, notably their antioxidant and anti-inflammatory properties, are discussed, as well as the synthetic processes set up to produce these diketopiperazine derivatives. Their molecular targets and mechanism of action are also discussed. The review takes the sponge G. barretti from the depths of knowledge and brings barettin and analogues to the surface, with the hope of guiding future research in this field.

Marine Drugs doi: 10.3390/md24030109

Authors: Oleg Kit Sergey Golovin Evgeniya Kirichenko Alina Sereda Yulia Gordeeva Evgeniy Sadyrin Andrey Nikolaev Pavel Antipov Aleksandr Logvinov Maria Kaplya Magomed Abdulkadyrov Stanislav Rodkin

Collagen is a major extracellular-matrix protein widely used in regenerative medicine, yet conventional terrestrial sources raise biosafety and acceptability concerns, motivating the search for marine alternatives. This study evaluates the jellyfish Rhizostoma pulmo (R. pulmo) from the Azov Sea as a sustainable collagen source and assesses its suitability for biomedical materials. Acid-soluble collagen was extracted using 0.5 M acetic acid and purified by salt precipitation and dialysis, followed by physicochemical/structural characterization (sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), Limulus amebocyte lysate (LAL) endotoxin testing, transmission electron microscopy (TEM), and immunofluorescence with type I collagen antibodies) and biological evaluation in vitro (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity on MRC5 fibroblasts; adhesion and proliferation assays on HeLa cells). The extracted collagen showed a high yield (~26.2%), a type I-like electrophoretic profile with α-, β-, and γ-components, fibrillar ultrastructure by TEM, and positive type I collagen immunoreactivity; endotoxin levels were low (0.461 EU/µL), and no cytotoxicity was detected under the tested conditions. Porous collagen sponges/scaffolds were fabricated by lyophilization, displaying interconnected pores with an average size of ~80 µm and pH-dependent swelling, and they supported 3D cell growth and tumor-cell dissemination in an in vitro breast carcinoma scaffold model. Overall, Azov Sea R. pulmo collagen demonstrates promising structural quality, low endotoxin burden, and cytocompatibility, supporting its potential as a marine biomaterial for sponge/scaffold-based tissue engineering and wound-related applications.

Marine Drugs doi: 10.3390/md24030108

Authors: Guangli Deng Wu Ruan Qun Li Qingyun Peng Yunan Liu Lingbin Lin Yuan Li Qianqian Shen Yangrong Zhao Junfeng Wang Yi Chen Ming-Wei Wang

Nine new mycophenolic acid derivatives, penicacids O–W (1–9), two first-time reported natural products (10, 11), and five known compounds (12–16), were isolated from a marine-derived fungus Penicillium senticosum RCDB005 found in a South China Sea sediment sample. Their structures were determined using NMR, HRESIMS, and optical rotatory dispersion (ORD) spectra, electronic circular dichroism (ECD) calculations, X-ray crystallography, and modified Mosher’s methods. Eight of these compounds were evaluated for anti-proliferative effects against nine human cancer cell lines and the IC50 values ranged from nM to μM levels. Compounds 5, 7–9 showed potent inhibition activity against MOLM-13 acute myeloid leukemia cells with IC50 values between 0.13 and 1.13 μM.

Marine Drugs doi: 10.3390/md24030107

Authors: Liangquan Xie Chaoxuan Wu Weilin Du Jiaying Chen Zijie He Tingting Li Chuangye Yang Yuewen Deng Zhe Zheng

As primary producers in aquatic ecosystems, microalgae function not only as a natural source of nourishment for several economically important aquatic species but also as reservoirs of bioactive molecules. Microalgae can secrete exosome-like nanoparticles that transport functional biomolecules, such as proteins and nucleic acids, into the extracellular milieu, thereby mediating intercellular signaling and eliciting ecological or biomedical responses. Although plant-derived exosome-like nanoparticles have attracted attention for their utility in drug delivery and dermatology, the functional properties of microalgae-derived nanoparticles—particularly from species extensively applied in aquaculture—remain inadequately characterized. In this study, exosome-like nanovesicles were isolated from Nannochloropsis oculata (N-ELNs), a microalgal species widely used in aquaculture, and their skin-whitening potential was evaluated using the B16-F10 mouse melanoma cell model. The highest N-ELN yield was observed during the adaptation, exponential, and stationary growth phases. Uptake analyses confirmed the efficient internalization of N-ELNs by B16-F10 cells. Cell counting kit-8 assays indicated that N-ELNs exhibited no cytotoxic effects on melanoma cells or normal human dermal fibroblasts (HFF-1). Scratch wound healing assays revealed that N-ELNs exerted no significant effect on cellular migration. In B16-F10 cells, N-ELNs suppressed tyrosinase activity by downregulating Mitf and its downstream genes Tyr and Tyrp1, resulting in a substantial reduction in melanin synthesis (p < 0.05). The inhibitory effects of N-ELNs on melanin production, tyrosinase activity, and gene expression of Tyr, Tyrp1, and Mitf were comparable to those of the positive control, arbutin. Collectively, these findings suggest that N. oculata exhibits promising skin-whitening properties, providing a novel perspective for clinical applications and supporting the high-value utilization of the microalgae aquaculture industry.

Marine Drugs doi: 10.3390/md24030106

Authors: Qiuxia Fu Kezhi Yu Yuanyuan Wang Chenxing Liu Wei Liu Wenze Ou Wei Sun Fei Yan

Gas vesicles (GVs) are hollow protein nanostructures derived from microorganisms and show significant potential for ultrasound imaging applications. However, the direct production of gas vesicles (GVs) from their native hosts faces several limitations: poor contrast imaging performance, insufficient yield, and high costs associated with extraction and purification. These challenges heavily hinder their clinical translation and application. The heterologous expression of GV genes varies significantly among different chassis strains due to their distinct intracellular environments, which ultimately affects GV performance and yield. Therefore, it is crucial to select an appropriate chassis cell that can produce GVs with excellent imaging performance. In this study, the GV gene cluster from Serratia sp. ATCC 39006 was heterologously expressed in five different bacterial chassis strains: Escherichia coli BL21 (AI), Escherichia coli K-12 MG1655, Escherichia coli Nissle 1917, Salmonella YB1, and Vibrio natriegens. By systematically comparing the yield, particle morphology, and ultrasound imaging performance of GVs produced by these strains, we elucidated the impact of chassis cells on GV synthesis and function. This work provides experimental evidence and theoretical support for screening robust GV-producing strains and facilitates future biomedical applications of GVs.

Marine Drugs doi: 10.3390/md24030105

Authors: Guan-Yuan Zhang Xue-Gong Li Hai-Rong Fang Jin-Wei Gao Wei-Jia Zhang

Despite its extreme conditions, the hadal environment harbors abundant but largely underexplored microbial resources. In this study, samples from the Kuril-Kamchatka Trench (KKT) were enriched at low temperature using R2A and 2216E media. Carotenoid-producing microorganisms (CPMs) were isolated from approximately one-third of the samples, yielding a total of 124 isolated strains spanning 4 phyla and 11 genera. Planococcus, Kocuria, Paracoccus, and Exiguobacterium collectively accounted for 75.8% of the isolates. The choice of culture medium significantly influenced CPM diversity at the family and genus levels, though not at the phylum or class level. Water depth, sample type, and sediment layer also significantly affected CPM community structure. Carotenoid spectral profiles correlated with phylogenetic lineage, and closer phylogenetic relationships corresponded to greater similarity in carotenoid biosynthesis gene clusters. Antioxidant assays (FRAP, ABTS, DPPH) demonstrated strong total antioxidant and radical scavenging capacities in carotenoid extracts from Citricoccus, Kocuria, Arthrobacter, and Olleya. Scavenging activity toward ABTS or DPPH radicals varied significantly among genera, suggesting genus-specific antioxidant mechanisms. These findings highlight the hadal zone as a promising reservoir of diverse CPMs and a valuable source of novel carotenoids and antioxidant-producing strains with potential biotechnological applications.

Marine Drugs doi: 10.3390/md24030104

Authors: Eleonora Montuori Espen Holst Hansen Calum J. McMullen Katja Rietdorf Carlos Almeida Antera Martel Quintana Assunta Saide Chiara Lauritano

Malignant melanoma is skin cancer arising from genetically altered melanocytes. Recently, a complex relationship between melanoma and chronic inflammation has been highlighted, representing an excellent condition for tumor development. Microalgae have been shown to be a promising source of bioactive compounds for drug discovery. In this study, we investigated Halamphora sp. (BEA0050) to identify possible compounds with immunomodulatory activity. The most active fraction (fraction D) showed anti-inflammatory activity against human melanoma cancer cells (A2058) stimulated using lipopolysaccharide (LPS) to induce an inflammatory phenotype. Chemical profiling of the bioactive fraction using chromatography and high-resolution mass spectrometry (UHPLC-HR-MS) revealed hydroxypheophorbide a, a breakdown product of chlorophyll a. In order to investigate the mechanism of action, the TNF-α release was detected through ELISA sandwich assays in A2058 cells and through confocal microscopy in LPS-stimulated HaCaT cells. Gene expression of principal pro-inflammatory cytokines and pathways was detected through real-time PCR, which showed the down-regulation of the inflammatory pathway in LPS-induced A2058 and HaCaT cells treated with 12.5 µg/mL of fraction D. This study reports for the first time the anti-melanoma and anti-inflammatory activities of Halamphora sp., identifying protein mediators and highlighting its biotechnological potential.

Marine Drugs doi: 10.3390/md24030103

Authors: Wenzheng Wei Xiaodong Jiang Yiguang Zhu Wenjun Zhang Chunfang Yang Qingbo Zhang Changsheng Zhang

Nenestatins (NENs) belong to benzo[b]fluorene-containing atypical angucyclines, a structurally diverse class of microbial natural products. Bioinformatic analysis of the NEN biosynthetic gene cluster (nes BGC) from the deep-sea sediment-derived Micromonospora echinospora SCSIO 04089 implicated Nes5 as an α/β hydrolase. The targeted inactivation of the nes5 gene led to the accumulation of five new analogs, NENs E–I (1–5), together with the known monomer homo-dehydrorabelomycin E (6). Their structures were elucidated by comprehensive spectroscopic analysis and electronic circular dichroism calculations. Notably, both NEN A and NEN B were absent in the Δnes5 mutant, indicating that Nes5 is essential for their biosynthesis; however, the exact function of Nes5 requires further exploration.

Marine Drugs doi: 10.3390/md24030102

Authors: Chang-Eui Hong Su-Yun Lyu

Marine lectins function as pattern recognition receptors in innate immunity through carbohydrate-binding mechanisms. However, mechanistic evidence detailing intracellular signaling cascades (e.g., MAPK/NF-κB/JAK-STAT activation linked to defined cytokine outputs) remains taxonomically uneven. Bivalve mollusks—particularly the Mytilectin family—represent the most extensively characterized group, whereas lectins from other marine phyla (echinoderms, cnidarians, fish, algae) have been studied primarily for structural and glycan-binding properties alongside phenotypic antimicrobial outcomes. Signaling-level resolution in native immune-cell contexts, while present in some cases, remains comparatively limited. This review synthesizes mechanistic insights dominated by bivalve-derived lectins, while integrating cross-taxa comparisons at evidence-supported levels. Specific bivalve lectins induce macrophage activation and pro-inflammatory cytokine production through reactive oxygen species-dependent activation of key signaling pathways including MAPK, NF-κB, and JAK-STAT cascades. These lectins exhibit context-dependent properties, promoting inflammatory responses in resting cells while inducing endotoxin tolerance in pre-activated macrophages through epigenetic reprogramming. Functional outcomes include broad-spectrum antiviral activity through viral envelope glycoprotein binding, anti-inflammatory effects in pain models, and cancer-associated immune responses through tumor glycan recognition and macrophage polarization. Critical gaps include uncharacterized effects on adaptive immunity, limited understanding of dendritic cell and natural killer cell interactions, and incomplete evaluation of cancer immunotherapy potential. Future research should prioritize mechanistic characterization of marine lectin-based immunotherapeutics.

