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Marine Drugs
Volume 16
Issue 12
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Mar. Drugs, Volume 16, Issue 12 (December 2018) – 60 articles

Cover Story (view full-size image): Collagen is the most abundant structural protein in vertebrates, found in skin, bones and cartilage, among other tissues, with a pivotal role in the maintenance of their biological and structural integrity. Collagen is thus a key building block in biomaterials design for tissue engineering and regeneration. Conventionally, collagen has porcine or bovine origin, which present some ethical and safety constrains, and marine species have been presented as a sustainable alternative, particularly when considering fish processing industry by-products. In the highlighted work, collagen type I was isolated from codfish skins and, despite the lower denaturation temperature, the high purity extracts enable the production of collagen coating supporting the culture of human fibroblast cell line, with promising biomedical application. View this paper.
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12 pages, 1308 KiB  
Article
Cyclodepsipeptides and Sesquiterpenes from Marine-Derived Fungus Trichothecium roseum and Their Biological Functions
by Yuan-Ming Zhou, Guang-Lin Ju, Lin Xiao, Xiang-Fei Zhang and Feng-Yu Du
Mar. Drugs 2018, 16(12), 519; https://doi.org/10.3390/md16120519 - 19 Dec 2018
Cited by 26 | Viewed by 4568
Abstract
On the basis of the ‘one strain, many compounds’ (OSMAC) strategy, chemical investigation of the marine-derived fungus Trichothecium roseum resulted in the isolation of trichomide cyclodepsipeptides (compounds 1–4) from PDB medium, and destruxin cyclodepsipeptides (compounds 5–7) and cyclonerodiol sesquiterpenes (compounds 8–10) from rice [...] Read more.
On the basis of the ‘one strain, many compounds’ (OSMAC) strategy, chemical investigation of the marine-derived fungus Trichothecium roseum resulted in the isolation of trichomide cyclodepsipeptides (compounds 1–4) from PDB medium, and destruxin cyclodepsipeptides (compounds 5–7) and cyclonerodiol sesquiterpenes (compounds 8–10) from rice medium. The structures and absolute configurations of novel (compounds 1, 8, and 9) and known compounds were elucidated by extensive spectroscopic analyses, X-ray crystallographic analysis, and ECD calculations. All isolated compounds were evaluated for cytotoxic, nematicidal, and antifungal activities, as well as brine shrimp lethality. The novel compound 1 exhibited significant cytotoxic activities against the human cancer cell lines MCF-7, SW480, and HL-60, with IC50 values of 0.079, 0.107, and 0.149 μM, respectively. In addition, it also showed significant brine shrimp lethality, with an LD50 value of 0.48 μM, and moderate nematicidal activity against Heterodera avenae, with an LC50 value of 94.9 μg/mL. This study constitutes the first report on the cytotoxic and nematicidal potential of trichomide cyclodepsipeptides. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Metabolome of Marine-Derived Fungi)
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19 pages, 3187 KiB  
Article
Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1(R), 6(S), 1’(R), 6’(S), 11(R), 17(S)-Fistularin-3 and Bcl-2 Inhibitor Venetoclax
by Cristina Florean, Kyung Rok Kim, Michael Schnekenburger, Hyun-Jung Kim, Céline Moriou, Cécile Debitus, Mario Dicato, Ali Al-Mourabit, Byung Woo Han and Marc Diederich
Mar. Drugs 2018, 16(12), 518; https://doi.org/10.3390/md16120518 - 19 Dec 2018
Cited by 17 | Viewed by 5000
Abstract
Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy [...] Read more.
Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(R), 6(S), 1’(R), 6’(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1’(R), and 6’(S) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity. Full article
(This article belongs to the Special Issue Cell Stress, Canonical and Non-Canonical Cell Death Modalities by Marine Natural Compounds and Derivatives)
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15 pages, 1627 KiB  
Article
Metabolites from the Paracel Islands Soft Coral Sinularia cf. molesta
by Mei-Jun Chu, Xu-Li Tang, Xiao Han, Tao Li, Xiang-Chao Luo, Ming-Ming Jiang, Leen Van Ofwegen, Lian-Zhong Luo, Gang Zhang, Ping-Lin Li and Guo-Qiang Li
Mar. Drugs 2018, 16(12), 517; https://doi.org/10.3390/md16120517 - 19 Dec 2018
Cited by 14 | Viewed by 3652
Abstract
Five new oxygenated sesquiterpenes, molestins A–D (1, 3–5) and epi-gibberodione (2), three new cyclopentenone derivatives, ent-sinulolides C, D, and F ((+)-9–(+)-11), one new butenolide derivative, ent-sinulolide H ((+)-13 [...] Read more.
