Marine Drugs — Open Access Journal

Perinereis aibuhitensis peptide (PAP) is a decapeptide (Ile-Glu-Pro-Gly-Thr-Val-Gly-Met-Met-Phe, IEPGTVGMMF) with anticancer activity that was purified from an enzymatic hydrolysate of Perinereis aibuhitensis. In the present study, the anticancer effect of PAP on H1299 cell proliferation was investigated. Our results showed that PAP promoted apoptosis and inhibited the proliferation of H1299 cells in a time- and dose-dependent manner. When the PAP concentration reached 0.92 mM, more than 95% of treated cells died after 72 h of treatment. Changes in cell morphology were further analyzed using an inverted microscope and AO/EB staining and flow cytometry was adopted for detecting apoptosis and cell cycle phase. The results showed that the early and late apoptosis rates of H1299 cells increased significantly after treatment with PAP and the total apoptosis rate was significantly higher than that of the control group. Moreover, after treatment with PAP, the number of cells in the S phase of cells was significantly reduced and the ability for the cells to proliferate was also reduced. H1299 cells were arrested in the G2/M phase and cell cycle progression was inhibited. Furthermore, the results of western blotting showed that nm23-H1 and vascular endothelial growth factor (VEGF) protein levels decreased in a dose-dependent manner, while the pro-apoptotic protein and anti-apoptotic protein ratios and the level of apoptosis-related caspase protein increased in a dose-dependent manner. In conclusion, our results indicated that PAP, as a natural marine bioactive substance, inhibited proliferation and induced apoptosis of human lung cancer H1299 cells. PAP is likely to be exploited as the functional food or adjuvant that may be used for prevention or treatment of human non-small cell lung cancer in the future. Full article

β-Amyloid (Aβ) is regarded as an important pathogenic target for Alzheimer’s disease (AD), the most prevalent neurodegenerative disease. Aβ can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Aβ aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Aβ fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Aβ fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Aβ directly reduced Aβ oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Aβ₄₂ with polar binding energy. Hydrogen bonds and π–π interactions between the key amino acid residues of Aβ₄₂ and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Aβ oligomer, Aβ modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Aβ neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Aβ aggregation along with other target mechanisms. Full article

Three new eunicellin-derived diterpenoids of briarellin type, briarenones A‒C (1‒3), were isolated from a Formosan gorgonian Briareum violaceum. The chemical structures of the compounds were elucidated on the basis of extensive spectroscopic analyses, including two-dimensional (2D) NMR. The absolute configuration of 1 was further confirmed by a single crystal X-ray diffraction analysis. The in vitro cytotoxic and anti-inflammatory potentialities of the isolated metabolites were tested against the growth of a limited panel of cancer cell lines and against the production of superoxide anions and elastase release in N-formyl-methionyl-leucyl-phenyl-alanine and cytochalasin B (fMLF/CB)-stimulated human neutrophils, respectively. Full article

Polyunsaturated fatty acids (PUFAs) are essential for human function, however they have to be provided through the diet. As their production from fish oil is environmentally unsustainable, there is demand for new sources of PUFAs. The aim of the present work was to establish the microalgal platform to produce nutraceutical-value PUFAs from forest biomass. To this end, the growth of Phaeodactylum tricornutum on birch and spruce hydrolysates was compared to autotrophic cultivation and glucose synthetic media. Total lipid generated by P. tricornutum grown mixotrophically on glucose, birch, and spruce hydrolysates was 1.21, 1.26, and 1.29 g/L, respectively. The highest eicosapentaenoic acid (EPA) production (256 mg/L) and productivity (19.69 mg/L/d) were observed on spruce hydrolysates. These values were considerably higher than those obtained from the cultivation without glucose (79.80 mg/L and 6.14 mg/L/d, respectively) and also from the photoautotrophic cultivation (26.86 mg/L and 2.44 mg/L/d, respectively). To the best of our knowledge, this is the first report describing the use of forest biomass as raw material for EPA and docosapentaenoic acid (DHA) production. Full article

The extraction and purification of collagen are of great interest due to its biological function and medicinal applications. Although marine invertebrates are abundant in the animal kingdom, our knowledge of their extracellular matrix (ECM), which mainly contains collagen, is lacking. The functions of collagen isolated from marine invertebrates remain an untouched source of the proteinaceous component in the development of groundbreaking pharmaceuticals. This review will give an overview of currently used collagens and their future applications, as well as the methodological issues of collagens from marine invertebrates for potential drug discovery. Full article