Marine Drugs doi: 10.3390/md24030101

Authors: Mamoru Takeda Risako Chida

Recently, complementary and alternative medicine (CAM) has been actively employed for patients experiencing symptoms unresponsive to Western medical treatments like drug therapy. The natural compounds carotenoids and astaxanthin (AST) have demonstrated various beneficial biological actions for human health in several studies. Given their broad pharmacological activities and reduced toxicity, ASTs possess significant potential as resources for the development of natural analgesic drugs. Given recent studies showing that AST can modulate neuronal excitability, including nociceptive sensory transmission through voltage-gated Ca2+ channels and the n-methyl-D-aspartate (NMDA) glutamate receptor, and inhibit the cyclooxygenase-2 cascade, AST holds promise as a CAM, particularly as a therapeutic agent for nociceptive and pathological pain. Based on the in vivo research findings from our laboratory presented in this review, we have confirmed that carotenoid ASTs possess: (i) an intravenous anesthetic effect on both nociceptive and inflammatory pain comparable to existing analgesics such as ketamine; and (ii) an anti-inflammatory effect on chronic pain with an efficacy almost equivalent to that of the commonly used non-steroidal anti-inflammatory drug (NSAID) celecoxib. Therefore, these findings suggest that, as natural compounds, ASTs contribute to the relief of nociceptive and inflammatory pain, implying their potential for clinical application.

Marine Drugs doi: 10.3390/md24030100

Authors: Younghoon Jeon Eunjung Heo Xian Jin Dong-Kyo Lee Xiangguo Che Hyun-Ju Kim Sung-Hye Byun Je-Yong Choi Jeongkyu Choi Jinyoung Oh

Developing novel anabolic agents for bone regeneration remains a clinical priority. Polydeoxyribonucleotide (PDRN) exhibits tissue-regenerative properties, but its direct cellular effects on bone remodeling remain unclear. This in vitro study investigated PDRN’s effects on osteoblast (MC3T3-E1) and osteoclast (primary bone marrow-derived macrophages) differentiation. We evaluated metabolic activity, gene/protein expression, and specific differentiation markers using MTS, qRT-PCR, Western blotting, and functional assays (ALP, Alizarin Red S, TRAP, pit formation). In osteoblasts, PDRN dose-dependently modulated metabolic activity while upregulating the early transcription factor Runx2. PDRN significantly enhanced osteoblast differentiation, evidenced by increased ALP activity, elevated mineralized matrix deposition, and robust upregulation of osteocalcin and Runx2. Conversely, PDRN exhibited no direct effect on osteoclast precursor metabolic activity, differentiation, or resorptive function. These findings support a working hypothesis in which PDRN selectively promotes osteoblast differentiation without directly affecting osteoclastogenesis. While further pharmacological investigations are required to definitively elucidate the specific purinergic receptor mechanisms, our results highlight PDRN as a promising candidate anabolic agent for bone regeneration.

Marine Drugs doi: 10.3390/md24030099

Authors: Fabien Havas Shlomo Krispin Moshe Cohen Joan Attia-Vigneau

Red microalga Porphyridium cruentum produces a sulfated exopolysaccharide (EPS), which enables its survival in challenging intertidal and spray zones. Extracellular polysaccharide hyaluronic acid (HA) plays important roles in skin hydration, elasticity, and volume. However, with aging, HA decreases and loses effectiveness, reducing skin moisture retention and firmness, and increasing signs of aging. An effective topical alternative to injectable HA replacement remains a largely unmet need. An extract of Porphyridium cultivated in natural sunlight, rich in EPS and polydeoxyribonucleotides (PDRNs), significantly activated the ADORA2A receptor in a CHO model, as well as reduced inflammation and increased collagen and HA production, autophagic flux, and key autophagy gene expression in dermal fibroblast cultures. In a double-blind clinical trial with placebo and HA benchmark controls, the Porphyridium extract delivered significant HA-like skin plumpness, hydration, and radiance benefits, and reduced signs of aging. The extract generally equaled or exceeded the HA benchmark. Its meaningful, swift HA-like activity shows potential for a safe, natural, and arguably more powerful HA-like alternative.

Marine Drugs doi: 10.3390/md24030098

Authors: Soeun Park Saitbyul Park Nok Hyun Park Eun-Soo Lee Kilsun Myoung Heung-Soo Baek Jaewoo Jang Sang-Jip Nam Jaeyoung Ko Chang Seok Lee

Porphyra-334 (PPR-334) is one of the species of mycosporine-like amino acids (MAAs), known as biological UV protection ingredients. In this study, we developed a large-scale purification process to extract PPR-334 from Saccharomyces cerevisiae and confirmed the previously identified efficacy of PPR-334, while also demonstrating its efficacy under UV-independent conditions. PPR-334 scavenged reactivity oxygen species (ROS) and increased catalase (CAT) gene expression in human epidermal keratinocyte cells (HEKa). In both HEKa and normal human dermal fibroblast cells (NHDF), PPR-334 suppressed the gene expression of matrix metalloproteinase-1 (MMP-1). NHDF treated with PPR-334 showed increased collagen expression and proliferation, while advanced glycation end-product (AGE) production was decreased. It was confirmed that the efficacy in vitro was also reproduced in human artificial skin tissue models. Above all, the antioxidant efficacy mechanism of PPR-334 through nuclear factor erythroid 2-related factor 2 (NRF2) and Caspase-9 signals was identified. It was determined that the proliferation efficacy of PPR-334 was due to factors related to the cell cycle. These results demonstrate the anti-aging efficacy of PPR-334 independent of UV irradiation, while enhancing the UV-blocking and antioxidant effects. Thus, we suggest the potential of PPR-334 as a sunscreen agent as well as a dual- or multifunctional material.

Marine Drugs doi: 10.3390/md24030097

Authors: Mengfen Wei Dongcheng Liu Shiyuan Chang Lijun You Oliy Akhmedov

Pinctada martensii is a marine resource with potential for bioactive peptide development, but its anti-photoaging properties remain underexplored. In this study, Pinctada martensii meat hydrolysates (PME) were prepared by enzymatic hydrolysis, and their anti-photoaging effects were evaluated in an in vivo ultraviolet-B (UVB)-irradiated nude mouse model. The results showed that PME markedly ameliorated UVB-induced skin damage. UVB increased epidermal thickness from 21.60 μm in the Control to 47.50 μm in the Model, and PME reduced epidermal thickness to 22.46 μm. Dermal collagen content decreased from 64.58% in the Control to 26.22% in the Model and was restored to 52.75% by PME. UVB upregulated matrix metalloproteinases-1 (MMP-1), MMP-3 and MMP-9 by approximately 2.20-, 1.93- and 3.09-fold relative to the Control, and PME suppressed these matrix metalloproteinases (MMPs) by approximately 61%, 65% and 52%, respectively. Extracellular signal-regulated kinase (ERK) expression increased to 1.41-fold in the Model and was reduced to about 1.05-fold after PME treatment, suggesting inhibition of collagen degradation-related pathways. Untargeted serum metabolomics identified 205 differential metabolites between the Model and the Control, and PME shifted metabolite profiles toward those of the Control. Total short-chain fatty acids (SCFAs) decreased from 868.69 μmol/g in the Control to 301.34 μmol/g in the Model and increased to approximately 562 μmol/g after PME treatment, accompanied by modulation of the gut microbiota including recovery of Lachnospiraceae members, indicating involvement of the gut–skin axis. These findings support the potential of Pinctada martensii meat as a source for developing novel functional foods targeting skin photoaging.

Marine Drugs doi: 10.3390/md24030096

Authors: Patricio A. Díaz María García-Portela Gonzalo Álvarez Francisco Rodríguez Iván Pérez-Santos Daniel Varela Michael Araya Camila Schwerter Ángela M. Baldrich Barbara Cantarero Beatriz Reguera

Dinophysis acuminata, the main agent of diarrhetic shellfish poisoning (DSP) worldwide, shows a high variability in morphology and toxin content between strains from contrasting habitats. Most frequent uncertainties in morphological discrimination are within the “D. acuminata complex”, but confusion with other species (e.g., D. norvegica, D. fortii) also occurs. Here we describe a unique PTX2-containing population of Dinophysis cf acuminata observed during opportunistic samplings in San Rafael Lagoon (Chilean Patagonia), the only tidewater glacier lagoon remaining in the glacier with the world’s lowest latitude. Dinophysis acuminata was the only Dinophysis species observed during three seasonal surveys in the well-mixed cold (4–7° C) and brackish (salinity 14–15) waters of the lagoon. Cell densities ranged from 500 cells L−1 (winter) to 2800 cells L−1 (summer). Partial sequences of their ITS rDNA aligned them with D. acuminata strains from Europe and North America, and sequences of their stolen plastids 23S rDNA confirmed ciliates of the Mesodinium rubrum + major complex as their prey and plastid source. All these reasons make this lagoon a highly sensitive area and natural laboratory for climate change-related topics and Dinophysis issues related to (i) the effect of long-term exposure of marine fauna to pectenotoxins and (ii) the adaptations of D. cf acuminata to persist in a unique ecosystem with austral water characteristics located in a warm temperate latitude light regime. Results here add knowledge to the biogeography and habitat ranges of D. acuminata and the problems faced to monitor and provide early warning of its distribution.

Marine Drugs doi: 10.3390/md24030095

Authors: Wenjun Chang Yanhua Yang Ruijun Duan Heye Qin Shiwen Chen Yanbo Zeng

Marine-derived filamentous fungi are a rich source of structurally diverse and biologically active natural products. However, many biosynthetic gene clusters (BGCs) in fungi remain silent under standard conditions. In this study, we employed a metabolic shunting strategy to disrupt azaphilone biosynthesis in the marine-derived fungus Penicillium sclerotiorum E23Y-1A by deleting the pathway-specific regulator gene A00667. HPLC analysis revealed the emergence of new metabolite peaks in the mutant strain Δ667 compared to the wild type. Subsequent purification yielded seven compounds: the mutant produced two novel meroterpenoids sclerotilins A and B (1 and 2) along with the known steroids ergosta-5,7,22-trien-3β-ol (3) and cerevisterol (4), while the wild type yielded the known steroid (22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol (5) and two azaphilones geumsanol G (6) and 5-chloro-3-[(1E,3R,4R,5S)-3,4-dihydroxy-3,5-dimethyl-1-hepten-1-yl]-1,7,8,8a-tetrahydro-7,8-dihydroxy-7-methyl-(7R,8R,8aS)-6H-2-benzopyran-6-one (7). Bioactivity assays showed that compound 6 exhibited moderate antimicrobial activity against Staphylococcus aureus, and compound 3 displayed moderate cytotoxicity against five human cancer cell lines. These results demonstrate that A00667 is essential for azaphilone biosynthesis and that its disruption leads to the production of structurally distinct natural products, highlighting the potential of pathway engineering to redirect fungal metabolism to yield novel natural products.

Marine Drugs doi: 10.3390/md24030094

Authors: Jianlin He Chao Tang Siwen Niu Qingqing Le Lin Yu Bihong Hong

Depression remains a major global health challenge, with a significant proportion of patients failing to respond to conventional antidepressants. This study aimed to evaluate the potential antidepressant effects and toxicological profile of a novel tetrodotoxin (TTX) oral film formulation in a mouse model of chronic unpredictable mild stress (CUMS). Male C57BL/6J mice were subjected to CUMS and treated daily with TTX oral film at doses of 10, 20, and 40 μg/kg, with fluoxetine (18 mg/kg) serving as a positive control. Behavioral assessments, including sucrose preference test, open field test, forced swimming test, elevated plus maze, and novel object recognition, demonstrated that TTX oral film administration alleviated depression- and anxiety-like behaviors and improved cognitive function. Furthermore, TTX oral film treatment restored hippocampal serotonin levels, which were depleted in CUMS mice, and showed no adverse effects on organ indexes after long-term use. Toxicological evaluation through acute toxicity testing revealed an oral LD50 of 919 μg/kg, indicating a substantially improved safety profile compared to pure TTX and a wide therapeutic window. These findings suggest that the TTX oral film possesses significant antidepressant activity with favorable toxicological properties, supporting its potential as a novel and safe treatment for depression.