Five new oxygenated sesquiterpenes, molestins A–D (1, 3–5) and epi-gibberodione (2), three new cyclopentenone derivatives, ent-sinulolides C, D, and F ((+)-9–(+)-11), one new butenolide derivative, ent-sinulolide H ((+)-13), and one new cembranolide, molestin E (14), together with 14 known related metabolites (6–8, (–)-9–(–)-11, (±)-12, (–)-13, 15–19) were isolated from the Paracel Islands soft coral Sinularia cf. molesta. The structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, quantum chemical calculations, and comparison with the literature data. Compound 5 is the first example of a norsesquiterpene with a de-isopropyl guaiane skeleton isolated from the genus Sinularia. Molestin E (14) exhibited cytotoxicities against HeLa and HCT-116 cell lines with IC50 values of 5.26 and 8.37 μM, respectively. Compounds 4, 5, and 8 showed significant inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 218, 344, and 1.24 μM, respectively. Full article
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11 pages, 621 KiB  
Review
Marine Compound Xyloketal B as a Potential Drug Development Target for Neuroprotection
by Haifan Gong, Zhengwei Luo, Wenliang Chen, Zhong-Ping Feng, Guan-Lei Wang and Hong-Shuo Sun
Mar. Drugs 2018, 16(12), 516; https://doi.org/10.3390/md16120516 - 19 Dec 2018
Cited by 18 | Viewed by 3900
Abstract
Xyloketal B is a natural compound isolated from the mangrove fungus, Xylaria sp. in the South China Sea. In the past decade, studies have shown that xyloketal B exhibits anti-oxidative, anti-inflammatory, and anti-apoptotic abilities and may serve as a treatment for ischemic stroke. [...] Read more.
Xyloketal B is a natural compound isolated from the mangrove fungus, Xylaria sp. in the South China Sea. In the past decade, studies have shown that xyloketal B exhibits anti-oxidative, anti-inflammatory, and anti-apoptotic abilities and may serve as a treatment for ischemic stroke. Xyloketal B has been shown to interact with both neurons and residential microglial cells and regulate a number of proteins involved in the apoptotic events during ischemia. Such mechanisms include inhibition of specific NADPH oxidase subunits, upregulation of HO-1, increase of Bcl-1/Bax ratio, and downregulation of TLR4 receptor. Both in vitro and in vivo stroke models have validated its potential in preventing ischemia-induced neuronal cell death. This review summarizes our current understanding of the effects of xyloketal B in ischemic conditions. As stroke ranks second in the causes of mortality worldwide and still lacks effective treatment, it is necessary to seek novel therapeutic options. Understanding the role of xyloketal B in ischemic stroke could reveal a new aspect of stroke treatment. Full article
(This article belongs to the Special Issue Marine Organisms with Neuroprotective Activity: Molecular Targets and Action Mechanisms)
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18 pages, 2562 KiB  
Article
Reduced Number of Adipose Lineage and Endothelial Cells in Epididymal fat in Response to Omega-3 PUFA in Mice Fed High-Fat Diet
by Katerina Adamcova, Olga Horakova, Kristina Bardova, Petra Janovska, Marie Brezinova, Ondrej Kuda, Martin Rossmeisl and Jan Kopecky
Mar. Drugs 2018, 16(12), 515; https://doi.org/10.3390/md16120515 - 18 Dec 2018
Cited by 14 | Viewed by 5577
Abstract
We found previously that white adipose tissue (WAT) hyperplasia in obese mice was limited by dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA). Here we aimed to characterize the underlying mechanism. C57BL/6N mice were fed a high-fat diet supplemented or not with omega-3 PUFA [...] Read more.