Fucosylated oligosaccharide (FO) is known to selectively promote the growth of probiotic bacteria and is currently marketed as a functional health food and prebiotic in infant formula. Despite widespread interest in FO among functional food customers, high production costs due to high raw material costs, especially those related to fucose, are a significant production issue. Therefore, several actions are required before efficient large-scale operations can occur, including (i) identification of inexpensive raw materials from which fucosylated oligosaccharides may be produced and (ii) development of production methods to which functional food consumers will not object (e.g., no genetically modified organisms (GMOs)). Undaria pinnatifida, commonly called Miyeok in Korea, is a common edible brown seaweed plentiful on the shores of the Korean peninsula. In particular, the sporophyll of Undaria pinnatifida contains significant levels of l-fucose in the form of fucoidan (a marine sulfated polysaccharide). If the l-fucose present in Undaria pinnatifida sporophyll was capable of being separated and recovered, l-fucose molecules could be covalently joined to other monosaccharides via glycosidic linkages, making this FO manufacturing technology of value in the functional food market. In our previous work, β-galactosidase (EC 3.2.2.23) from Bifidobacterium longum RD47 (B. longum RD47) was found to have transglycosylation activity and produce FO using purified l-fucose and lactose as substrates (reference). In this research, crude fucodian hydrolysates were separated and recovered from edible seaweed (i.e., U. pinnatifida sporophyll). The extracted l-fucose was purified via gel permeation and ion exchange chromatographies and the recovered l-fucose was used to synthesize FO. B. longum RD47 successfully transglycosilated and produced FO using l-fucose derived from Undaria pinnatifida and lactose as substrates. To the best of our knowledge, this is the first report of synthesized FO using Bifidobacterium spp. Full article

Antioxidative peptides were produced from false abalone (Volutharpa ampullacea perryi) using enzymatic hydrolysis. Trypsin produced the most bioactive hydrolysates with the highest scavenging ABTS^+• free radicals compared to pepsin, alcalase, neutrase, and flavourzyme. The response surface methodology studies on trypsin hydrolysis indicated that the hydrolysis temperature, time, and pH were interacted with each other (p < 0.05), and the optimal conditions were hydrolysis at 51.8 °C for 4.1 h, pH 7.7 and the maximum predicted hydrolysis degree was 13.18% and ABTS^+• scavenging activity of 79.42%. The optimized hydrolysate was subjected to ultrafiltration fractionation, and the fraction with MW < 3 kDa showed the highest ABTS^+• scavenging activity. There were 193 peptide sequences identified from this peptide fraction and 133 of them were successfully docked onto human myeloperoxidase (MPO), an enzyme involved in forming reactive oxidants in vivo. The highest scored peptide, no. 39, consists of DTETGVPT. Its structure and molecular interactions with MPO active site were compared with previously characterized peptide hLF1-11. The interactions between peptide no. 39 and MPO include electrostatic charge, hydrogen bonds, and covalent bonds. The antioxidative peptide produced in this research may exert antioxidant activity in vivo due to its potential inhibition effect on MPO. Full article

Marine natural products (MNPs) continue to be in the spotlight in the global drug discovery endeavor. Currently, more than 30,000 structurally diverse secondary metabolites from marine sources have been isolated, making MNPs a profound, renewable source to investigate novel drug compounds. Marine sponges of the genus Suberea (family: Aplysinellidae) are recognized as producers of bromotyrosine derivatives, which are considered distinct chemotaxonomic markers for the marine sponges belonging to the order Verongida. This class of compounds exhibits structural diversity, ranging from simple monomeric molecules to more complex molecular scaffolds, displaying a myriad of biological and pharmacological potentialities. In this review, a comprehensive literature survey covering the period of 1998–2018, focusing on the chemistry and biological/pharmacological activities of marine natural products from marine spongesof the genus Suberea, with special attention to the biogenesis of the different skeletons of halogenated compounds, is presented. Full article