Marine Drugs doi: 10.3390/md24030093

Authors: Kim-Hoa Phi Eun Jin Heo Sunbeom Kwon Ui Joung Youn Seulah Lee

Marine organisms living in extreme environments such as the Arctic and Antarctic have evolved remarkable adaptation mechanisms to survive harsh conditions, including low temperatures, high salinity, and seasonal fluctuations in light and nutrients. Among these adaptations, unique biochemical pathways have given rise to secondary metabolites with unprecedented chemical structures and diverse biological activities. This review focuses on bioactive natural products that have been isolated from polar aquatic organisms between 2015 and 2025. It provides a comprehensive overview of these compounds, highlighting their chemical structures, source organisms, and documented biological activities. By examining recent discoveries from the ends of the Earth, this review underscores the rich chemical diversity of polar marine ecosystems and their continued potential as a source of novel molecules for drug discovery and biotechnology.

Marine Drugs doi: 10.3390/md24030092

Authors: Limin Lin Meiling Huang Wanting Yang Ziqiang Hua Zhen Chen Panmin He Kailin Mao Shuanghuai Cheng Linlin Ma Shuaiying Cui Bo Yi Bingmiao Gao

Glioblastoma is a highly invasive primary brain tumor with a poor prognosis, highlighting the need for new therapeutic strategies. Toxins derived from Macrodactyla doreensis have attracted attention for their potential anticancer activity. This study evaluated the anticancer and cytotoxic effects of M. doreensis crude venom on two commonly used glioblastoma cell lines (U251 and LN229), which mirror the phenotype of primary tumors. Cell viability and proliferation were assessed using the CCK-8 assay and colony formation assay, while cell migration and invasion capabilities were detected via wound healing assay and Transwell assay. Annexin V/PI staining and PI-based cell cycle analysis indicated that the crude venom significantly induced cell apoptosis and caused S-phase arrest. Proteomic analysis combined with GO and KEGG enrichment analyses as well as bioinformatics approaches showed that M. doreensis crude venom inhibits glioblastoma cell proliferation by downregulating the expression of CDK2, RRM2, and CHEK1, thereby hindering cell cycle progression and regulating the p53 signaling pathway. Notably, the downregulation of these key glioblastoma-related target genes was validated by qPCR. In addition, network pharmacology analysis indicated that several peptide families present in the sea anemone crude venom, including ShK peptides, inhibitor cystine knot (ICK) peptides, and EGF-like peptides, exhibit notable antitumor potential. Combined with AlphaFold2-based structural modeling and molecular docking, these analyses further elucidated the potential molecular mechanisms underlying their interactions with key targets, such as MD-381 with RRM2, MD-322 with CDK2, and MD-429 with CHEK1. Collectively, these findings highlight the therapeutic potential of M. doreensis crude venom and lay a foundation for the subsequent isolation of novel peptides and their further development in glioblastoma treatment.

Marine Drugs doi: 10.3390/md24030091

Authors: Sakhi Ghelichi Seyed Hossein Helalat Mona Hajfathalian Birte Svensson Charlotte Jacobsen

This study investigated the α-glucosidase inhibitory potential of enzymatic/alkaline treatments from Palmaria palmata using different proteases and pairwise combinations thereof. Treatments prepared with Alcalase®, Flavourzyme®, and Formea® Prime, alone or in combination, were evaluated for dose-dependent inhibitory activity. Alcalase®-derived treatments exhibited the highest α-glucosidase inhibition, achieving an IC50 of 2.48 mg·mL−1, outperforming other treatments and combinations. Membrane fractionation of the Alcalase®-derived treatment into >5 kDa, 3–5 kDa, 1–3 kDa, and <1 kDa fractions revealed a size-dependent trend, with the <1 kDa fraction showing the strongest inhibition (IC50 of 1.94 mg·mL−1). Three peptides, RADIPFRRA, DGIAEAWLG, and FWSQIFGVAF, from the <1 kDa fraction were identified as potential α-glucosidase inhibitors using the BIOPEP-UWM database and were further selected based on a Peptide Ranker score above 0.6 for in silico docking analyses. Docking revealed distinct binding modes: RADIPFRRA and DGIAEAWLG occupied the catalytic cleft, interacting with key residues (Asp518, Asp616, Trp481, Trp613) consistent with competitive inhibition, whereas FWSQIFGVAF bound to a peripheral site, suggesting potential allosteric modulation. Physicochemical analysis further highlighted differences in charge and isoelectric point correlating with their binding behavior. Together, these findings demonstrate that low-molecular-weight peptides derived from P. palmata proteins, particularly those generated by Alcalase®, possess significant α-glucosidase inhibitory activity, and provide structural insights for the rational design of peptide-based modulators of carbohydrate metabolism.

Marine Drugs doi: 10.3390/md24030090

Authors: Xinglong Dai Jie Hao Yan Zhang Yaping Yang Wanli Meng Fang Lu Jianchun Zhao Guanhua Du Shengbiao Wan Jiejie Hao

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disorder with a globally increasing prevalence. Current therapeutic strategies are limited by drug resistance and safety concerns. Studies suggest that inhibiting the secretion of inflammatory cytokines represents a promising approach for COPD treatment. Phosphodiesterase-4 (PDE4) inhibitors have emerged as potent anti-inflammatory agents for respiratory diseases. In this study, we integrated a marine-derived natural product with computer-aided drug design to develop 32 novel PDE4 inhibitors. Compound B7 exhibited potent PDE4 inhibitory activity and a favorable safety profile. In rat model of COPD, B7 significantly reduced inflammatory cell infiltration and cytokine levels, ameliorated pathological changes in the lung, decreased the percentage of goblet cell positivity, and reduced expiratory resistance. Furthermore, in vitro mechanistic studies revealed that B7 exerts its anti-inflammatory effects by activating the cAMP-PKA-CREB signaling pathway and suppressing the NF-κB pathway in RAW264.7 cells. In conclusion, B7 demonstrates potential as a safe and effective PDE4-targeted candidate for the treatment of COPD.

Marine Drugs doi: 10.3390/md24030089

Authors: Jung Min Shin

Squid ink has recently garnered considerable attention as a natural melanin source for the development of biocompatible nanomaterials. Although numerous studies have explored the biological and therapeutic applications of squid ink, the fabrication and modification strategies for squid ink-derived nanoparticles (SINPs) have yet to be comprehensively reviewed. This paper provides an integrated overview of current extraction, purification, and functionalization strategies for SINPs, with a particular focus on how functionalization approaches modulate their physicochemical characteristics and biological behaviors. The review begins by outlining the natural mechanisms of melanin formation and summarizing common extraction methods—including centrifugation, ultrasonication, and dialysis. Subsequently, various surface modification and hybridization techniques—including polymer coating, incorporation of metallic elements (e.g., Se and Fe), and loading of photosensitizers—are compared in terms of their contributions to functional enhancement. Finally, the challenges of reproducibility, batch-to-batch variability, and scalable manufacturing are discussed, outlining future directions for the development of squid ink-derived nanomaterials into standardized biomedical platforms.

Marine Drugs doi: 10.3390/md24030088

Authors: Leonie Deppe Philipp Dörschmann H. Burkhard Dick Alexa Klettner Stephanie C. Joachim

Degeneration of retinal ganglion cells (RGCs) is a hallmark of glaucoma. As RGCs are vulnerable to oxidative imbalance, anti-oxidative strategies are of significant interest as novel therapeutic targets. Fucoidans, bioactive compounds derived from algae, are known to be anti-oxidative. Hence, we investigated if fucoidans have protective effects in a retina organ culture model. Porcine explants were pre-treated with fucoidan (Fucus vesiculosus; FVs) for 0.5 h (10 or 50 µg/mL). Afterwards, damage was induced through H2O2 (500 µM; 3 h). Four groups were investigated: control, H2O2, 10 FVs + H2O2, and 50 FVs + H2O2. RGCs, glial cells, hypoxic/oxidative, apoptotic, and ferroptotic markers were examined by immunohistology, RT-qPCR, and a caspase assay. H2O2 led to lower RGC numbers and RBPMS expression levels while FVs prevented this degeneration. An upregulation of glial expressions and more microglia/macrophages were observed in H2O2 samples, mitigated by FVs. Anti-oxidative genes increased during stress but normalized with FVs. Apoptotic signaling increased while GPX4 mRNA expression decreased with H2O2, both restored by FVs. Consequently, RGC loss was prevented through the attenuation of glial activation, inhibition of hypoxic/oxidative stress, and anti-ferroptotic/apoptotic action mediated by FVs. Advancing glaucoma research, this study emphasizes the therapeutic potential of FVs and offers new directions for future research.

Marine Drugs doi: 10.3390/md24020087

Authors: Yixuan Lai Yuan Wang Abdul Mueed Peng Shu Lijun You Jiangming Zhong

The red alga Kappaphycus alvarezii is a rich source of polysaccharides, but their high molecular weight limits skin permeability and bioavailability. To address this, we employed a free-radical degradation method to produce a low-molecular-weight polysaccharide, KP-90. Evaluation in UVB-irradiated HaCaT cells and UVA-irradiated human dermal fibroblasts demonstrated that KP-90 significantly enhanced cell viability and mitigated oxidative stress by suppressing reactive oxygen species and malondialdehyde, while restoring antioxidant enzymes (SOD, CAT and GSH-Px). Furthermore, KP-90 downregulated matrix metalloproteinases (MMP-1, -3, -9) and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), thereby reducing extracellular matrix degradation and inflammation. These in vitro findings were corroborated in a UVB/UVA-irradiated nude mice model, where KP-90 alleviated epidermal hyperplasia, increased collagen I and hyaluronic acid synthesis, and improved visible signs such as wrinkles and skin laxity. These findings identify KP-90 against skin photoaging and provide a strategic approach for valorization underexploited marine biomass.

Marine Drugs doi: 10.3390/md24020086

Authors: Elisabetta Bigagli Niccolò Meriggi Mario D’Ambrosio Natascia Biondi Liliana Rodolfi Alberto Niccolai Gianluca Bartolucci Marta Menicatti Carlotta de Filippo Cristina Luceri

Modulation of the gut microbiota represents a promising approach to counteract diet-induced metabolic alterations, with microalgae emerging as potential interventions. Building on our previous in vivo evidence that dietary supplementation with the marine microalga Tisochrysis lutea F&M-M36 (T. lutea) positively modulates selected metabolic alterations under high-fat feeding, the present study aimed to identify potential associations between these metabolic changes and coordinated modifications of the gut microbiota. Animals were fed normal-fat (NF), high-fat (HF), or HF supplemented with 5% T. lutea (HFTiso) diets for three months. Gut microbial profiles were analyzed by 16S rRNA sequencing and correlated with plasma lipids, glucose, blood pressure, fecal lipid excretion, and adiponectin levels. T. lutea supplementation was associated with significant modulation of selected metabolic parameters and coherent alterations in gut microbial communities. Multivariate analyses revealed treatment-dependent clustering of metabolic profiles, with HFTiso forming an intermediate group between HF and NF diets. Beta-diversity analyses showed marked treatment-specific shifts, while alpha-diversity remained stable. Linear discriminant analysis identified 31 discriminative genera, with the HFTiso group enriched in taxa associated with fermentative metabolism and lipid-related metabolic pathways including Anaerotruncus, Marvinbryantia, and Eubacterium coprostanoligenes, while the HF group was linked to Clostridium sensu stricto 1 and Terrisporobacter. Positive correlations between HFTiso-associated taxa and adiponectin levels were consistent with microbiota-associated metabolic signatures. In parallel, T. lutea supplementation was associated with downregulation of colonic Niemann-Pick C1-like 1 (NPC1L1) mRNA expression, a key mediator of intestinal cholesterol uptake. The bioactivity of T. lutea likely reflects its content of polyunsaturated fatty acids, oleic acid, phytosterols, and fucoxanthin; however, whether these components act synergistically or whether specific bioactive compounds are primarily responsible remains to be clarified. Together, these findings indicate that T. lutea supplementation is associated with coordinated changes in gut microbiota composition and transcriptional modulation of the intestinal cholesterol transporter NPC1L1 in the context of selected early-stage metabolic alterations under high-fat feeding. While direct extrapolation to humans remains limited, these results suggest potential translational relevance of T. lutea as a nutraceutical approach targeting early-stage metabolic dysregulation. Future studies will be required to determine the mechanistic contribution of individual bioactive components and to assess whether microbiota- and gene expression-associated changes play a causal role in mediating the observed metabolic outcomes, thereby informing the rational development of T. lutea-derived interventions.

