Marine Drugs

23 pages, 1536 KB

Open AccessReview

Insights into the Bioactivities and Mechanism of Action of the Microbial Diketopiperazine Cyclic Dipeptide Cyclo(L-leucyl-L-prolyl)

by Christian Bailly

Mar. Drugs 2025, 23(10), 397; https://doi.org/10.3390/md23100397 - 9 Oct 2025

Abstract

Diketopiperazines (DKPs) are biologically important cyclic dipeptides widespread in nature, associated primarily with microorganisms. This is the case for the 2,5-DKP derivative cyclo(L-Leu-L-Pro) (cLP), also known as gancidin W or PPDHMP, identified from a variety of bacteria and fungi, and occasionally found in [...] Read more.

Diketopiperazines (DKPs) are biologically important cyclic dipeptides widespread in nature, associated primarily with microorganisms. This is the case for the 2,5-DKP derivative cyclo(L-Leu-L-Pro) (cLP), also known as gancidin W or PPDHMP, identified from a variety of bacteria and fungi, and occasionally found in food products. The present review retraces the discovery of cLP, its identification in living species, its chemical syntheses, and its biochemical properties. In bacteria, cLP is often associated with other DKPs to serve as a defense element against other microorganisms and/or as a regulator of bacterial growth. cLP plays a role in quorum-sensing and functions as an anticariogenic and antifungal agent. The antimicrobial mechanism of action and molecular targets of cLP are evoked. The interest in cLP for combatting certain parasitic diseases, such as malaria, and cancers is discussed. The capacity of cLP to interact with CD151 and to down-regulate the expression of this tetraspanin can be exploited to reduce tumor dissemination and metastases. The review sheds light on the pharmacology and specific properties of cyclo(L-Leu-L-Pro), which can be useful for the development of a novel therapeutic approach for different human pathologies. It is also of interest to help define the bioactivity and mechanisms of action of closely related DKP-based natural products. Full article

(This article belongs to the Section Marine Pharmacology)

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36 pages, 1058 KB

Open AccessSystematic Review

Functionalization Strategies of Chitosan-Based Scaffolds with Growth Factors for Bone Regeneration: A Systematic Review

by Jan Kiryk, Mateusz Michalak, Zuzanna Majchrzak, Marzena Laszczyńska, Sylwia Kiryk, Sylwia Szotek, Hanna Gerber, Izabela Nawrot-Hadzik, Jacek Matys and Maciej Dobrzyński

Mar. Drugs 2025, 23(10), 396; https://doi.org/10.3390/md23100396 - 9 Oct 2025

Abstract

Bioactive agents can stimulate osteogenesis, angiogenesis, and cell proliferation; therefore, their application in bone regeneration offers significant therapeutic potential. The aim of this systematic review was to evaluate strategies for applying chitosan-based scaffolds with growth factors in bone regeneration. A structured literature search [...] Read more.

Bioactive agents can stimulate osteogenesis, angiogenesis, and cell proliferation; therefore, their application in bone regeneration offers significant therapeutic potential. The aim of this systematic review was to evaluate strategies for applying chitosan-based scaffolds with growth factors in bone regeneration. A structured literature search was conducted in July 2025 across the PubMed, Scopus, and Web of Science databases. Search terms included combinations of (chitosan scaffold) AND (growth factor OR BMP-2 OR VEGF OR FGF OR TGF-beta OR periostin OR PDGF OR IGF-1 OR EGF OR ANG-1 OR ANG-2 OR GDF-5 OR SDF-1 OR osteopontin). The study selection process followed PRISMA 2020 guidelines and the PICO framework. Out of 367 records, 226 were screened, and 17 studies met the eligibility criteria for qualitative analysis. BMP-2 was the most frequently investigated growth factor, studied in both in vitro and in vivo models, with rats and rabbits as the most common animal models. Scaffold compositions varied, incorporating hydroxyapatite, heparin, polyethylene glycol diacrylate, octacalcium phosphate-mineralized graphene, silk fibroin, and aloe vera. Growth factors were introduced using diverse methods, including microspheres, chemical grafting, covalent coupling, protein carriers, and nanohydroxyapatite mesopores. Most studies reported enhanced bone regeneration, although differences in models, scaffold composition, and delivery methods preclude definitive conclusions. The addition of growth factors generally improved osteoblast proliferation, angiogenesis, bone density, and expression of osteogenic markers (RunX2, COL1, OPN, OCN). Combining two bioactive agents further amplified osteoinduction and vascularization. Sustained-release systems, particularly those using heparin or hydroxyapatite, prolonged biological activity and improved regenerative outcomes. In conclusion, functionalization of chitosan-based scaffolds with growth factors shows promising potential for bone regeneration. Controlled-release systems and combinations of different bioactive molecules may offer synergistic effects on osteogenesis and angiogenesis. Further research should focus on optimizing scaffold compositions and delivery methods to tailor bioactive agent release for specific clinical applications. Full article

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

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18 pages, 1349 KB

Open AccessArticle

Enzymatic Spirulina Extract Enhances the Vasodilation in Aorta and Mesenteric Arteries of Aged Rats

by Michal S. Majewski, Mercedes Klett-Mingo, Carlos M. Verdasco-Martín, Cristina Otero and Mercedes Ferrer

Mar. Drugs 2025, 23(10), 395; https://doi.org/10.3390/md23100395 - 8 Oct 2025

Abstract

Aging, one of the main factors associated with cardiovascular diseases, induces vascular modifications through nitric oxide (NO) release and oxidative stress. Based on the antioxidant properties of the non-enzymatic spirulina extract (non-Enz-Spir-E) and that degrading enzymes enhances the extract bioactivity, the aim of [...] Read more.