We found previously that white adipose tissue (WAT) hyperplasia in obese mice was limited by dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA). Here we aimed to characterize the underlying mechanism. C57BL/6N mice were fed a high-fat diet supplemented or not with omega-3 PUFA for one week or eight weeks; mice fed a standard chow diet were also used. In epididymal WAT (eWAT), DNA content was quantified, immunohistochemical analysis was used to reveal the size of adipocytes and macrophage content, and lipidomic analysis and a gene expression screen were performed to assess inflammatory status. The stromal-vascular fraction of eWAT, which contained most of the eWAT cells, except for adipocytes, was characterized using flow cytometry. Omega-3 PUFA supplementation limited the high-fat diet-induced increase in eWAT weight, cell number (DNA content), inflammation, and adipocyte growth. eWAT hyperplasia was compromised due to the limited increase in the number of preadipocytes and a decrease in the number of endothelial cells. The number of leukocytes and macrophages was unaffected, but a shift in macrophage polarization towards a less inflammatory phenotype was observed. Our results document that the counteraction of eWAT hyperplasia by omega-3 PUFA in dietary-obese mice reflects an effect on the number of adipose lineage and endothelial cells. Full article
(This article belongs to the Special Issue Marine Natural Products and Obesity)
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20 pages, 5686 KiB  
Review
Sterol and Sphingoid Glycoconjugates from Microalgae
by Valentin A. Stonik and Inna V. Stonik
Mar. Drugs 2018, 16(12), 514; https://doi.org/10.3390/md16120514 - 17 Dec 2018
Cited by 40 | Viewed by 5230
Abstract
Microalgae are well known as primary producers in the hydrosphere. As sources of natural products, microalgae are attracting major attention due to the potential of their practical applications as valuable food constituents, raw material for biofuels, drug candidates, and components of drug delivery [...] Read more.
Microalgae are well known as primary producers in the hydrosphere. As sources of natural products, microalgae are attracting major attention due to the potential of their practical applications as valuable food constituents, raw material for biofuels, drug candidates, and components of drug delivery systems. This paper presents a short review of a low-molecular-weight steroid and sphingolipid glycoconjugates, with an analysis of the literature on their structures, functions, and bioactivities. The discussed data on sterols and the corresponding glycoconjugates not only demonstrate their structural diversity and properties, but also allow for a better understanding of steroid biogenesis in some echinoderms, mollusks, and other invertebrates which receive these substances from food and possibly from their microalgal symbionts. In another part of this review, the structures and biological functions of sphingolipid glycoconjugates are discussed. Their role in limiting microalgal blooms as a result of viral infections is emphasized. Full article
(This article belongs to the Special Issue Marine Glycoconjugates: Trends and Perspectives)
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11 pages, 1447 KiB  
Article
Bromopyrrole Alkaloids from the Sponge Agelas kosrae
by Oh-Seok Kwon, Donghwa Kim, Heegyu Kim, Yeon-Ju Lee, Hyi-Seung Lee, Chung J. Sim, Dong-Chan Oh, Sang Kook Lee, Ki-Bong Oh and Jongheon Shin
Mar. Drugs 2018, 16(12), 513; https://doi.org/10.3390/md16120513 - 17 Dec 2018
Cited by 15 | Viewed by 4298
Abstract
Two new sceptrin derivatives (1,2) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge Agelas kosrae. By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin (1) and ageleste C (2 [...] Read more.
Two new sceptrin derivatives (1,2) and eight structurally-related known bromopyrrole-bearing alkaloids were isolated from the tropical sponge Agelas kosrae. By a combination of spectroscopic methods, the new compounds, designated dioxysceptrin (1) and ageleste C (2), were determined to be structural analogs of each other that differ at the imidazole moiety. Dioxysceptrin was also found to exist as a mixture of α-amido epimers. The sceptrin alkaloids exhibited weak cytotoxicity against cancer cells. Compounds 1 and 2 also moderately exhibited anti-angiogenic and isocitrate lyase-inhibitory activities, respectively. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)
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18 pages, 1606 KiB  
Article
Potential Usefulness of a Wakame/Carob Functional Snack for the Treatment of Several Aspects of Metabolic Syndrome: From In Vitro to In Vivo Studies
by Cristina Martínez-Villaluenga, Elena Peñas, Daniel Rico, Ana Belén Martin-Diana, Maria P. Portillo, Maria Teresa Macarulla, Daniel Antonio De Luis and Jonatan Miranda
Mar. Drugs 2018, 16(12), 512; https://doi.org/10.3390/md16120512 - 17 Dec 2018
Cited by 11 | Viewed by 4077
Abstract
Metabolic syndrome (MetS) greatly increases the risk of cardiovascular diseases and type 2 diabetes mellitus. The aim of this study was to evaluate the efficacy of functional snacks containing a combination of wakame (W) and carob pod (CP) flours in reducing markers associated [...] Read more.