Marine Drugs doi: 10.3390/md24020085

Authors: Marzia Vasarri Donatella Degl’Innocenti Matteo Lulli Nicola Schiavone Alice Verdelli Marzia Caproni Emiliano Antiga Emanuela Barletta

Skin inflammation is characterized by oxidative stress, excessive keratinocyte activation, and the overproduction of pro-inflammatory cytokines. In a previous study, we demonstrated that the hydroalcoholic extract from Posidonia oceanica leaves (POE) mitigates psoriasis-like skin inflammation in a mouse model. In the present study, we investigated the cellular mechanisms underlying these effects in human HaCaT keratinocytes. Non-cytotoxic lipopolysaccharide (LPS) stimulation reproduced key inflammatory features, including impaired cell proliferation, increased production of ROS and NO, and the upregulation of IL-1β, IL-6, TNF-α and CXCL8/IL-8. Co-treatment with POE significantly attenuated these alterations by restoring cell proliferation, suppressing oxidative stress, particularly NOS2/NO, and normalizing both cytokine expression and release. POE alone did not affect cell viability or inflammatory markers, confirming its favorable safety profile. However, POE alone induced a mild pro-apoptotic response, which may contribute to overcoming the apoptosis resistance typically observed in psoriatic keratinocytes. Overall, these findings demonstrate that POE exerts antioxidant and anti-inflammatory effects in activated keratinocytes and support its potential as a marine-derived candidate for complementary strategies in the management of psoriasis-associated inflammatory skin disorders.

Marine Drugs doi: 10.3390/md24020084

Authors: Wenjie Wang Kun Gao Guantian Li Zongji Wang Kecheng Li Song Liu Huahua Yu Ronge Xing

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic diseases, and inhibition of α-glucosidase activity represents an effective therapeutic strategy. Chitin is the most abundant renewable polysaccharide in the ocean, with its monosaccharide being N-acetylglucosamine (NAG). To evaluate the potential of NAG glycosides as novel α-glucosidase inhibitors, three common phenolic compounds were modified via NAG glycosylation. Their inhibitory activities were assessed at both the enzymatic and cellular levels. In addition, density functional theory (DFT), molecular dynamics (MD) simulations, and molecular docking analyses were employed to systematically investigate the effects of NAG glycosylation on enzyme inhibition and the underlying mechanisms. Compared with the parent phenolic compounds, NAG glycosides exhibited significantly enhanced α-glucosidase inhibitory activity, with NAG introduction markedly improving their binding affinity to α-glucosidase. Among them, glycoside 3a displayed the optimal inhibitory effect, comparable to acarbose, and at the cellular level, its activity at high concentrations was comparable to or slightly higher than that of metformin. Circular dichroism (CD) and MD analyses indicated that glycoside 3a increased the conformational flexibility of key residues and enhanced the structural looseness of the enzyme, thereby inhibiting its activity. NAG glycosides constitute a promising class of marine-derived α-glucosidase inhibitors, warranting further structural optimization and rational design to enhance their activity and selectivity.

Marine Drugs doi: 10.3390/md24020083

Authors: Cecilia Faraloni Gergely Erno Lakatos Francesco Balestra Anna Pugliese Graziella Chini Zittelli Bernardo Cicchi Eleftherios Touloupakis Giuseppe Torzillo

Light and salt stress affect the growth of plants and microorganisms, causing photo-oxidative stress. The cyanobacterium Synechocystis is notable for its adaptability to and sustainability in seawater. In this study, the synergistic effects of different light intensities and salt concentrations on the growth and biomass composition of Synechocystis were examined. Cultures were grown in BG11 medium (control) and with 20 and 40 g L−1 marine salts (obtained from a commercial sea water preparation) at 100, 200, and 400 μmoles photons m−2 s−1 (LL, ML, and HL, respectively) to assess the interactive effects of salinity stress and increasing light intensity. The effect of salinity stress was most pronounced under LL and ML, where the highest accumulation of all major carotenoids was observed; under HL, the contents of most carotenoids significantly increased mainly at the highest salt concentration but to a lesser extent). Under LL and ML echinenone reached the highest values (2.71-fold and 3.75-fold higher than in the control, respectively), whereas β-carotene showed the highest increase at LL, reaching concentrations three times those of the control. At HL myxoxanthophyll exhibited the highest increase with marine salt (1.9-fold higher than in the control). The results show that Synechocystis could grow at all light intensities and marine salt concentrations via increased synthesis of carotenoids in response to physiological stress.

Marine Drugs doi: 10.3390/md24020082

Authors: Fahrul Nurkolis Annette d’Arqom Evhy Apryani Nurmawati Fatimah Adha Fauzi Hendrawan Izza Afkarina Reggie Surya Happy Kurnia Permatasari Dante Saksono Harbuwono Nurpudji Astuti Taslim Arifa Mustika Raymond Rubianto Tjandrawinata

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder requiring safe, multitarget therapeutic strategies. Marine macroalgae represent an underexplored source of bioactives with pleiotropic metabolic effects. This study investigated the antidiabetic potential of an ultrasound-assisted ethanolic extract of Caulerpa racemosa (UAECr) and its key phytosterol, campesterol, through an integrative framework combining metabolomics, network pharmacology, molecular docking, molecular dynamics simulation, and in vitro validation. Untargeted ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC–HRMS) metabolomics characterized UAECr constituents, followed by in silico bioactivity prediction, target-network analysis, molecular docking, and 100 ns molecular dynamics simulation of the peroxisome proliferator-activated receptor gamma (PPARγ)–campesterol complex. Functional validation was performed in differentiated 3T3-L1 adipocytes assessing glucose uptake, PPARγ expression, dipeptidyl peptidase 4 (DPP-4) inhibition, and cytotoxicity. Metabolomics identified campesterol as a prominent bioactive. Network pharmacology highlighted PPARγ as a central hub, supported by strong docking affinity of campesterol toward PPARγ (−11.4 kcal/mol) and DPP-4 (−8.3 kcal/mol). Molecular dynamics simulations demonstrated stable PPARγ–campesterol interactions, with preserved protein compactness and low residue fluctuation. In vitro, UAECr and campesterol significantly enhanced glucose uptake (up to 134% vs. control, p < 0.001), upregulated PPARγ expression (4-fold, p < 0.0001), and moderately inhibited DPP-4 activity (p < 0.01) without cytotoxicity. C. racemosa-derived extracts and campesterol exert antidiabetic effects primarily via stable PPARγ-mediated insulin sensitization with complementary DPP-4 modulation, supporting its potential as a marine-derived functional food candidate.

Marine Drugs doi: 10.3390/md24020081

Authors: Rebecca Serna-García Ysis Lanzoni Octavio García-Depraect Raul Muñoz Sara Cantera

The conversion of biogas into high-value chemicals for pharmaceutical, cosmetic, and nutraceutical markets offers an attractive alternative to conventional fossil-based production routes, enabling circular value chains with significant socio-economic impact. This study evaluated the valorization of biogas into osmolyte and carotenoid compounds with market prices ranging from 1000 to 7000 $·kg−1. Specifically, an algal–methanotrophic co-culture operated under saline conditions, preventing external microbial contamination and stimulating osmolytes and carotenoids, was assessed for its capacity to simultaneously remove methane (CH4) and carbon dioxide (CO2), with efficiencies of 92 and 89%, respectively. while producing ectoine, hydroxyectoine, lutein, β-carotene, and astaxanthin. Shotgun metagenomic analyses identified the key microorganisms driving the process, predominantly alkaliphilic and halophilic green algae (Chlorella, Dunaliella) and cyanobacteria (Leptolyngbya), and halotolerant methanotrophs (Methylotuvimicrobium) and methylotrophs (Methylophaga). Metagenomics further revealed the presence of key metabolisms related to C1 utilization and biosynthetic genes associated with carotenoid and osmolyte production, confirming the metabolic potential of the consortium to convert biogas-derived carbon directly into high-value compounds. Overall, these results demonstrate the feasibility of an efficient, biologically driven bio-platform capable of transforming greenhouse gas-rich waste streams into economically relevant bioactive molecules, contributing to global priorities in sustainable biomass-to-biochemical innovation.

Marine Drugs doi: 10.3390/md24020080

Authors: Parakkrama Wijerathna Xinqi Chen Yi Chen Yufan Zhang Jian Cai Mengjing Cong Ying Liu Lalith Jayasinghe Yonghong Liu Disna Ratnasekera Xuefeng Zhou

Three previously uncharacterized lactones, namely penicianstinoid L (1), talaromyketide J (2) and peniciisocoumarin K (3), along with twenty-eight known compounds (4–31), were yielded from the mangrove-derived fungus Talaromyces sp. SCSIO41445, collected from Mangrove Park (NARA), Sri Lanka. Their structures were established by HRESIMS and NMR spectroscopic analysis (including 1H and 13C NMR, HSQC, and HMBC), with the stereostructures of 2 and 3 being confirmed by single-crystal X-ray crystallographic analysis. Furthermore, compounds 1–31 were evaluated in terms of their neuraminidase (NA) inhibitory activities. These bioassay results revealed that three lactones (11, 15, and 16) of them exerted NA inhibitory effects, with IC50 values of 46.66 ± 2.31, 20.78 ± 1.89, and 34.14 ± 2.56 µM, respectively. Moreover, molecular docking analysis demonstrated the potential of these compounds to inhibit NA enzymes, revealing specific interactions between the compounds and target proteins.

Marine Drugs doi: 10.3390/md24020079

Authors: Sen Wang Yunuo Hao Tengsheng Qiao Ruihao Zhang Deliang Yu Hailiang Wang Yongliang Liu Yuhao Sun Di Xu Xiaojin Song Kehou Pan

Phaeodactylum tricornutum is one of the most well-characterized microalgae and serves as a pivotal model diatom in global carbon fixation and the mediation of biogeochemical cycling of essential nutrients. Over the past few decades, the availability of a complete genome assembly, coupled with the development of robust DNA manipulation tools and efficient DNA delivery methodologies, has established P. tricornutum as a promising photosynthetic chassis for the sustainable bioproduction of high-value compounds, including fucoxanthin and eicosapentaenoic acid (EPA). This review systematically summarizes the research progress in the strain improvement toolkit of P. tricornutum, encompassing both genetic and non-genetic engineering strategies. It elaborates on the types and applications of its representative bioactive products, as well as the molecular mechanisms underlying key synthetic pathways. Additionally, this work synthesizes the research findings on the optimization of critical cultivation conditions (e.g., light, temperature, and nutrient composition) that modulate the growth and product synthesis of P. tricornutum. On this basis, the challenges encountered by P. tricornutum in industrial applications are proposed for further discussion, aiming to provide a reference for in-depth exploration of related research directions and facilitate the expansion of its application scope in the field of biomanufacturing.

Marine Drugs doi: 10.3390/md24020078

Authors: Wen-Ping Cheng Han-Yang Yeh Yen-Ling Chen Yi-Jung Chen Fat-Tin Agassi Sze Chi-Cheng Huang Fan-Hua Nan Ming-Chih Fang Meng-Chou Lee

The marine unicellular red alga Rhodosorus marinus is a promising source of the valuable phycobiliprotein phycoerythrin and essential omega-3 polyunsaturated fatty acids (PUFAs), yet the environmental triggers for their optimal co-production remain to be fully elucidated. This study was conducted to investigate the effects of thermal and photic stress in terms of maximizing the yield of these high-value bioactive compounds. R. marinus was cultivated under a range of temperatures (18–24 °C) and light intensities (100–335 µmol photons m−2 s−1) to assess its physiological and biochemical responses, particularly focusing on lipid accumulation. This study investigates the effects of thermal (18–24 °C) and photic (100–335 µmol photons m−2 s−1) stress on the concurrent production of the valuable phycobiliprotein, phycoerythrin (PE), and essential omega-3 polyunsaturated fatty acids (PUFAs) in the marine red microalga Rhodosorus marinus. Fatty acid profiles were quantified using gas chromatography (GC), while pigment content was assessed via spectrophotometry. Statistical analyses, including one-way ANOVA and Tukey’s post hoc test, were employed to determine the significance of environmental effects. Our results demonstrate that a mild hypothermic condition of 18 °C significantly enhanced the production of eicosapentaenoic acid (EPA) compared to higher temperatures. Conversely, cell density was maximized at 22 °C. Under the 18 °C thermal regime, lower light intensities (100–185 µmol photons m−2 s−1) promoted a superior synthesis of both bioactive lipids and pigments. In conclusion, the strategic application of mild hypothermia combined with moderate light intensity is an effective approach to substantially boost the metabolic yield of high-value compounds in R. marinus, highlighting its potential as a sustainable source for nutraceutical and pharmaceutical applications.