Aging, one of the main factors associated with cardiovascular diseases, induces vascular modifications through nitric oxide (NO) release and oxidative stress. Based on the antioxidant properties of the non-enzymatic spirulina extract (non-Enz-Spir-E) and that degrading enzymes enhances the extract bioactivity, the aim of this study was to analyze the in vitro effect of an Alcalase-assisted Enz-Spir-E on the vasodilator function of conduit and resistance arteries (which differently contribute to blood pressure regulation) in aging. Therefore, thoracic aorta (TA) and mesenteric arteries (MA) from male Sprague–Dawley rats (20–22 months-old) were divided into two groups: non-incubated vessels and vessels exposed to Enz-Spir-E (0.1% w/v) for 3 h. The vasodilation to acetylcholine (ACh), sodium nitroprusside (SNP, a NO donor), carbon-monoxide-releasing molecule (CORM), and cromakalim (a potassium channel opener), as well as NO and superoxide anion production, were studied. Enz-Spir-E increased the ACh-, SNP-, and CORM-induced responses in both types of arteries, while the cromalakim-induced relaxation was increased only in MA. Enz-Spir-E increased NO release (TA: 5.69-fold; MA: 1.79-fold), while it reduced superoxide anion formation (TA: 0.52-fold; MA: 0.66-fold). These results indicate that Enz-Spir-E improves aging-associated vasodilation through increasing NO release/bioavailability in both types of arteries and hyperpolarizing mechanisms only in MA. Full article

(This article belongs to the Special Issue Marine Antioxidants 2025)

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19 pages, 2759 KB

Open AccessArticle

Carbon-Source Effects on Growth and Secondary Metabolism in the Marine Bacteroidota Tenacibaculum mesophilum and Fulvivirga kasyanovii

by Luis Linares-Otoya, Virginia Linares-Otoya, Gladys Galliani-Huamanchumo, Terecita Carrion-Zavaleta, Jose Condor-Goytizolo, Till F. Schäberle, Mayar L. Ganoza-Yupanqui and Julio Campos-Florian

Mar. Drugs 2025, 23(10), 394; https://doi.org/10.3390/md23100394 - 4 Oct 2025

Abstract

Marine Bacteroidota are recognized bacterial producers of bioactive metabolites, yet their biosynthetic potential remains cryptic under standard laboratory conditions. Here, we developed chemically defined media for Fulvivirga kasyanovii 48LL (Cytophagia) and Tenacibaculum mesophilum fLL (Flavobacteriia) to evaluate the effect of environmentally relevant carbon [...] Read more.

Marine Bacteroidota are recognized bacterial producers of bioactive metabolites, yet their biosynthetic potential remains cryptic under standard laboratory conditions. Here, we developed chemically defined media for Fulvivirga kasyanovii 48LL (Cytophagia) and Tenacibaculum mesophilum fLL (Flavobacteriia) to evaluate the effect of environmentally relevant carbon sources on growth and secondary metabolism. F. kasyanovii utilized 31 of 34 tested carbon sources whereas T. mesophilum grew on only five substrates, underscoring a distinct nutritional preferences. Substrate significantly influenced the antibacterial activity of F. kasyanovii extracts. Growth on β-1,3-glucan, glycerol, poly(β-hydroxybutyrate) (PHB), fish gelatin, or pectin resulted in extracts generating the largest inhibition zones (10–13 mm) against Bacillus subtilis or Rossellomorea marisflavi. Genome analysis revealed F. kasyanovii to be enriched in biosynthetic gene clusters (BGCs), notably harboring a ~570 kb genomic island comprising five large NRPS/PKS-type clusters. Quantitative PCR confirmed carbon-source-dependent regulation of these operons: glucose induced BGC1, BGC3, and BGC4, while κ-carrageenan and PHB upregulated BGC2. Conversely, yeast–peptone medium (analogous to standard marine broth) repressed transcription across all active clusters. These findings demonstrate that naturally occurring carbon sources can selectively activate cryptic BGCs and modulate antibacterial activity in F. kasyanovii, suggesting that similar strategy can be used for natural-product discovery in marine Bacteroidota. Full article

(This article belongs to the Special Issue Fermentation Processes for Obtaining Marine Bioactive Products)

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19 pages, 1165 KB

Open AccessArticle

In Vitro Antioxidant and Antidiabetic Effects of Atlantic Mackerel and Sardine By-Product Hydrolysates

by Cristina Fuentes, Samuel Verdú, Raúl Grau, José Manuel Barat and Ana Fuentes

Mar. Drugs 2025, 23(10), 393; https://doi.org/10.3390/md23100393 - 4 Oct 2025

Abstract

This work evaluates the effect of raw material and protease enzymes on the antioxidant and antidiabetic potential of fish by-product hydrolysates. For this, mackerel (Scomber scombrus) and sardine (Sardina pilchardus) by-products were hydrolyzed using papain, pepsin, and Protamex^TM [...] Read more.