Metabolic syndrome (MetS) greatly increases the risk of cardiovascular diseases and type 2 diabetes mellitus. The aim of this study was to evaluate the efficacy of functional snacks containing a combination of wakame (W) and carob pod (CP) flours in reducing markers associated with MetS. The mechanisms of action underlying these effects were also evaluated. In vitro approaches were carried out in mature 3T3-L1 adipocytes and RAW 264.7 macrophages treated with different doses of extracts from W, CP, or a combination of both. Furthermore, an in vivo experiment was conducted in rats with MetS treated with normal-caloric diets containing different snack formulations with combinations of 1/50 (snack A) or 1/5 of wakame/carob (snack B). In vitro experiments results indicated that both W and CP had delipidating effects, but only the latter induced anti-inflammatory and anti-hypertensive effects. As far as the in vivo study is concerned, snack B was ineffective and snack A showed an anti-hypertensive effect in rats with MetS. The present study shows for the first time the in vitro efficacy of a W and CP combination as an anti-inflammatory, delipidating, and anti-hypertensive tool, and its potential usefulness in treating MetS. Full article
(This article belongs to the Special Issue Marine Bioactive Natural Product Studies in Europe)
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17 pages, 3791 KiB  
Article
Transcriptome Analysis of Phycocyanin-Mediated Inhibitory Functions on Non-Small Cell Lung Cancer A549 Cell Growth
by Shuai Hao, Shuang Li, Jing Wang, Lei Zhao, Yan Yan, Qi Cao, Tingting Wu, Liyun Liu and Chengtao Wang
Mar. Drugs 2018, 16(12), 511; https://doi.org/10.3390/md16120511 - 15 Dec 2018
Cited by 27 | Viewed by 5475
Abstract
Phycocyanin (PC), derived from cyanobacteria and Spirulina cells, is a type of natural antineoplastic marine protein. It has been reported that phycocyanin exerts an antitumor function in non-small cell lung cancer (NSCLC) cells, but the underlying mechanism has not been elucidated. In this [...] Read more.
Phycocyanin (PC), derived from cyanobacteria and Spirulina cells, is a type of natural antineoplastic marine protein. It has been reported that phycocyanin exerts an antitumor function in non-small cell lung cancer (NSCLC) cells, but the underlying mechanism has not been elucidated. In this research, a transcriptome study was performed to investigate the regulatory mechanisms of phycocyanin on human NSCLC A549 cells. The survival rate and proliferation ability of A549 cells were markedly reduced by phycocyanin, along with abnormal morphologic changes. The transcriptome analysis showed that 2970 genes were differentially expressed after phycocyanin treatment in A549 cells, including 1431 down-regulated and 1539 up-regulated genes. Gene ontology and KEGG analysis suggested that some classical pathways, such as Wnt, NF-κB, and PI3K-AKT signaling, were significantly enriched. Strikingly, protein–protein interaction (PPI) analysis showed that ubiquitin-C (UBC) occupied the highest degree (the highest number of interactions) in differential genes, indicating that it might play a key role in the phycocyanin-mediated regulatory process in A549 cells. Moreover, qRT-PCR results showed consistent expression trends of differential genes with transcriptome analysis. Consequently, this study has provided a theoretical basis for regulation of phycocyanin in A549 cells, which lays a foundation for the treatment of NSCLC. Full article
(This article belongs to the Special Issue Cell Stress, Canonical and Non-Canonical Cell Death Modalities by Marine Natural Compounds and Derivatives)
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16 pages, 19145 KiB  
Article
Fucoidan-Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Co-Targeting Tumor Hypoxia and Angiogenesis
by Sung-Won Shin, Wooju Jung, Changhoon Choi, Shin-Yeong Kim, Arang Son, Hakyoung Kim, Nohyun Lee and Hee Chul Park
Mar. Drugs 2018, 16(12), 510; https://doi.org/10.3390/md16120510 - 15 Dec 2018
Cited by 54 | Viewed by 5361
Abstract
Tumor hypoxia is a major mechanism of resistance to radiation therapy (RT), which is associated with poor prognosis in affected cancer patients. Various approaches to treat hypoxic and radioresistant cancers, including pancreatic cancer, have shown limited success. Fucoidan, a polysaccharide from brown seaweed, [...] Read more.