Marine Drugs doi: 10.3390/md24020077

Authors: Ivan Citakovic Gaël Bougaran Fabienne Hervé Damien Réveillon Cyril El Khoury Francis Mairet Bruno Saint-Jean

As agriculture faces increasing pressure to reduce pesticide residues and heavy metal accumulation in soils, marine microalgae are emerging as sustainable sources of biopesticides. Among them, Amphidinium carterae produces amphidinols (AMs), polyketide metabolites with strong antifungal activity against crop pathogens. Currently, large-scale AM production remains constrained by a limited understanding of AM biosynthesis across different A. carterae growth phases and by the lack of high-performing industrial strains. In this study, AM production dynamics were investigated in one wild-type (WT) and five mutagenized A. carterae strains. The production of bioactive AM18 and its sulfated inactive form AM19 was monitored through exponential, linear, and early stationary growth phases. The maximum AM productivity occurred between the linear and early stationary phase, with the average values of 5.58 ± 0.4 and 3.58 ± 0.2 µg/mL/day for AM18 and AM19, respectively. The AM18/AM19 ratio consistently decreased with the culture age, indicating that earlier harvesting favors higher proportions of bioactive AMs. UV mutagenesis increased the AM18 cell content by more than twofold and the growth rate by up to 20% in certain mutagenized strains compared to the WT strain, but did not enhance the volumetric AM productivity. Overall, these results identify optimal AM harvesting windows and clarify the potential benefits of mutagenesis strain improvement for industrial AM production improvement.

Marine Drugs doi: 10.3390/md24020076

Authors: Yi Lu Baomei Zhang Zishuo Wang Yidi He Hezi Ge Hongyue Ma Pengfei Cui

Antimicrobial peptides (AMPs) are increasingly promoted as alternatives or complements to conventional antibiotics, yet growing evidence demonstrates that resistance to AMPs is neither rare nor incidental. Here, we define the anti-AMP resistome as a coordinated network of genetic, regulatory, and physiological mechanisms that enable bacteria to tolerate or evade AMP-mediated stress. We synthesize advances in understanding how envelope remodeling, efflux and sequestration, extracellular proteolysis, biofilm-associated buffering, and inducible stress responses collectively shape AMP susceptibility. We further distinguish transient, inducible tolerance from stable, heritable resistance, and discuss how chronic subinhibitory exposure can drive their evolutionary interconversion. Extending beyond clinical pathogens, we highlight environmental microbiomes as major reservoirs of anti-AMP determinants with implications for horizontal transfer and One Health risk. Finally, we argue that AMP development and deployment must adopt a resistome-aware framework that integrates molecular mechanisms, evolutionary dynamics, and environmental context to preserve long-term therapeutic efficacy.

Marine Drugs doi: 10.3390/md24020075

Authors: Olesya S. Malyarenko Timofey V. Malyarenko Alla A. Kicha Svetlana P. Ermakova Natalia V. Ivanchina

Triple-negative breast cancer (TNBC) represents significant therapeutic challenges due to its aggressive behavior, metabolic plasticity, and lack of targeted treatments, prompting investigation of biologically active triterpene glycosides from the starfish Solaster pacificus. This study evaluated the ability of pacificusoside D (SpD) to synergistically enhance the anticancer efficacy of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) in TNBC MDA-MB-231 cells by targeting mitochondrial oxidative phosphorylation (OXPHOS). Methods included metabolic profiling via glucose uptake, lactate, and glutamate Glo assays; IC50 determination by MTS and trypan blue assays; colony formation evaluation using a soft agar assay; and molecular mechanism elucidation by Western blot, fluorescence microscopy and spectrometry, and flow cytometry analyses. Results demonstrated that MDA-MB-231 cells predominantly utilized glycolysis under basal conditions, shifting to OXPHOS with 2-DG (0.5 mM). IC50 values were 8.0/8.4 mM for 2-DG and 0.3/0.25 μM for SpD after 24 h of cell treatment. SpD exhibited a significant decrease in the number of colonies in MDA-MB-231 cells and possessed synergistic anticancer effects with 2-DG. Mechanistically, SpD increased tumor suppressor VHL expression level, down-regulated expression level of electron transport chain enzymes, generated reactive oxygen species, induced mitochondrial dysfunction, and triggered Bax/Bak-mediated apoptosis. These findings highlighted the synergistic anticancer potential of SpD in combination with 2-DG in aggressive breast cancer, offering insights into improved clinical outcomes in the future.

Marine Drugs doi: 10.3390/md24020074

Authors: N. M. Liyanage Li Yiqiao K. K. Asanka Sanjeewa Kyung Yuk Ko D. P. Nagahawatta You-Jin Jeon

Shellfish are a diverse group of marine animals that play a significant role, as a high proportion of the world’s seafood is produced by shellfish. In general, shellfish contain higher amounts of nutrients that benefit consumer health. In recent years, research has focused on the potential health benefits of consuming shellfish, including their anti-cancer and anti-microbial properties. Studies have shown that certain types of shellfish contain bioactive compounds that can inhibit growth and proliferation as well as induce apoptosis in cancer cells both in vitro and in vivo. In addition, shellfish also possess anti-microbial properties which arise from their proteins, peptides, fatty acids, and polysaccharides, which can disrupt the bacterial cell membrane, inhibit bacterial cell division, and interfere with cellular processes. These make them beneficial in preventing and treating infectious diseases. This review explored the findings related to the potential of shellfish bioactive compounds against cancer and microbial infections. Furthermore, this analysis demonstrates unequivocally that shellfish have vast potential for producing functional foods and that the bioactive compounds have the potential to be used in pharmaceutical applications.

Marine Drugs doi: 10.3390/md24020073

Authors: Andrew Turner Panagiota Katikou

Marine toxins are natural compounds produced by a variety of marine organisms, including microalgae, bacteria, and macroalgae [...]

Marine Drugs doi: 10.3390/md24020072

Authors: Xin-Yi Tong Xue-Wu Chen Jia-Yi Zhang Jian-Ming Ouyang

Objective: The formation of calcium oxalate (CaOx) kidney stones is accompanied by the pyroptosis of renal epithelial cells. The risk of kidney stone formation can possibly be reduced through pyroptosis inhibition. Methods: Pyroptosis of HK-2 cells induced by 3 µm CaOx monohydrate (COM-3 µm) was inhibited by Pelvetia siliquosa polysaccharides before and after sulfation (PSP0 and PSP3, with −OSO3− contents of 1.04% and 36.12%, respectively). The inhibitory efficiency and mechanism of PSP0 and PSP3 were evaluated via caspase-1/PI double staining and Western blot detection of pathway proteins in pyroptosis cells. The potential anti-stone effect of polysaccharides was evaluated through measurement of the extent of crystal adhesion on the cell surface. Results: The proportion of pyroptosis cells induced by COM-3 µm reached 17.87%. After protection by PSP0 and PSP3, the percentage of pyroptosis cells was reduced to 12.7% and 6.35%. The levels of NLRP3, ASC, gasdermin D, IL-1β, and IL-18 related to pyroptosis were downregulated. In addition, the activation of the NF-κB pathway was considerably inhibited. During inhibition of pyroptosis, reactive oxygen species and lactate dehydrogenase levels were decreased, the integrity of zonula occludens-1 protein was restored, and the expressions of CaOx-specific adhesion proteins (ANXA3 and CD44) were substantially decreased. As a result, the adhesion of COM crystals on the cell surface was reduced. PSP3 exhibited a higher protection energy efficiency than PSP0. Conclusions: PSP0 and PSP3 inhibited the pyroptosis of HK-2 cells through the NLRP3/ASC/caspase-1/IL-1β pathway, which caused the inhibition of cell inflammation and injury, reduced the expressions of adhesion proteins, and reduced the risk of CaOx crystal adhesion and stone formation. The biological activity of PSP0 and PSP3 after sulfation modification increased.

Marine Drugs doi: 10.3390/md24020071

Authors: Won Sek Lee Sung-Ae Son Yong-Il Kim

This scoping review mapped the available evidence on marine algae-derived bioactive compounds, focusing on their biological activities related to collagen stabilization, matrix metalloproteinase (MMP) inhibition, and enamel remineralization in dental hard tissues. Four electronic databases (PubMed, Scopus, Embase, and Web of Science) were systematically searched following a predefined protocol. Original experimental studies involving human or animal dental hard tissues were included. Nine studies met the inclusion criteria. Brown algal derivatives, including fucoxanthin, fucosterol, and phloroglucinol, exhibited significant MMP inhibition and, in selected compounds, collagen cross-linking, contributing to enhanced mechanical properties and improved stability of collagen-rich matrices. In contrast, red algae extracts such as Lithothamnion calcareum primarily promoted enamel remineralization, achieving surface microhardness recovery comparable to or superior to 0.05% sodium fluoride. Alginate, a brown algae-derived polysaccharide, also demonstrated functional potential as a scaffold biomaterial through strong hydroxyapatite adsorption and suitability for three-dimensional scaffold fabrication. Overall, marine algae-derived compounds demonstrate biologically relevant activities that modulate collagen stability, enzymatic function, and mineral deposition processes. These findings highlight the pharmacological potential of marine bioactive compounds, with dental hard tissues representing a primary application context. However, further validation using clinically relevant models is required.

Marine Drugs doi: 10.3390/md24020070

Authors: Tiago Santos Ana Pintão Carolina S. Marques Pedro Brandão

Marine ecosystems have yielded a remarkable diversity of bioactive metabolites with relevance for antiviral drug discovery. This article reviews recent advances in marine-derived compounds investigated as anti-HIV agents. Metabolites, such as sulfated polysaccharides, lectins, alkaloids, and terpenoids, display inhibitory activity across multiple stages of the HIV life cycle, including viral entry, reverse transcription, integration, and maturation. From sponge-inspired development of AZT to the application of Griffithin in clinical trials for the prophylaxis of the HIV infection, recent discoveries showcase the chemical diversity of marine ecosystems and validate their utility as hit and compound sources in drug discovery. We highlight possible mechanisms of action, as well as translational hurdles from research to clinical trials. Overall, marine biodiversity represents a valuable and underexploited reservoir for the development of novel HIV therapeutics.

Marine Drugs doi: 10.3390/md24020069

Authors: Xuan Zhang Tuxiang Mo Yuyue Qin Meiling Le Li Tang Zhao Zhang Jiling Yi Fuling Cen Wanshan Li Guangying Chen

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammation of the colonic mucosa, and there is currently a lack of safe and effective treatment drugs. Resorcylic acid lactones (RALs) are a natural product that have been reported to have anti-inflammatory effects. However, the mechanism of whether RALs can treat UC and their anti-inflammatory effects remains underexplored. In this study, three new RAL derivatives, Penicillactones A–C (1–3), along with seven known analogs (4–10), were isolated from the marine fungus Penicillium sp. HN20. The structures of compounds 1–3 were elucidated by spectroscopic methods, 13C NMR theoretical calculations, and ECD analysis. Among these, compound 4 exhibited potent anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages. In a dextran sulfate sodium (DSS)-induced UC model, compound 4 alleviated body weight loss, disease activity, colon shortening, and spleen enlargement, and protected intestinal epithelial integrity. Mechanistic studies revealed that compound 4 primarily exerts its effects by downregulating the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) signaling pathway, inhibiting pro-inflammatory cytokine production. Collectively, these findings provide the first evidence that marine-derived RAL derivatives exert anti-inflammatory effects by inhibiting the MAPK/ERK pathway, highlighting compound 4 as a promising therapeutic candidate for inflammation and UC.