This work evaluates the effect of raw material and protease enzymes on the antioxidant and antidiabetic potential of fish by-product hydrolysates. For this, mackerel (Scomber scombrus) and sardine (Sardina pilchardus) by-products were hydrolyzed using papain, pepsin, and Protamex^TM. Pepsine produced hydrolysates with a lower degree of hydrolysis (34%) and longer peptide chain lengths (2.9), regardless of the raw material. The highest DH was found for the sardine by-products hydrolyzed with papain and Protamex^TM, exceeding 55% for both enzymes. The mackerel by-product hydrolysates exhibited higher antioxidant activity, while the sardine samples showed more potent antidiabetic effects. Accordingly, sardine by-products and pepsin would be preferable for producing hydrolysates with antidiabetic potential, and mackerel by-products, hydrolyzed papain, and Protamex^TM would be useful for producing antioxidant peptides. This study demonstrates the potential of Atlantic mackerel and sardine waste as a source of bioactive peptides and the opportunity for revalorizing these by-products. Full article

(This article belongs to the Special Issue High-Value-Added Resources Recovered from Marine By-Products)

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22 pages, 2754 KB

Open AccessArticle

Purification, Identification, and In Silico Analysis of Anti-Obesity and Antidiabetic Peptides from the Red Seaweed Palmaria palmata

by Sakhi Ghelichi, Mona Hajfathalian, Seyed Hossein Helalat, Birte Svensson and Charlotte Jacobsen

Mar. Drugs 2025, 23(10), 392; https://doi.org/10.3390/md23100392 - 3 Oct 2025

Abstract

This study investigates the anti-obesity and antidiabetic potential of P. palmata extracts produced through sequential enzymatic and alkaline treatments. Among the treatment groups, the extract treated solely with Alcalase^® (Alc) demonstrated the highest protein content (10.11 ± 0.15%) and degree of hydrolysis [...] Read more.

This study investigates the anti-obesity and antidiabetic potential of P. palmata extracts produced through sequential enzymatic and alkaline treatments. Among the treatment groups, the extract treated solely with Alcalase^® (Alc) demonstrated the highest protein content (10.11 ± 0.15%) and degree of hydrolysis (30.36 ± 0.77%), significantly outperforming other treatments (p < 0.05). The Alc extract also exhibited superior inhibitory activity against porcine pancreatic lipase and α-amylase, achieving the lowest IC₅₀ for lipase (2.29 ± 0.87 mg.mL⁻¹) and showing significant enzyme inhibition across all tested concentrations (p < 0.05). Ultrafiltration of the Alc extract revealed that peptide fractions < 1 kDa and 1–3 kDa were most effective in enzyme inhibition, with IC₅₀ values of 3.25–3.55 mg.mL⁻¹ for both lipase and α-amylase. Peptides were identified via LC-MS/MS analysis and database searching using SequestHT, resulting in 536 sequences, of which bioinformatic screening yielded 51 non-toxic, non-allergenic candidates (PeptideRanker score > 0.6); four of these contained known inhibitory motifs for lipase and α-amylase. Molecular docking confirmed strong binding affinities between these peptides and their respective enzymes, supporting their potential as natural enzyme inhibitors. These findings indicate the functional food potential of Alcalase^®-derived P. palmata peptides for managing obesity and type 2 diabetes. Full article

(This article belongs to the Special Issue Marine Algae as Functional Foods)

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20 pages, 4119 KB

Open AccessArticle

The Effect of Ultraviolet Light Irradiation on Pigment Performance in Microwave-Assisted Extraction of Arthrospira platensis

by Anna Trubetskaya, Roland Haseneder, Maximilian Lippold, Rob J. F. van Haren, Volker Herdegen, Lisa Ditscherlein, James J. Leahy, Italo Pisano, Yvonne Joseph, Carla Vogt and Jan Zuber

Mar. Drugs 2025, 23(10), 391; https://doi.org/10.3390/md23100391 - 30 Sep 2025

Abstract

Phycocyanin, a blue pigment from Arthrospira platensis, is widely used as a natural colorant in food products, but its application is limited by its sensitivity to light and temperature during extraction and storage. This study explored the impact of UV light on [...] Read more.