The isolation and structural elucidation of a structurally new desertomycin, designated as desertomycin G (1), with strong antibiotic activity against several clinically relevant antibiotic resistant pathogens are described herein. This new natural product was obtained from cultures of the marine actinomycete Streptomyces althioticus MSM3, isolated from samples of the intertidal seaweed Ulva sp. collected in the Cantabrian Sea (Northeast Atlantic Ocean). Particularly interesting is its strong antibiotic activity against Mycobacterium tuberculosis clinical isolates, resistant to antibiotics in clinical use. To the best of our knowledge, this is the first report on a member of the desertomycin family displaying such activity. Additionally, desertomycin G shows strong antibiotic activities against other relevant Gram-positive clinical pathogens such as Corynebacterium urealyticum, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, and Clostridium perfringens. Desertomycin G also displays moderate antibiotic activity against relevant Gram-negative clinical pathogens such as Bacteroides fragilis, Haemophilus influenzae and Neisseria meningitidis. In addition, the compound affects viability of tumor cell lines, such as human breast adenocarcinoma (MCF-7) and colon carcinoma (DLD-1), but not normal mammary fibroblasts. Full article

Over-regulation of Heme oxygenase 1 (HO-1) has been recently identified in many types of human cancer, and in these cases, poor clinical outcomes are normally reported. Indeed, the inhibition of HO-1 is being considered as an anticancer approach. Imidazole scaffold is normally present in most of the classical HO-1 inhibitors and seems indispensable to the inhibitory activity due to its strong interaction with the Fe(II) of the heme group. In this paper, we searched for new potentially HO-1 inhibitors among three different databases: Marine Natural Products (MNP), ZINC Natural Products (ZNP) and Super Natural II (SN2). 484,527 compounds were retrieved from the databases and filtered through four statistical/computational filters (2D descriptors, 2D-QSAR pharmacophoric model, 3D-QSAR pharmacophoric model, and docking). Different imidazole-based compounds were suggested by our methodology to be potentially active in inhibiting the HO-1, and the results have been rationalized by the bioactivity of the filtered molecules reported in the literature. Full article

Oral mucositis and esophagitis represent the most frequent and clinically significant complications of cytoreductive chemotherapy and radiotherapy, which severely compromise the patient quality of life. The local application of polymeric gels could protect the injured tissues, alleviating the most painful symptoms. The present work aims at developing in situ gelling formulations for the treatment of oral mucositis and esophagitis. To reach these targets, κ-carrageenan (κ-CG) was selected as a polymer having wound healing properties and able to gelify in the presence of saliva ions, while hydroxypropyl cellulose (HPC) was used to improve the mucoadhesive properties of the formulations. CaCl₂ was identified as a salt able to enhance the interaction between κ-CG and saliva ions. Different salt and polymer concentrations were investigated in order to obtain a formulation having the following features: (i) low viscosity at room temperature to facilitate administration, (ii) marked elastic properties at 37 °C, functional to a protective action towards damaged tissues, and (iii) mucoadhesive properties. Prototypes characterized by different κ-CG, HPC, and CaCl₂ concentrations were subjected to a thorough rheological characterization and to in vitro mucoadhesion and washability tests. The overall results pointed out the ability of the developed formulations to produce a gel able to interact with saliva ions and to adhere to the biological substrates. Full article

The cyclic peptides portoamides produced by the cyanobacterium Phormidium sp. LEGE 05292 were previously isolated and their ability to condition microcommunities by allelopathic effect was described. These interesting bioactive properties are, however, still underexplored as their biotechnological applications may be vast. This study aims to investigate the antifouling potential of portoamides, given that a challenge in the search for new environmentally friendly antifouling products is to find non-toxic natural alternatives with the ability to prevent colonization of different biofouling species, from bacteria to macroinvertebrates. A multi-bioassay approach was applied to assess portoamides antifouling properties, marine ecotoxicity and molecular mode of action. Results showed high effectiveness in the prevention of mussel larvae settlement (EC₅₀ = 3.16 µM), and also bioactivity towards growth and biofilm disruption of marine biofouling bacterial strains, while not showing toxicity towards both target and non-target species. Antifouling molecular targets in mussel larvae include energy metabolism modifications (failure in proton-transporting ATPases activity), structural alterations of the gills and protein and gene regulatory mechanisms. Overall, portoamides reveal a broad-spectrum bioactivity towards diverse biofouling species, including a non-toxic and reversible effect towards mussel larvae, showing potential to be incorporated as an active ingredient in antifouling coatings. Full article