Marine Drugs doi: 10.3390/md24020068

Authors: Miguel P. Coelho Pablo Suárez-Moo Mariana Rocha Artur O. G. Matos Vanda Marques Sara Margarida Mário Mil-Homens Alejandra Prieto-Davó Cecília M. P. Rodrigues Anelize Bauermeister Rita G. Sobral Susana P. Gaudêncio

This study explores the taxonomic diversity, metabolic profile, and bioactivity of marine-derived actinomycetes isolated from sediments collected off the coast of Lisbon and Setúbal Peninsula, Portugal. The combined use of two sediment pre-treatments (heat shock and dry overnight) and four growth media with varying nutrient concentrations revealed that formulations 10% A1 and SWA were most effective for recovering diverse actinomycetes, including rare Actinomadura, resulting in a total of 142 cultivable strains closely related to 47 phylogenetic distinct species dominated by Streptomyces and Micromonospora. Antimicrobial screening against methicillin-resistant Staphylococcus aureus (MRSA, COL) and Escherichia coli (K12) identified 22 bioactive strains, with strain PTS-083 exhibiting the strongest activity against MRSA (MIC = 1.95 µg/mL) and a 98.30% 16S rRNA gene identity to S. chumphonensis, highlighting it as a strong candidate for further metabolite and genomic studies. Cytotoxicity assays against HCT-116 human colorectal adenocarcinoma cells revealed eight bioactive strains with potent anticancer activity for extracts from strains related to S. sundarbansensis, S. violaceorubidus, and S. aculeolatus (IC50 < 0.005–5.08 µg/mL). Untargeted LC-MS/MS metabolomic analysis uncovered a wide array of secondary metabolites, including macrolides, siderophores, fatty acids, and cyclic peptides. Comparative analyses with other Portuguese coastal studies revealed both shared and distinctive metabolomic profiles, emphasizing the importance of exhaustive sampling, even at nearby locations, since localized environmental conditions can influence metabolic diversity and are crucial for uncovering unique metabolites with potential biotechnological value. These findings highlight Portugal’s coastal sediments as a rich and underexplored source of novel actinomycetes and bioactive compounds with promising pharmaceutical applications.

Marine Drugs doi: 10.3390/md24020067

Authors: Zouher Amzil Amélie Derrien Korian Lhaute Aouregan Terre Terrillon Simon Tanniou

In France, as part of the monitoring program for the emergence of marine toxins in shellfish (EMERGTOX), brevetoxins (BTX-2, BTX-3) were first detected in shellfish from Corsica (Mediterranean Sea) in 2018. The complex metabolic transformation of brevetoxins in shellfish, coupled with the limited availability of analytical standards for most metabolites, complicates the accurate evaluation of contamination levels. To address this challenge, two complementary analytical approaches were implemented to quantify brevetoxin metabolites in shellfish samples collected from 2018 to 2023: (i) a targeted LC-MS/MS method specially developed for brevetoxins; and (ii) an ELISA capable of detecting metabolites for which no reference standards are available. Of the 11 brevetoxin metabolites targeted, 4 were quantified by LC-MS/MS: BTX-2, BTX-3, BTX-B5, and S-deoxy-BTX-B2 (including its isomers). The ELISA consistently detected brevetoxins in all Corsican samples previously confirmed positive by LC-MS/MS, with concentrations systematically exceeding those measured by LC-MS/MS. This overestimation may result from antibody cross-reactivity and from the presence of unidentified brevetoxin metabolites not detected by LC-MS/MS. Regardless of the analytical method used, the highest concentration detected exceeded the current French guideline value for brevetoxins in shellfish. To ensure consumer protection, a two-step monitoring strategy is proposed: initial screening via ELISA to estimate brevetoxin contamination, followed by confirmatory LC-MS/MS analysis to identify and quantify the specific metabolites.

Marine Drugs doi: 10.3390/md24020066

Authors: Galey Tenzin Kira Schipper Harshit Rathore Hemil Shah Edgar Brea Ben Hankamer Damian Hine

After numerous false starts, the global microalgae industry is re-emerging, driven by its potential to address critical challenges in food and nutrition, sustainable energy, nutraceuticals, cosmetics and pharmaceuticals, and climate change mitigation. Although technical advances in microalgae production show value adding potential, progressing from innovation to product launch and competitiveness is complex. It requires an integrated understanding of technology readiness, regulatory compliance, financial necessities, and market competition. This study presents a novel analytical framework underpinning a data-enabled, evidence-based approach to navigating the innovation pathways to market and beyond. The framework integrates value-add opportunities, identifying key stages faced in pre-competitive (including Technology Readiness Level (TRL), R&D spend, and patent trends), and competitive market stages (including product launches, product claims, market size, market share, growth/maturity, international markets, distribution channels, sectoral profile, and competitive landscape), aligned with regulatory requirements. Although not without limitations, such as incomplete data for emerging products, as well as reliance on secondary sources for product stage determination and market size estimates which can influence the accuracy of TRL classification and market potential estimates. This integration of multiple analyses can help in identifying market opportunities and business competitiveness via product, business, and industry level analyses in the pre-competitive (pre-market launch) and competitive (on market) landscapes. Building on the team’s interdisciplinary experience of developing interactive dashboards for food and beverage industries, and microalga processes, this paper provides an overview of the framework, which was designed to guide businesses and researchers in an emerging microalgae industry through the complex landscape of product development along regulatory and commercial pathways.

Marine Drugs doi: 10.3390/md24020065

Authors: Surendraraj Alagarsamy Sabeena Farvin Koduvayur Habeebullah Ismail Saheb Azad Saja Adel Fakhraldeen Turki Al Said Aws Al Ghuniam Faiza Al-Yamani

Sabkhas, hypersaline ecosystems along Kuwait’s coastal zone, are extreme environments that harbor diverse halophilic microorganisms with significant biotechnological potential. Despite this, they remain underexplored, particularly in the context of enzymes that can function under high salinity. The aim of this study is to identify bacterial isolates from Kuwait’s sabkhas that produce α-amylase under extreme environmental conditions and to purify and characterize the resulting halotolerant α-amylase. Among the seven α-amylase-producing isolates, Priestia sp. W243, isolated from Mina Abdullah, exhibited the highest enzyme production under optimal growth conditions of pH 9.0, 37 °C, and 7.5% NaCl. A novel halotolerant α-amylase with a remarkably high specific activity (8112.1 U/mg) was purified from this isolate using ultrafiltration, ion-exchange chromatography, and gel-filtration. The purified enzyme, with a molecular weight of 25 kDa, showed optimal activity at 40 °C, pH 8, and 3% NaCl. Notably, the enzyme remained active in the absence of salt and up to 15% NaCl, demonstrating exceptional halotolerance. Metal ion profiling revealed that enzyme activity was significantly enhanced by Co2+, whereas Ca2+ had a comparatively moderate effect on enzyme activity. When the effects of metal chelators were examined, EDTA, a strong metal chelator, inhibited the enzyme. However, the enzyme remained active when Ca2+ was specifically removed using EGTA, suggesting that this α-amylase may be a cobalt-dependent metalloenzyme, which is an unusual characteristic among known α-amylases. Additionally, the enzyme retained its catalytic activity under reducing conditions (e.g., in the presence of DTT and β-mercaptoethanol), indicating structural stability is independent of disulfide bonds. These unique properties distinguish this α-amylase from typical salt- or calcium-dependent counterparts and highlight its potential for industrial applications in high-salt food processing, baking, brewing, and environmental remediation.

Marine Drugs doi: 10.3390/md24020064

Authors: Femke Hacker Johann Roider Alexa Klettner Philipp Dörschmann

Fucoidans are natural compounds that exhibit bioactivity against age-related macular degeneration (AMD), the leading cause of central vision loss in industrialized nations. Pathological factors like oxidative stress and lipid peroxidation play vital roles in AMD pathogenesis. Lipid-induced alterations in the retinal pigment epithelium (RPE) contribute to AMD development. In this study, a commercial fucoidan from Fucus vesiculosus (FVs) was tested for its activity regarding lipid-peroxidation-related effects. The human RPE cell line ARPE-19, primary porcine RPE, and RPE/choroid explants were stimulated with erastin, acting as an inducer of lipid peroxidation, and treated with fucoidan. Effects on cell viability (tetrazolium bromide (MTT) or calcein staining), vascular endothelial growth factor (VEGF) and interleukin 8 (IL8) secretion (ELISA), reactive oxygen species (ROS), protein expression (glutathione peroxidase 4 (GPX4), CD59, and retinoid isomerohydrolase (RPE65), analyzed via Western blot), and gene expression (RT-qPCR) were investigated. FVs showed protective effects against erastin-induced reduction in viability (with a 12.7% increase in viability compared to erastin), RPE65 expression (with a 4.2-fold increase compared to erastin), and GPX4 expression (with a 2.3-fold increase compared to erastin) in primary RPE. Erastin-induced VEGF secretion was attenuated by FVs in ARPE-19 and primary RPE (with an up to 1.7-fold reduction compared to erastin). Elevated IL8 levels were reduced by FV treatment in primary RPE (with a 9.1-fold reduction compared to erastin). Induced VEGF in RPE/choroid explants was reduced by FVs (with an up to 2.9-fold reduction compared to erastin), and this reduction was correlated with slight improvements in viability. In conclusion, FVs exerted protective effects against lipid-induced stress. This study reveals further effects of fucoidans against AMD-related pathologies.

Marine Drugs doi: 10.3390/md24020063

Authors: Xiang Chen Liting Zhang Jinqi Huang Mingzhi Su Yuewei Guo Xin Jin

Phorbazoles are bioactive marine alkaloids whose development is hampered by limited supply. We report a concise synthesis of the deschloro-phorbazole core via an optimized iodine-catalyzed oxazole annulation (56% yield). This route enabled efficient access to the scaffold and the preparation of analog B1. B1 showed nanomolar cytotoxicity (IC50 = 0.04 µM) against MV4-11 leukemia cells by inducing G0/G1 arrest (via cyclin D1/CDK6 downregulation) and apoptosis. As a multi-kinase inhibitor, B1 also potently inhibited endothelial network formation and migration, demonstrating anti-angiogenic activity. This work provides an efficient synthetic strategy and identifies B1 as a promising dual-function anticancer lead compound.

Marine Drugs doi: 10.3390/md24020060

Authors: Joana Corrêa Mendes Joana F. A. Valente Fani Sousa Raul Bernardino Susana Bernardino Clélia Afonso Bárbara Chagas

Alginate is a widely used and versatile biopolymer with an ever-expanding range of applications in the pharmaceutical and biomedical industries. This highlights the importance of developing sustainable and renewable production sources. Conventional extraction methods, although effective, are often energy-intensive and rely on harsh chemicals. In this context, brown algae are a promising alternative due to their abundance and renewability. This study investigated the potential of Saccorhiza polyschides and Sargassum muticum as sources of sodium alginate (SA), thus optimising an extraction process that combines acid treatment with an alkaline step. The extracted biopolymers were characterised using FTIR, H-NMR, STA, SEM/EDX, viscosity measurements, dynamic light scattering, and spectrophotometric assays of residual polyphenols and proteins. The optimised extraction conditions produced yields above 20% of high-purity alginate. When compared with commercial SA, the extracted materials showed comparable quality while relying on a simplified, solvent-reduced protocol that improves process efficiency and reduces the environmental impact. These results demonstrate that S. polyschides and S. muticum are promising, locally available sources of high-quality sodium alginate, and that industrially relevant yields (>20%) can be achieved through an environmentally conscious two-step extraction process.

Marine Drugs doi: 10.3390/md24020061

Authors: Angélica R. Soares Nathalia Nocchi Ana R. Díaz-Marrero Renato C. Pereira José J. Fernández

The concept of “Smart Secondary Metabolites” is introduced here to describe a privileged class of natural products defined by structural originality, biosynthetic adaptability, and broad interaction potential with biological systems. Elatol, a halogenated sesquiterpene chiefly produced by Laurencia red seaweeds and occasionally accumulated by their consumers, exemplifies this concept with remarkable clarity. Its biosynthesis unfolds from farnesyl diphosphate via γ-bisabolane cations, bromochlorination, and stereoselective cyclization to chamigrene scaffolds, generating both (+)- and (–)-enantiomers, two metabolites with clearly distinct potential ecological roles and pharmacological profiles. This review synthesizes the current state of knowledge on elatol’s distribution, biosynthetic origins, ecological relevance, and therapeutic potential. Elatol serves as a multifunctional chemical mediator, fulfilling defensive, communicative, and regulatory roles whose intensity shifts in response to herbivory, biofouling, temperature, and salinity. In parallel, its potent activities against infectious, metabolic, and neoplastic diseases highlight its growing value as a drug lead, reflected in a rising number of patent claims. Altogether, elatol emerges as a model Smart Secondary Metabolite whose ecological sophistication and biochemical versatility position it as a promising scaffold for marine-derived drug discovery.