Phycocyanin, a blue pigment from Arthrospira platensis, is widely used as a natural colorant in food products, but its application is limited by its sensitivity to light and temperature during extraction and storage. This study explored the impact of UV light on phycocyanin extracted from A. platensis using a microwave-assisted method. Water proved to be the most effective solvent, yielding the highest phycocyanin concentration and stability. The optimal extraction conditions to avoid phycocyanin degradation were identified as 45 °C and 100 W of microwave power. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) analysis revealed increased chemical complexity at higher temperatures and identified biopterin–pentoside complexes, which enhanced phycocyanin stability during UV degradation. These findings provide new insights into the molecular mechanisms of interactions between phycocyanin and proteins, enhancing phycocyanin stability and functionality and thus providing food products with longer shelf lives by maintaining their nutritional and aesthetic qualities. Full article

(This article belongs to the Special Issue Bioactive Metabolites Produced by Marine Cyanobacteria and Other Microalgae)

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21 pages, 10082 KB

Open AccessArticle

Ulvan-Na, an Ulvan Subjected to Na⁺ Cation Exchange, Improves Intestinal Barrier Function in Age-Related Leaky Gut

by Yuka Maejima, Yuki Morioka, Yusei Sato, Masanori Hiraoka, Ayumu Onda and Takushi Namba

Mar. Drugs 2025, 23(10), 390; https://doi.org/10.3390/md23100390 - 30 Sep 2025

Abstract

The global increase in life expectancy underscores the need to promote healthy aging, particularly by addressing age-related leaky gut syndrome, which contributes to systemic inflammation and chronic disease. This study focused on the sustainable production and functional development of Ulva meridionalis, a [...] Read more.

The global increase in life expectancy underscores the need to promote healthy aging, particularly by addressing age-related leaky gut syndrome, which contributes to systemic inflammation and chronic disease. This study focused on the sustainable production and functional development of Ulva meridionalis, a fast-growing seaweed, to improve gut health and mitigate the effects of aging. Using land-based aquaculture, a scalable cultivation system for U. meridionalis was established, and its polysaccharide, ulvan, was extracted. Ion exchange treatment enhanced the functionality of ulvan to produce ulvan-Na, which contains high levels of Na⁺ and conveys superior anti-aging properties. Ulvan-Na restored intestinal barrier integrity in aged mice by reducing serum LPS levels and increasing claudin-1 expression. Ulvan-Na modulated the gut microbiota, increasing beneficial bacteria such as Clostridiales vadin BB60 and suppressing inflammatory bacteria such as Turicibacter. The mechanism was clarified whereby ulvan-Na activates β-catenin to enhance claudin-1 expression. These findings highlight ulvan-Na as a bioactive compound that ameliorates age-related intestinal dysfunction while demonstrating the feasibility of sustainable U. meridionalis production for functional food innovation and environmental conservation. Full article

(This article belongs to the Section Marine-Derived Ingredients for Drugs, Cosmeceuticals and Nutraceuticals)

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15 pages, 488 KB

Open AccessReview

Marine-Derived Ligands of Nicotinic Acetylcholine Receptors in Cancer Research

by Igor E. Kasheverov, Irina V. Shelukhina, Yuri N. Utkin and Victor I. Tsetlin

Mar. Drugs 2025, 23(10), 389; https://doi.org/10.3390/md23100389 - 30 Sep 2025

Abstract

Marine sources contain compounds that act on a wide variety of systems, including ligand-gated ion channels. This review will focus on the effectors of nicotinic acetylcholine receptors (nAChRs), for which the diversity of ligands and modulators from marine sources is determined mainly by [...] Read more.

Marine sources contain compounds that act on a wide variety of systems, including ligand-gated ion channels. This review will focus on the effectors of nicotinic acetylcholine receptors (nAChRs), for which the diversity of ligands and modulators from marine sources is determined mainly by neurotoxic peptides (α-conotoxins) from mollusks of the Conus genus. These are very selective compounds that allow the study of the role of different nAChR subtypes in the cancer cells. They have analgesic or anti-inflammatory activities associated with cholinergic transmission and have shown analgesic effect in case of chemotherapy-induced neuropathic pain. Another class of marine compounds targeting nAChRs for which cytotoxicity for cancer cells was shown is represented by low molecular organic substances found mostly in dinoflagellates and marine sponges. Some of the compounds discussed in this review show promise for developing drugs that suppress cancer growth. Full article

(This article belongs to the Section Marine Pharmacology)

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17 pages, 1247 KB

Open AccessArticle

Nemertide Alpha-1 as a Biopesticide: Aphid Deterrence, Antimicrobial Activity, and Safety Aspects

by Quentin Laborde, Katarzyna Dancewicz, Erik Jacobsson, Adam A. Strömstedt, Taj Muhammad, Camilla Eriksson, Blazej Slazak, Ulf Göransson and Håkan S. Andersson

Mar. Drugs 2025, 23(10), 388; https://doi.org/10.3390/md23100388 - 29 Sep 2025

Abstract

Aphid control often relies on synthetic pesticides, but their overuse has raised concerns about resistance development and negative impact on wildlife and human health. Consequently, the search for new biopesticide agents has gained significant attention. Nemertide alpha-1, a peptide toxin from the marine [...] Read more.