Tumor hypoxia is a major mechanism of resistance to radiation therapy (RT), which is associated with poor prognosis in affected cancer patients. Various approaches to treat hypoxic and radioresistant cancers, including pancreatic cancer, have shown limited success. Fucoidan, a polysaccharide from brown seaweed, has antitumor and antiangiogenesis activities. Here, we discuss the development of fucoidan-coated manganese dioxide nanoparticles (Fuco-MnO2-NPs) and testing of the therapeutic potential with RT using pancreatic cancer models. In vitro data showed that Fuco-MnO2-NPs generated oxygen efficiently in the presence of H2O2 and substantially suppressed HIF-1 expression under a hypoxic condition in human pancreatic cancer cells. Fuco-MnO2-NPs reversed hypoxia-induced radioresistance by decreasing clonogenic survival and increasing DNA damage and apoptotic cell death in response to RT. In a BxPC3 xenograft mouse model, the combination treatment with Fuco-MnO2-NPs and RT resulted in a greater tumor growth delay than RT alone. Fucoidan-coated NPs, but not naked ones, further suppressed tumor angiogenesis, as judged by immunohistochemistry data with diminished expression of phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2) and CD31. These data suggest that Fuco-MnO2-NPs may potentiate the effects of RT via dual targeting of tumor hypoxia and angiogenesis, and they are of great clinical potential in the treatment of hypoxic, radioresistant pancreatic cancer. Full article
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10 pages, 1435 KiB  
Article
Antiviral and Antioxidant Properties of Echinochrome A
by Sergey A. Fedoreyev, Natalia V. Krylova, Natalia P. Mishchenko, Elena A. Vasileva, Evgeny A. Pislyagin, Olga V. Iunikhina, Vyacheslav F. Lavrov, Oksana A. Svitich, Linna K. Ebralidze and Galina N. Leonova
Mar. Drugs 2018, 16(12), 509; https://doi.org/10.3390/md16120509 - 15 Dec 2018
Cited by 67 | Viewed by 6140
Abstract
The aim of this study was to examine the in vitro antioxidant and antiviral activities of echinochrome A and echinochrome-based antioxidant composition against tick-borne encephalitis virus (TBEV) and herpes simplex virus type 1 (HSV-1). The antioxidant composition, which is a mixture of echinochrome [...] Read more.
The aim of this study was to examine the in vitro antioxidant and antiviral activities of echinochrome A and echinochrome-based antioxidant composition against tick-borne encephalitis virus (TBEV) and herpes simplex virus type 1 (HSV-1). The antioxidant composition, which is a mixture of echinochrome A, ascorbic acid, and α-tocopherol (5:5:1), showed higher antioxidant and antiviral effects than echinochrome A. We suppose that echinochrome A and its composition can both directly affect virus particles and indirectly enhance antioxidant defense mechanisms in the hosting cell. The obtained results allow considering the echinochrome A and the composition of antioxidants on its basis as the promising agents with the both antioxidant and antiviral activities. Full article
(This article belongs to the Special Issue Selected Papers from the 3rd International Symposium on Life Science)
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15 pages, 1350 KiB  
Article
Diversity and Ecology of Marine Algicolous Arthrinium Species as a Source of Bioactive Natural Products
by Young Mok Heo, Kyeongwon Kim, Seung Mok Ryu, Sun Lul Kwon, Min Young Park, Ji Eun Kang, Joo-Hyun Hong, Young Woon Lim, Changmu Kim, Beom Seok Kim, Dongho Lee and Jae-Jin Kim
Mar. Drugs 2018, 16(12), 508; https://doi.org/10.3390/md16120508 - 14 Dec 2018
Cited by 25 | Viewed by 5212
Abstract
In our previous study, all Arthrinium isolates from Sargassum sp. showed high bioactivities, but studies on marine Arthrinium spp. are insufficient. In this study, a phylogenetic analysis of 28 Arthrinium isolates from seaweeds and egg masses of Arctoscopus japonicus was conducted using internal [...] Read more.