The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (−)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling. Full article

Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches. Full article

The G protein-coupled receptor (GPCR) family of proteins comprises signaling proteins that mediate cellular responses to various hormones and neurotransmitters, and serves as a prime target for drug discovery. Towards our goal of discovering secondary metabolites from natural sources that can function as neuronal drugs, we evaluated the modulatory effect of eckol on various GPCRs via cell-based functional assays. In addition, we conducted in silico predictions to obtain molecular insights into the functional effects of eckol. Functional assays revealed that eckol had a concentration-dependent agonist effect on dopamine D₃ and D₄ receptors. The half maximal effective concentration (EC₅₀) of eckol for the dopamine D₃ and D₄ receptors was 48.62 ± 3.21 and 42.55 ± 2.54 µM, respectively, while the EC₅₀ values of dopamine as a reference agonist for these two receptors were 2.9 and 3.3 nM, respectively. In silico studies revealed that a low binding energy in addition to hydrophilic, hydrophobic, π–alkyl, and π–π T-shaped interactions are potential mechanisms by which eckol binds to the dopamine receptors to exert its agonist effects. Molecular dynamics (MD) simulation revealed that Phe346 of the dopamine receptors is important for binding of eckol, similar to eticlopride and dopamine. Our results collectively suggest that eckol is a potential D₃/D₄ agonist for the management of neurodegenerative diseases, such as Parkinson’s disease. Full article

This review provides a systematic overview of the spatial and temporal variations in the content of biomolecular constituents of Saccharina latissima on the basis of 34 currently-available scientific studies containing primary measurements. We demonstrate the potential revenue of seaweed production and biorefinery systems by compiling a product portfolio of high-value extract products. An investigation into the endogenous rhythms and extrinsic factors that impact the biomolecular composition of S. latissima is presented, and key performance factors for optimizing seaweed production are identified. Besides the provisioning ecosystem service, we highlight the contribution of green-engineered seaweed production systems to the mitigation of the ongoing and historical anthropogenic disturbances of the climate balance and nutrient flows. We conclude that there are risks of mismanagement, and we stress the importance and necessity of creating an adaptive ecosystem-based management framework within a triple-helix partnership for balancing the utilization of ecosystem services and long-term resilience of aquatic environment. Full article

Green seaweeds are rich sources of sulfated polysaccharides (SPs) with potential biomedical and nutraceutical applications. The aim of this work was to evaluate the immunostimulatory activity of SPs from the seaweed, Caulerpa cupressoides var. flabellata on murine RAW 264.7 macrophages. SPs were evaluated for their ability to modify cell viability and to stimulate the production of inflammatory mediators, such as nitric oxide (NO), intracellular reactive oxygen species (ROS), and cytokines. Additionally, their effect on inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) gene expression was investigated. The results showed that SPs were not cytotoxic and were able to increase in the production of NO, ROS and the cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). It was also observed that treatment with SPs increased iNOS and COX-2 gene expression. Together, these results indicate that C. cupressoides var. flabellata SPs have strong immunostimulatory activity, with potential biomedical applications. Full article

Nonalcoholic steatohepatitis (NASH) progresses from nonalcoholic fatty liver disease (NAFLD); however, efficacious drugs for NASH treatment are lacking. Sodium alginate (SA), a soluble dietary fiber extracted from brown algae, could protect the small intestine from enterobacterial invasion. NASH pathogenesis has been suggested to be associated with enterobacterial invasion, so we examined the effect of SA on methionine- and choline-deficient (MCD) diet-induced steatohepatitis in mice (the most widely-used model of NASH). The mice (n = 31) were divided into three groups (mice fed with regular chow, MCD diet, and MCD diet premixed with 5% SA) for 4 and 8 weeks. The MCD diet increased lipid accumulation and inflammation in the liver, the NAFLD Activity Score and hepatic mRNA expression of tumor necrosis factor- and collagen 11, and induced macrophage infiltration. Villus shortening, disruption of zonula occludens-1 localization and depletion of mucus production were observed in the small intestine of the MCD-group mice. SA administration improved lipid accumulation and inflammation in the liver, and impaired barrier function in the small intestine. Collectively, these results suggest that SA is useful for NASH treatment because it can prevent hepatic inflammation and fatty degeneration by maintaining intestinal barrier function. Full article