Aphid control often relies on synthetic pesticides, but their overuse has raised concerns about resistance development and negative impact on wildlife and human health. Consequently, the search for new biopesticide agents has gained significant attention. Nemertide alpha-1, a peptide toxin from the marine nemertean worm Lineus longissimus (Gunnerus, 1770), is known for its pesticide activity but has less documented biological safety. This study investigates the aphid feeding deterrence and biological safety of the experimental biopesticide nemertide alpha-1. Nemertide alpha-1 demonstrated a clear dose-dependent repellent effect on the penetration behaviour of the green peach aphid (Myzus persicae, Sulzer). It also demonstrates bacteriostatic and bactericidal effects in an MIC (Minimum Inhibitory Concentration) assay, respectively, on E. coli (MIC: 112.5 µM) and S. aureus (MIC: 28.4 µM). In a bacterial liposome leakage assay, nemertide alpha-1 exhibits a less pronounced effect than the melittin control (20% maximum leakage at 100 µM), strengthening the hypothesis on the specificity of its neurotoxic mode of action. It is not toxic to mammalian cell U-937 GTB with only a slight decline in the percentage of survival at the highest concentration tested (80 µM). Finally, nemertide alpha-1 displays thermal stability over time for four weeks in three different conditions: cold (6 °C), room temperature (20–24 °C), and physiological temperature (37 °C). Nemertide alpha-1 deters green peach aphid feeding in the low micromolar range and exhibits low antimicrobial properties and very low toxicity to human cells. Its potential utility is further underscored by thermal stability over time. Full article

(This article belongs to the Topic Research on Natural Bioactive Product-Based Pesticidal Agents—2nd Edition)

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16 pages, 1430 KB

Open AccessArticle

Structural Elucidation and Antiviral Activity Evaluation of Novelly Synthesized Guaiazulene Derivatives

by Canling Cheng, Lei Hou, Xuli Tang and Guoqiang Li

Mar. Drugs 2025, 23(10), 387; https://doi.org/10.3390/md23100387 - 28 Sep 2025

Abstract

A series of guaiazulene derivatives were efficiently synthesized by one-step reaction using guaiazulene as the substrate. Their structures were fully characterized by comprehensive spectroscopic methods, and their antiviral activities against influenza A (H1N1) virus were evaluated. Compounds 2b, 2d, 2e, [...] Read more.

A series of guaiazulene derivatives were efficiently synthesized by one-step reaction using guaiazulene as the substrate. Their structures were fully characterized by comprehensive spectroscopic methods, and their antiviral activities against influenza A (H1N1) virus were evaluated. Compounds 2b, 2d, 2e, 2f, 3a, and 3b exhibited significant anti-influenza activity, with IC₅₀ values of 89.03 µM, 98.48 µM, 78.38 µM, 108.20 µM, 50.96 µM, and 56.09 µM, respectively. Ribavirin was used as a positive control (IC₅₀ = 130.22 µM). Full article

(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)

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41 pages, 18792 KB

Open AccessArticle

A Robust Marine Collagen Peptide–Agarose 3D Culture System for In Vitro Modeling of Hepatocellular Carcinoma and Anti-Cancer Therapeutic Development

by Lata Rajbongshi, Ji-Eun Kim, Jin-Eui Lee, Su-Rin Lee, Seon-Yeong Hwang, Yuna Kim, Young Mi Hong, Sae-Ock Oh, Byoung Soo Kim, Dongjun Lee and Sik Yoon

Mar. Drugs 2025, 23(10), 386; https://doi.org/10.3390/md23100386 - 27 Sep 2025

Abstract

The development of physiologically relevant three-dimensional (3D) culture systems is essential for modeling tumor complexity and improving the translational impact of cancer research. We established a 3D in vitro model of human hepatocellular carcinoma (HCC) using a marine collagen peptide-based (MCP-B) biomimetic hydrogel [...] Read more.

The development of physiologically relevant three-dimensional (3D) culture systems is essential for modeling tumor complexity and improving the translational impact of cancer research. We established a 3D in vitro model of human hepatocellular carcinoma (HCC) using a marine collagen peptide-based (MCP-B) biomimetic hydrogel scaffold optimized for multicellular spheroid growth. Compared with conventional two-dimensional (2D) cultures, the MCP-B hydrogel more accurately recapitulated native tumor biology while offering simplicity, reproducibility, bioactivity, and cost efficiency. HCC cells cultured in MCP-B hydrogel displayed tumor-associated behaviors, including enhanced proliferation, colony formation, migration, invasion, and chemoresistance, and enriched cancer stem cell (CSC) populations. Molecular analyses revealed upregulated expression of genes associated with multidrug resistance; stemness regulation and markers; epithelial–mesenchymal transition (EMT) transcription factors, markers, and effectors; growth factors and their receptors; and cancer progression. The spheroids also retained liver-specific functions, suppressed apoptotic signaling, and exhibited extracellular matrix remodeling signatures. Collectively, these findings demonstrate that the 3D HCC model using MCP-B hydrogel recapitulates key hallmarks of tumor biology and provides a robust, physiologically relevant platform for mechanistic studies of HCC and CSC biology. This model further holds translational value for preclinical drug screening and the development of novel anti-HCC and anti-CSC therapeutics. Full article

(This article belongs to the Special Issue Marine Collagen: From Biological Insights to Biomedical Breakthroughs)