Marine Drugs doi: 10.3390/md24020062

Authors: Chenqi Zhang Luning Zhou Shuo Zhao Wenxue Wang Xiaomin Zhang Qian Che Tianjiao Zhu Mei Han Dehai Li

Ten new epipolythiodioxopiperazine (ETP) alkaloids, named corallomycetellains A–J (1–10), along with one known analogue, haematocin (11), were isolated from the fungi Corallomycetella repens HDN23-0007. Their structures, including absolute configurations, were established by comprehensive spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1–2 represent the first two examples of aranotin-type ETPs possessing an aromatic indole moiety. Compounds 2–4 all featured a unique C2-methyl disulfide substituent, whereas compound 4 additionally possessed a C2′-oxomethyl group. In in vitro cytotoxicity assays, compounds 7–10, which contained α–α′ polysulfide bridges, exhibited strong anticancer activity, with IC50 values ranging from 1.1 to 9.3 μM.

Marine Drugs doi: 10.3390/md24020059

Authors: Vladimir M. Pavlov Anastasia Yu. Fedotova Victor A. Palikov Yulia A. Logashina Kamilla I. Zagitova Igor A. Dyachenko Alexander V. Popov Yaroslav A. Andreev

One of the attractive targets for the relief of stress conditions is TRPV1, which is expressed mostly in primary afferent neurons (nociceptors) and in the central nervous system, mainly in the cortex and hippocampus. We evaluated the action of a potent low-molecular-weight antagonist of TRPV1 (AMG517) and peptide modulator of this channel (APHC3) on long-term potentiation (LTP) and Paired-Pulse Ratio (PPR) in the CA3-CA1 region of the hippocampus of mice. In vivo, we used intranasal administration to provide effective peptide delivery into the brain and analyzed the effects of APHC3 in acute stress tests in comparison with intramuscular administration of APHC3, AMG517, and the reference anxiolytic drug Fabomotizole (Fab). In electrophysiology studies, APHC3 significantly enhanced LTP and PPR, while AMG517 enhanced only PPR. Intranasal administration of APHC3 to mice provided a moderate anxiolytic effect in the single dose (0.01 mg/kg). Intramuscular administration of APHC3 and AMG517 significantly reduced acute stress in mice equal to the reference drug Fab. Thus, TRPV1 modulation in either the peripheral or central nervous system is sufficient to produce an anxiolytic-like effect, likely through distinct underlying mechanisms.

Marine Drugs doi: 10.3390/md24020058

Authors: Ria Desai Amane A. Alaroud Gagan Preet Rishi Vachaspathy Astakala Rainer Ebel Marcel Jaspars

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a leading global threat, escalated now by the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. In search of a novel anti-tubercular agent with a distinct mechanism of action, this study explores deep-sea marine metabolites as potential inhibitors of the F420-dependent oxidoreductase Rv1155, a redox enzyme essential for M. tb survival. A total of 2773 marine-derived compounds curated from the CMNPD, Reaxys, and MarinLit databases were screened using an integrated CADD workflow combining molecular docking, in-silico ADMET profiling, and molecular dynamics (MD) simulations. Docking identified 68 metabolites with strong affinity (−10.98 to −15.95 kcal/mol) for the Rv1155 binding pocket, and from which three compounds, Upenamide (CMNPD_22964), Aspyronol (Compound_1749), and Fiscpropionate F (Compound_1796), were shortlisted as hit candidates. Among these, Upenamide displayed the strongest binding (ΔG = −28.56 kcal/mol) with stable RMSD and hydrogen bond persistence during 100 ns MD simulation, while Aspyronol demonstrated a promising ADMET profile comparable to the native cofactor F4202. MM-GBSA analysis further confirmed the strong binding strength (ΔG _bind = −24.77 to −34.07 kcal/mol) for all three hit candidates. These findings confirm the strong and stable interaction of selected deep-sea marine metabolites with Rv1155. This validated screening pipeline established here provides a cost-effective framework for future experimental validation and expansion to additional F420-related drug targets in M. tb.

Marine Drugs doi: 10.3390/md24020057

Authors: Hiromi Kurokawa Makoto M. Watanabe

Sunlight exposure contributes to human health; however, excessive light exposure to skin, especially ultraviolet B (UV-B), can produce high amounts of reactive oxygen species (ROS) and induce inflammation. Some antioxidants, such as squalene, can prevent UV-B-induced inflammation. C34H58 botryococcene is the most common triterpene hydrocarbon produced by green alga Botryococcus braunii; it is biosynthesized via a pathway similar to squalene and appears to have a similar chemical structure to squalene. However, there are no reports on the bioactivity of botryococcene. In this study, we evaluated that botryococcene can prevent the skin photoaging. Using ESR assay, botryococcene could not scavenge any ROS. However, treatment of epidermis cells with the botryococcene significantly suppressed intracellular ROS production by hydrogen peroxide (H2O2) and attenuated H2O2 cytotoxicity. Botryococcene enhanced the antioxidant enzymes in gastric cells, thus botryococcene may scavenge ROS indirectly, not directly. Moreover, botryococcene inhibited production of intracellular interleukin-1 and exhibited suppression of melanogenesis activity by UV-B irradiation. Addition of botryococcene-treated epidermal cells culture medium mitigated the increase in matrix metalloproteinase-1 production and the decrease in type I collagen production induced by UV-B irradiation in dermis cells. These results showed that botryococcene has anti-photoaging effects, including preventing wrinkles and blemishes on the skin.

Marine Drugs doi: 10.3390/md24020056

Authors: Chathuri Kaushalya Marasinghe Kumju Youn Chi-Tang Ho Mira Jun

Cardiovascular diseases (CVDs) and Alzheimer’s disease (AD) are among the most prevalent chronic conditions, contributing significantly to global morbidity and healthcare burdens. These diseases are increasingly recognized as interconnected through shared mechanisms such as vascular dysfunction, oxidative stress, hypertension, and systemic inflammation, collectively referred to as the CVD-AD axis. Although therapeutic strategies exist for each condition, integrated approaches targeting these common pathways remain limited. This review highlights marine-derived bioactive peptides (BAPs) as multifunctional, sustainable agents for the simultaneous prevention of CVD and AD. It summarizes recent advances in their production, purification, and characterization, with emphasis on enzymatic hydrolysis and separation techniques. Marine BAPs exhibit diverse bioactivities, antioxidant, anti-inflammatory, lipid-lowering, antihypertensive, and neuroprotective, addressing key pathological mechanisms of the CVD-AD axis. Their small size, stability, and favorable safety profile support absorption and initial bioavailability, while sustainable sourcing from underutilized marine biomass enables eco-friendly production. Despite their potential, barriers to scalable production, product standardization, and regulatory approval remain; however, incremental advances are being made toward overcoming these issues. Together with these advances, marine BAPs remain promising candidates for functional foods and nutraceuticals, providing integrated preventive strategies for age-related diseases and supporting long-term cardiovascular and cognitive health.

Marine Drugs doi: 10.3390/md24020055

Authors: Yingxing Xie Siyu Wang Haofei Du Sihan Wu Wei Wu Guoying Qian Haomiao Ding Caisheng Wang

Fucoxanthin, a marine carotenoid abundantly derived from brown algae, has been increasingly recognized for its broad-spectrum antitumor activities; however, its role in regulating ferroptosis remains insufficiently defined. Hypopharyngeal carcinoma is a highly aggressive head and neck malignancy with limited therapeutic options, highlighting the need for novel marine-derived anticancer agents. In this study, we investigated whether fucoxanthin induces ferroptosis in human hypopharyngeal carcinoma cells (Fadu) and elucidated the underlying molecular mechanisms. Transcriptome profiling combined with in vitro validation revealed that fucoxanthin markedly upregulated heme oxygenase−1 (HO−1), leading to increased intracellular Fe2+ levels, excessive reactive oxygen species (ROS) generation, and pronounced lipid peroxide accumulation. Fucoxanthin simultaneously reduced cysteine and glutathione (GSH) levels, disrupted mitochondrial membrane potential, and triggered ferroptotic cell death, which was significantly reversed by the ferroptosis inhibitor ferrostatin−1. Mechanistically, fucoxanthin activated the p53 pathway while suppressing SLC7A11 and GPX4, thereby impairing antioxidant defenses. Pharmacological inhibition of p53 with Pifithrin−α markedly attenuated fucoxanthin-induced cytotoxicity and ferroptosis. Together, these findings identify fucoxanthin as a promising marine-derived compound capable of inducing ferroptosis via modulation of the p53/SLC7A11/GPX4 axis, providing new insights into its potential application in hypopharyngeal carcinoma therapy.

Marine Drugs doi: 10.3390/md24020054

Authors: Xingyu Gu Pengneng Yu Yuyang Li Rui Feng Dong Lv Zhuoran Song Tong Geng Yubo Qin Ying Li Zhibo Li Qiancheng Zhao

Sea cucumber polysaccharide is a kind of heteropolysaccharide rich in sulfate groups, which has complex structures and various biological activities. Its biological activity is closely related to its chemical composition, molecular weight, and sulfated patterns. Therefore, in order to study the biological activity of sea cucumber polysaccharide, the analysis methods of a sea cucumber polysaccharide structure were comprehensively summarized, and the neutral polysaccharide, fucosylated chondroitin sulfate, and sulfated fucan of sea cucumber were reviewed. The structural characteristics of sea cucumber polysaccharide were expected to provide a theoretical basis for subsequent studies on the biological activity and structure–activity relationship of sea cucumber polysaccharide.

Marine Drugs doi: 10.3390/md24010053

Authors: Kaloyan Berberov Ivanka Boyadzhieva Boryana Yakimova Hristina Petkova Ivanka Stoineva Lilyana Nacheva Lyudmila Kabaivanova

Biosurfactants produced by halophilic bacteria are gaining attention as eco-friendly and biocompatible alternatives to synthetic surfactants due to their high surface activity, stability under extreme conditions, and intrinsic antimicrobial properties. These amphiphilic biomolecules hold great promise for bioremediation, biomedical, and pharmaceutical applications. In this study, moderately halophilic bacteria capable of biosurfactant production were isolated from saline mud collected at the Burgas solar salterns (Bulgaria). The halophilic microbiota was enriched in Bushnell–Haas (BH) medium containing 10% NaCl amended with different carbon sources. Primary screening in BH liquid medium evaluated the isolates’ ability to degrade n-hexadecane while at the same time producing biosurfactants. Thirty halophilic bacterial strains were isolated on BH agar plates supplemented with 2% n-hexadecane, 2% olive oil, or 2% glycerol. Four isolates—BS7OL, BS8OL, BS9GL, and BS10HD—with strong emulsifying activity (E24 = 56%) and reduced surface tension in the range of 27.3–45 mN/m were derived after 7 days of batch fermentation. Strain BS10HD was chosen as the most potent biosurfactant producer. Its phylogenetic affiliation was determined by 16S rRNA gene sequence analysis; according to the nucleotide sequence, it was assigned to Halomonas ventosae. The extract material was analysed by thin-layer chromatography (TLC) and Fourier transform infrared spectroscopy (FTIR). Upon spraying the TLC plate with ninhydrin reagent, the appearance of a pink spot indicated the presence of amine functional groups. FTIR analysis showed characteristic peaks for both lipid and peptide functional groups. Based on the observed physicochemical properties and analytical data, it can be suggested that the biosurfactant produced by Halomonas ventosae BS10HD is a lipopeptide compound.