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20 pages, 3628 KB

Open AccessArticle

A Stable Delivery System for Meretrix meretrix Derived Immunomodulatory Peptide (QLNWD): Fabrication and Characterization of Glycosylated Protein Nanoparticle

by Wanyi Wu, Zhixuan Wu, Jiamin Cai, Wenhong Cao, Haisheng Lin, Jialong Gao, Xiuping Fan, Huina Zheng and Xiaoming Qin

Mar. Drugs 2025, 23(10), 385; https://doi.org/10.3390/md23100385 - 27 Sep 2025

Abstract

In this study, nanoparticles prepared by the heat-induced self-assembly of bovine serum albumin-dextran conjugates (BSA-DX) were utilized as an effective delivery system for the immunoregulatory peptide Gln-Leu-Asn-Trp-Asp (QLNWD) from Meretrix meretrix. The effects of dry-heating duration on the fabrication and characteristics of [...] Read more.

In this study, nanoparticles prepared by the heat-induced self-assembly of bovine serum albumin-dextran conjugates (BSA-DX) were utilized as an effective delivery system for the immunoregulatory peptide Gln-Leu-Asn-Trp-Asp (QLNWD) from Meretrix meretrix. The effects of dry-heating duration on the fabrication and characteristics of glycoprotein nanoparticles (GBA NPs) were investigated. Stable GBA NPs (110.84 nm) were obtained after 9 h of dry-heating. Depending on the addition sequence of QLNWD, the QLNWD-loaded nanoparticles were categorized into two types: pre-loading and post-loading. The two strategies were evaluated based on physicochemical characterization, colloidal stability, and RAW264.7 macrophage uptake. Results showed that upon QLNWD incorporation, both pre-loading NPs and post-loading NPs exhibited spherical morphology, with particle sizes decreasing to 105.51 nm and 94.27 nm, respectively. The encapsulation efficiency of pre-loading NPs for QLNWD was higher (87.74%), and the co-localization ability between post-loading NPs and QLNWD was stronger (Pearson’s correlation coefficient = 0.95). In vitro simulated gastrointestinal digestion experiments showed that QLNWD bioaccessibility increased to 47.5% and 42.7% for pre-loaded and post-loaded NPs, respectively. Compared to free QLNWD, NP encapsulation significantly enhanced the uptake of QLNWD by macrophages. Thus, GBA NPs, particularly those prepared by the pre-loading method, are considered promising delivery systems for marine bioactive peptides. Full article

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26 pages, 4285 KB

Open AccessReview

Progress in the Application of Marine Polysaccharide Drug Delivery Systems in Tumor Immunotherapy: Multiple Mechanisms and Material Forms

by Mingxue Cha, Shuqiang Yan, Yiping Zhang and Peipei Wang

Mar. Drugs 2025, 23(10), 384; https://doi.org/10.3390/md23100384 - 27 Sep 2025

Abstract

Tumor immunotherapy, a revolutionary cancer treatment, is hindered by inadequate immune cell activation, immunosuppressive tumor microenvironment (TME), and off-target toxicities of immunotherapeutics. These bottlenecks necessitate innovative strategies to enhance efficacy and reduce side effects. Marine polysaccharides have garnered significant attention due to their [...] Read more.

Tumor immunotherapy, a revolutionary cancer treatment, is hindered by inadequate immune cell activation, immunosuppressive tumor microenvironment (TME), and off-target toxicities of immunotherapeutics. These bottlenecks necessitate innovative strategies to enhance efficacy and reduce side effects. Marine polysaccharides have garnered significant attention due to their potential to enhance immune cell activity and regulate the tumor microenvironment, among other benefits. Due to their excellent biocompatibility, modifiability, and relatively low cost, polysaccharides are increasingly being explored as materials for drug delivery systems. The development of marine polysaccharide-based drug delivery systems represents an opportunity for advancing tumor immunotherapy. This review focuses on the application of marine polysaccharide drug delivery systems in tumor immunotherapy, exploring the mechanisms underlying the bioactivity of marine polysaccharides, the design of drug delivery systems, and the interactions between these systems and tumor immunotherapy, aiming to provide a framework for advancing marine polysaccharide-based therapeutics, accelerating the clinical translation of effective, safe, and targeted tumor immunotherapy strategies. Full article

(This article belongs to the Special Issue Marine-Derived Polymers for Tissue Engineering and Drug Delivery Applications)

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22 pages, 2771 KB

Open AccessArticle

Sustainable and Integral Valorization of Dosidicus gigas Pen Waste: Combined Production of Chitosan with Antibacterial Properties and Human and Marine Probiotics

by Marta Lima, Adrián Pedreira, Noelia Sanz, José Antonio Vázquez, Míriam R. García, Filipe Mergulhão and Jesus Valcarcel

Mar. Drugs 2025, 23(10), 382; https://doi.org/10.3390/md23100382 - 27 Sep 2025

Abstract

This study details a biorefinery approach to valorize Dosidicus gigas squid pen waste. The process starts with the enzymatic deproteinization of squid pens, which prove effective with both Alcalase and Novozym, with the latter exhibiting a slightly higher efficiency to yield a material [...] Read more.

This study details a biorefinery approach to valorize Dosidicus gigas squid pen waste. The process starts with the enzymatic deproteinization of squid pens, which prove effective with both Alcalase and Novozym, with the latter exhibiting a slightly higher efficiency to yield a material with 73% chitin content. Subsequent alkaline hydrolysis produces highly deacetylated chitosan (>90% degree of deacetylation), followed by controlled depolymerization to obtain polymers with molecular weights ranging from 50 to 251 kDa. Both native and depolymerized chitosan exhibit antimicrobial activity against Escherichia coli and Bacillus cereus, with B. cereus demonstrating greater resistance to chitosan compared to E. coli. The research also explores the bioconversion of deproteinization and deacetylation effluents. Deproteinization effluents prove superior in sustaining microbial growth, supporting comparable growth and lactic acid production for human probiotic strains (Lactobacillus plantarum and Leuconostoc mesenteroides) when substituting commercial peptones. Marine bacteria (Pseudomonas fluorescens and Phaeobacter sp.) show lower productivity. Integrating these processes into a biorefinery framework enables the conversion of 1 kg of dry squid pens into 350 g of chitosan, and facilitates the production of 937–949 g of lactic acid using human lactic acid bacteria cultures in media formulated with squid pen-derived effluents, glucose, yeast extract, and mineral salts. This integrated approach highlights the potential for maximizing resource utilization from squid pen waste, reducing environmental impact and generating high-value bioproducts. Full article

(This article belongs to the Special Issue Innovative Biotechnology Processes for Marine By-Products: From Waste Stream to Value Stream)

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23 pages, 404 KB

Open AccessReview

Ecological Characteristics and Nutritional Values of Australia-Native Brown Algae Species

by Chao Dong, Cundong Xie, Ziqi Lou, Zu Jia Lee, Colin J. Barrow and Hafiz A. R. Suleria

Mar. Drugs 2025, 23(10), 383; https://doi.org/10.3390/md23100383 - 26 Sep 2025

Abstract

This review focuses on five native Australian brown algae species—Cystophora torulosa, Durvillaea potatorum, Ecklonia radiata, Hormosira banksii, and Phyllospora comosa—evaluating their environmental adaptability, biochemical composition, bioactive compounds, and potential for commercial development. Species-specific differences in temperature and [...] Read more.

This review focuses on five native Australian brown algae species—Cystophora torulosa, Durvillaea potatorum, Ecklonia radiata, Hormosira banksii, and Phyllospora comosa—evaluating their environmental adaptability, biochemical composition, bioactive compounds, and potential for commercial development. Species-specific differences in temperature and light tolerance influence their habitat distribution. Nutritional assessments reveal that these algae are rich in proteins, polysaccharides, polyunsaturated fatty acids, and essential trace elements. Bioactive compounds, including polyphenols and fucoidans, exhibit antioxidant, anti-inflammatory, and anti-diabetic properties. D. potatorum extracts have considerable economic value in agriculture by enhancing crop yield, improving nutritional value, and promoting root development. C. torulosa is predominantly found in cooler marine environments and is comparatively more thermally sensitive. In contrast, H. banksii has a higher heat tolerance of up to 40 °C and thrives in warmer environments. E. radiata is widely distributed, highly tolerant of environmental stresses, and exhibits notable disease-resistant activities. P. comosa, due to its high polysaccharide content, demonstrates strong potential for industrial applications. Consumer studies indicate growing acceptance of seaweed-based products in Australia, although knowledge gaps remain. This study highlights the need for continued research, optimized processing methods, and targeted education to support the sustainable development and utilization of Australia’s native brown algae resources. Full article

(This article belongs to the Section Marine Chemoecology for Drug Discovery)

19 pages, 3039 KB

Open AccessArticle

A Sulfated Polysaccharide from Gelidium crinale Suppresses Oxidative Stress and Epithelial–Mesenchymal Transition in Cultured Retinal Pigment Epithelial Cells

by Yurong Fang, Haiyan Zheng, Yizhu Chen, Bomi Ryu and Zhong-Ji Qian

Mar. Drugs 2025, 23(10), 381; https://doi.org/10.3390/md23100381 - 26 Sep 2025

Abstract

Age-related macular degeneration (AMD) progresses to vision-threatening dry and wet forms, with no effective dry AMD treatments available. The sulfated polysaccharide (GNP, 25.8 kDa) derived from Gelidium crinale exhibits diverse biological activities and represents a potential source of novel therapeutic agents. This study [...] Read more.