Marine Drugs doi: 10.3390/md24010052

Authors: Angeliki Barouti Vinh Le Ba Lars Herfindal Monica Jordheim

The epiphytic community of Laminaria hyperborea, dominated by red algae, is typically discarded during industrial processing despite its potential as a source of high-value natural products. This study aims to valorize this underutilized biomass by characterizing its secondary metabolites and evaluating the biological activities of its major bromophenols. A combined chromatographic workflow enabled the isolation and structural elucidation of five bromophenols (1–5), including one previously undescribed compound (5). Among these, compound 4 exhibited the strongest cytotoxicity against the acute myeloid leukemia (AML) cell line MOLM-13 (EC50 = 6.23 μM) and induced pronounced apoptotic features. When tested on two normal cell lines (NRK and H9c2) and in zebrafish larvae, it showed moderate toxicity at higher concentrations, indicating a reasonable selectivity window. In contrast, compound 5 was more toxic to normal cells than to MOLM-13 in vitro, while showing no acute toxicity in zebrafish; however, interpretations are preliminary due to compound purity. Bromophenols 1–4 were also tested for antioxidant activity, with 4 being the most potent (ABTS EC50 = 22.1 μM), although this did not translate into protection against doxorubicin-induced cardiotoxicity. Additionally, non-targeted UHPLC-QTOF MS/MS analysis tentatively identified nine additional bromophenols and provided an estimation of their origin species within the epiphytic assemblage.

Marine Drugs doi: 10.3390/md24010051

Authors: Xin Zhang Qihong Yang Le Zhou Yingying Chen Jianhua Ju Junying Ma

Three new pyrrole alkaloids, streptopyrroles D–F (1–3), along with four known analogs (4–7) were isolated from Sea Anemone-Associated Streptomyces sp. S1502 via an OSMAC (One Strain Many Compounds)-based strategy. Their structures were elucidated through comprehensive spectroscopic analyses, including HRESIMS and 1D/2D NMR experiments (COSY, HSQC, and HMBC), and further confirmed by X-ray crystallography. Biological evaluation identified streptopyrrole (4) as an anti-MRSA (methicillin-resistant Staphylococcus aureus) agent, while 4 and 6 displayed broad-spectrum cytotoxicity and good selectivity against a panel of human cancer cell lines. Notably, 4 and 6 showed particularly potent activity against the lung cancer cell lines H1299, SW1573, and A549, with IC50 values ranging from 5.43 to 16.24 μM. Further mechanistic investigation revealed that both compounds suppress the proliferation of lung cancer cells by inducing cell cycle arrest at the G0/G1 phase and impair metastatic potential by inhibiting migration and invasion. These findings not only expand the structural diversity of marine-derived pyrrole alkaloids but also reveal the anticancer mechanisms of 4 and 6, highlighting their promise as active candidates for further antitumor drug development, particularly in lung cancer.

Marine Drugs doi: 10.3390/md24010050

Authors: Jiansen Li Zhenfei Xu Zexuan Zhang Rui Liu Yuping Zhu Xiaoling Lu Huiying Xu Xiaoyu Liu Zhe Ning Xinyuan Wang Haobing Yu Bo Hu

In recent years, harmful algal blooms have led to frequent occurrences of shellfish toxin contamination, posing a significant threat to the safety of aquatic products and public health. As a potent neurotoxin, domoic acid (DA) can accumulate in shellfish, highlighting the urgent need for rapid and highly sensitive detection methods. In this study, we developed a fluorescent aptasensor based on a dual-signal amplification system by combining G-quadruplex (G4) dimers with multi-walled carbon nanotubes (CNTs). The sensor is designed with a hairpin-structured aptamer as the recognition probe, where short multi-walled CNTs serve as both a fluorescence quencher and platform, and G4 dimers are incorporated into the sensing interface to enhance signal output. In the absence of the target, the hairpin-structured aptamer remains closed, keeping the fluorescence signal “off”. Upon binding to DA, the aptamer undergoes a specific conformational change that exposes the G4-dimer sequence. The exposed sequence then binds to thioflavin T (ThT), which in turn generates a greatly enhanced fluorescence signal, leading to a substantial fluorescence enhancement and completing the second stage of the cascade amplification. Under optimal conditions, the constructed sensor achieves rapid detection of DA within 5 min, with a low detection limit of 1.1 ng/mL. This work presents a valuable tool for the rapid and sensitive detection of DA in shellfish, with promising applications in marine environmental monitoring and food safety regulation.

Marine Drugs doi: 10.3390/md24010049

Authors: Risako Chida Mamoru Takeda

Previous in vivo studies have clearly demonstrated that the intravenous administration of the carotenoid astaxanthin (AST) suppresses the excitability of rat trigeminal spinal nucleus caudalis (SpVc) neurons. This action is hypothesized to be mediated through the inhibition of both voltage-gated Ca2+ (Cav) channels and excitatory glutamate receptor transmission. The objective of this study was to determine whether acute intravenous administration of AST alleviates the hyperexcitability of SpVc wide dynamic range (WDR) neurons in a rat model of inflammation. Neuronal responses to both nociceptive and non-nociceptive mechanical stimulation were evaluated using an in vivo electrophysiological model. One day following inflammation induced by Complete Freund’s Adjuvant (CFA), the mechanical escape threshold was significantly reduced compared to pre-injection baseline values. Subsequently, extracellular single-unit recordings were performed on SpVc WDR neurons in anesthetized, inflamed rats. The neuronal responses to both non-noxious and noxious orofacial mechanical stimuli were then analyzed. Acute intravenous administration of AST at 1 and 5 mM elicited a dose-dependent reduction in the mean firing frequency of SpVc WDR neurons in response to noxious mechanical stimuli. This inhibition peaked within 10 min and was fully reversed after approximately 25 min. Importantly, AST preferentially inhibited the discharge frequency of SpVc WDR neurons in response to noxious stimulation, exhibiting a significantly greater effect than on the response evoked by non-noxious stimulation (41.5 ± 3.0% vs. 20.7 ± 4.2%, p < 0.05). Collectively, these findings demonstrate that acute intravenous administration of AST effectively suppresses noxious synaptic transmission within the SpVc during inflammation. We propose that this suppressive effect is mediated by the inhibition of upregulated Cav channels and glutamate receptors. Consequently, AST is implicated as a promising therapeutic candidate for the management of trigeminal inflammatory pain, given its potential for a favorable safety profile compared to conventional treatments.

Marine Drugs doi: 10.3390/md24010048

Authors: Xiao-Mei Liu Wen-Xuan Li Ling-Xiu Kong Guan-Ying Han Jinghan Gui Xu-Wen Li

The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven new derivatives (6–13) were synthesized based on an efficient biomimetic synthesis of sarocladione. Evaluation of their antiproliferative activities against human cancer cell lines demonstrated that the intact macrocyclic scaffold is indispensable for activity. Extension of the conjugated π-system led to the identification of compound 8, which exhibited approximately four-fold enhanced potency against HCT116 cells (IC50 = 1.86 µM) compared with the parent natural product. Stereochemical analysis further revealed the critical role of the (5R)-configuration at C-5. Phenotypic investigations indicated that compound 8 induces concentration-dependent G2/M phase cell cycle arrest, followed by apoptosis, suggesting a cell cycle-dependent antiproliferative effect. Overall, this study highlights sarocladione as a promising marine-derived scaffold for further antiproliferative optimization.

Marine Drugs doi: 10.3390/md24010047

Authors: Longhe Yang Yan Qiu Ying Liu Xiaoyu Wei Xiwen He Yiling Wang Yajun Yan Kaikai Bai Zhaokai Wang Jie Ren

Marine-derived fungi have become a vital resource for the discovery of novel secondary metabolites with diverse structures and significant biological activities. This study focuses on a systematic chemical investigation of the sponge-associated fungus Talaromyces stipitatus HF05001, leading to the isolation and identification of 20 compounds, including one new marine ketal natural product (Compound 17, Talarobispiral A). These compounds were structurally elucidated using comprehensive spectroscopic analyses, including 1D and 2D NMR, HRESIMS. All isolates were screened for their anti-inflammatory and anti-adipogenic properties. Among them, compound 4 (Secalonic acid D, SAD), 7 (Sch 725680) and 16 (bacillisporins C) demonstrated significant anti-inflammatory potential by markedly suppressing nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Notably, compound 4 showed superior inhibitory effect, with an IC50 value of 0.22 μM. Additionally, compound 4 exhibited the strongest dose-dependent inhibition of lipid droplet accumulation in 3T3-L1 preadipocytes. These findings highlight the dual therapeutic potential of metabolites from Talaromyces stipitatus, identifying promising lead compounds for the development of novel treatments for inflammatory and metabolic disorders.

Marine Drugs doi: 10.3390/md24010046

Authors: Mariele Staropoli Theresa Schwaiger Jasmina Tuzlak Renata Biba Lukas Petrowitsch Johannes Fessler Marin Roje Matteo Cammarata Nermina Malanović Andreja Jakas

Equinin B (GQCQRKCLGHCSKKCPKHPQCRKRCIRRCFGYCL), a marine peptide from Actinia equina exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria. To identify a smaller active region and explore tunable properties, three peptide fragments were synthesized: GQCQRKCLGHCS (EB1), KKCPKHPQCRK (EB2), and RCIRRCFGYCL (EB3), yielding peptides with key AMP-like properties, including the most positively charged and most hydrophobic regions. Only the 11-residue C-terminal fragment showed selective activity against Gram-positive bacteria, including Staphylococcus epidermidis, Bacillus subtilis, and Enterococcus hirae, while remaining inactive against Escherichia coli. Peptide modifications, achieved by replacing cysteine residues with arginine, generally did not enhance activity, but in the C-terminal fragment EB3 they reduced hemolytic activity and increased bacterial specificity. Membrane depolarization assays confirmed that the unmodified fragment EB3 strongly compromises bacterial membranes, whereas the modified variant showed minimal depolarization, highlighting its markedly reduced membrane-perturbing potential. In silico modelling revealed that the EB3 can adopt multiple membrane-disruption modes, from transient shallow pores to carpet-like mechanisms, while the cysteine-to-arginine variant interacts mainly via partial insertion anchored by arginine residues. Phenylalanine appears to interact with the membrane, and reducing hydrophobicity by its removal abolished antibacterial activity. These findings highlight the 11-residue C-terminal fragment as a tunable, membrane-targeting motif with mechanistic novelty, offering a blueprint for developing safer, selective antimicrobial peptides with reduced cytotoxicity.

Marine Drugs doi: 10.3390/md24010045

Authors: Dan Pu Hongwei Tao Jingwei Pang Huishao Shi Junjian Wang Wei Zhang

The misuse of antibacterial agents has contributed to the growing prevalence of antibiotic resistance, highlighting an urgent need to explore alternative anti-infection therapeutic strategies. Antimicrobial peptides (AMPs) are naturally occurring molecules. They exhibit broad-spectrum antimicrobial activity and represent promising candidates for the development of novel therapeutics. A cysteine-rich antimicrobial peptide was identified and characterized from the genome of Tigriopus japonicus and designated “TjRcys1”. The precursor form of TjRcys1 comprises 96 amino acids. Structural analyses of TjRcys1 revealed random coils, two α-helices, and two β-strands. Recombinant TjRcys1 had inhibitory effects upon Staphylococcus aureus and Bacillus sp. T2, with a minimum inhibitory concentration of 64 μM for both. TjRcys1 did not show complete inhibition against Vibrio alginolyticus, Klebsiella pneumoniae, or Aeromonas hydrophila at 64 μM, but it did slow their growth rate. TjRcys1 could disrupt the permeability of the cell membrane of S. aureus. Transcriptomic analyses indicated that TjRcys1 could interfere with the ribosome biosynthesis and nucleotide metabolism of K. pneumoniae. Our results provide a valuable reference for the development of new AMPs and optimization of their design.

Marine Drugs doi: 10.3390/md24010044

Authors: Céphas Xuma Alexandre Bourles Julien Colot Linda Guentas Mariko Matsui

Staphylococcus aureus is a major opportunistic pathogen responsible for a wide spectrum of human infections, including severe and difficult-to-treat cases. The emergence of multidrug-resistant strains limits the efficacy of conventional antibiotic therapies and poses a significant global public health challenge. In this context, the search for novel antibiotics has intensified, with increasing interest in marine resources, an ecosystem still largely underexplored. Marine bacteria produce a vast array of secondary metabolites with unique structures and potentially novel modes of antibacterial action. Several compounds isolated from marine bacterial strains have demonstrated promising activity against multidrug-resistant S. aureus, including antivirulence effects such as biofilm formation and Quorum-Sensing inhibition. This review explores the potential of marine bacteria as a source of new antibiotics against S. aureus, discusses both classical and advanced strategies for the discovery of bioactive molecules, and highlights the scientific and technological challenges involved in translating these findings into clinical applications.