Age-related macular degeneration (AMD) progresses to vision-threatening dry and wet forms, with no effective dry AMD treatments available. The sulfated polysaccharide (GNP, 25.8 kDa) derived from Gelidium crinale exhibits diverse biological activities and represents a potential source of novel therapeutic agents. This study employed a hydrogen peroxide (H₂O₂)-induced oxidative stress and epithelial–mesenchymal transition (EMT) model in retinal pigment epithelial (RPE) cells to investigate GNP’s protective mechanisms against both oxidative damage and EMT. The results demonstrated that GNP effectively suppressed oxidative stress, with the 600 μg/mL dose significantly inhibiting excessive reactive oxygen species (ROS) generation to levels comparable to untreated controls. Concurrently, at concentrations of 200–600 μg/mL, GNP inhibited NF-κB signaling and increased the Bax/Bcl-2 ratio, effectively counteracting H₂O₂-induced oxidative damage and cell apoptosis. Furthermore, in H₂O₂-treated ARPE-19 cells, 600 μg/mL GNP significantly reduced the secretion of N-cadherin (N-cad), Vimentin (Vim), and α-smooth muscle actin (α-SMA), while increasing E-cadherin (E-cad) expression, consequently inhibiting cell migration. Mechanistically, GNP activated the Nrf2/HO-1 pathway, thereby mitigating oxidative stress. These findings suggest that GNP may serve as a potential therapeutic agent for dry AMD. Full article

(This article belongs to the Special Issue Marine-Derived Bioactive Compounds with Potential Applications for Retinal Health)

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22 pages, 3161 KB

Open AccessArticle

The Marine Natural Compound Aplysinamisine I Selectively Induces Apoptosis and Exhibits Synergy with Taxol™ in Triple-Negative Breast Cancer Spheroids

by Esther A. Guzmán, Tara A. Peterson, Dedra K. Harmody and Amy E. Wright

Mar. Drugs 2025, 23(10), 380; https://doi.org/10.3390/md23100380 - 26 Sep 2025

Abstract

Triple-negative breast cancers (TNBC) lack estrogen, progesterone, and express little, if any, HER2 receptors on their surface. No targeted therapies exist for this aggressive form of breast cancer. A library of enriched fractions from marine organisms was screened in a multi-parametric cytotoxicity assay [...] Read more.

Triple-negative breast cancers (TNBC) lack estrogen, progesterone, and express little, if any, HER2 receptors on their surface. No targeted therapies exist for this aggressive form of breast cancer. A library of enriched fractions from marine organisms was screened in a multi-parametric cytotoxicity assay using MDA-MB-231 and MDA-MB-468 TNBC cells, grown as spheroids (3D cultures). Spheroids better resemble tumors and are considered more clinically predictive. The assay measures apoptosis via the cleavage of caspase 3/7, viability via DNA content, and loss of membrane integrity via 7AAD staining at 24 h of treatment. Fractions were also tested in a traditional 2D MTT assay at 72 h. A fraction from the sponge Aplysina was active in the 3D assay. Aplysinamisine I was identified as the compound responsible for the activity. Aplysinamisine I induces apoptosis in MDA-MB-268 spheroids with an IC₅₀ of 2.9 ± 0.28 µM at 24 h. This novel activity is the most potent for the compound to date. Its IC₅₀ in the MTT assay at 72 h is >80 µM. Striking synergy with Taxol™ is shown in both cell lines. Proteomic analysis led to a differential protein expression profile. Through bioinformatics, this profile led to the hypothesis that the inhibition of nucleophosmin is the potential mode of action of the compound. However, initial studies show only a modest decrease in nucleophosmin expression in spheroids treated with aplysinamisine I. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents, 5th Edition)

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22 pages, 4154 KB

Open AccessArticle

Characterization of YKL-40 Binding to Extracellular Matrix Glycosaminoglycans

by Unnur Magnusdottir, Yiming Yang Jonatansdottir, Kristinn R. Oskarsson, Jens G. Hjorleifsson, Jon M. Einarsson and Finnbogi R. Thormodsson

Mar. Drugs 2025, 23(10), 379; https://doi.org/10.3390/md23100379 - 26 Sep 2025

Abstract

YKL-40 is a chitinase-like glycoprotein implicated in various pathological processes, yet its glycosaminoglycan (GAG) binding profile beyond heparin has not been examined. In this study, we performed a Microscale Thermophoresis (MST) analysis on the heparin-binding glycoprotein YKL-40 using low molecular weight GAG oligosaccharides. [...] Read more.

YKL-40 is a chitinase-like glycoprotein implicated in various pathological processes, yet its glycosaminoglycan (GAG) binding profile beyond heparin has not been examined. In this study, we performed a Microscale Thermophoresis (MST) analysis on the heparin-binding glycoprotein YKL-40 using low molecular weight GAG oligosaccharides. We identified two new GAG ligands, dermatan sulfate (DS) and hyaluronan (HA), while chondroitin sulfate (CS) showed no detectable binding affinity. The results show that heparin is bound with the strongest affinity, followed by DS and HA. To further investigate these differences, molecular docking was used to evaluate possible binding modes. Molecular docking results indicated that both heparin and DS interacted with the same site on YKL-40, the heparin-binding site at residues 143–149, suggesting a multifunctional binding region that may act as a competitive switch or integration hub for spatially regulated signaling. Together, these findings expand the known ligand profile of YKL-40 and offer new insights into its ECM-context-dependent roles, with implications for targeting YKL-40 in diseases involving chronic inflammation, fibrosis, and cancer progression. Full article

(This article belongs to the Special Issue Marine Sulfated Polysaccharides and Their Biomedical Applications)

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