In our previous study, all Arthrinium isolates from Sargassum sp. showed high bioactivities, but studies on marine Arthrinium spp. are insufficient. In this study, a phylogenetic analysis of 28 Arthrinium isolates from seaweeds and egg masses of Arctoscopus japonicus was conducted using internal transcribed spacers, nuclear large subunit rDNA, β-tubulin, and translation elongation factor region sequences, and their bioactivities were investigated. They were analyzed as 15 species, and 11 of them were found to be new species. Most of the extracts exhibited radical-scavenging activity, and some showed antifungal activities, tyrosinase inhibition, and quorum sensing inhibition. It was implied that marine algicolous Arthrinium spp. support the regulation of reactive oxygen species in symbiotic algae and protect against pathogens and bacterial biofilm formation. The antioxidant from Arthrinium sp. 10 KUC21332 was separated by bioassay-guided isolation and identified to be gentisyl alcohol, and the antioxidant of Arthrinium saccharicola KUC21221 was identical. These results demonstrate that many unexploited Arthrinium species still exist in marine environments and that they are a great source of bioactive compounds. Full article
(This article belongs to the Special Issue Marine Microbial Diversity as a Source of Bioactive Natural Products)
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14 pages, 2753 KiB  
Article
Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor
by Jiong Ning, Rui Li, Jie Ren, Dongting Zhangsun, Xiaopeng Zhu, Yong Wu and Sulan Luo
Mar. Drugs 2018, 16(12), 507; https://doi.org/10.3390/md16120507 - 13 Dec 2018
Cited by 21 | Viewed by 3918
Abstract
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed [...] Read more.
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structure–activity relationship (SAR) between GI and mouse α1β1δε nAChRs. The Pro5, Gly8, Arg9, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1β1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1β1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1β1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1β1δε nAChR in detail that will help to develop the novel analogues of GI. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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10 pages, 2318 KiB  
Article
Nile Tilapia Derived TP4 Shows Broad Cytotoxicity toward to Non-Small-Cell Lung Cancer Cells
by Chen-Hung Ting and Jyh-Yih Chen
Mar. Drugs 2018, 16(12), 506; https://doi.org/10.3390/md16120506 - 13 Dec 2018
Cited by 24 | Viewed by 3647
Abstract
Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality due to a lack of effective treatments. Conventional chemotherapies affect healthy cells and cause multidrug resistance, while tumors may eventually develop resistance to less-toxic targeted therapies. Thus, the need to [...] Read more.
Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality due to a lack of effective treatments. Conventional chemotherapies affect healthy cells and cause multidrug resistance, while tumors may eventually develop resistance to less-toxic targeted therapies. Thus, the need to develop novel therapies for NSCLC is urgent. Here, we show that Nile tilapia-derived Tilapia piscidin (TP) 4 is cytotoxic to a panel of NSCLC cells with different genetic profiles. We observed that TP4 triggers NSCLC cell death through the necrosis and combining TP4 with potent Epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKI)s, Erlotinib, and Gefitinib, improved drug responses in EGFR-mutated NSCLC cells, but not in EGFR-wild-type NSCLC cells. This work provides novel insights into potential NSCLC treatments, which may utilize antimicrobial peptide TP4 as monotherapy or in combination with EGFR-TKIs. Full article
(This article belongs to the Collection Marine Compounds and Cancer)
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15 pages, 1694 KiB  
Article
MS/MS-Based Molecular Networking Approach for the Detection of Aplysiatoxin-Related Compounds in Environmental Marine Cyanobacteria
by Chi Ying Gary Ding, Li Mei Pang, Zhao-Xun Liang, Kau Kiat Kelvin Goh, Evgenia Glukhov, William H. Gerwick and Lik Tong Tan
Mar. Drugs 2018, 16(12), 505; https://doi.org/10.3390/md16120505 - 13 Dec 2018
Cited by 15 | Viewed by 5084
Abstract
Certain strains of cyanobacteria produce a wide array of cyanotoxins, such as microcystins, lyngbyatoxins and aplysiatoxins, that are associated with public health issues. In this pilot study, an approach combining LC-MS/MS and molecular networking was employed as a rapid analytical method to detect [...] Read more.
Certain strains of cyanobacteria produce a wide array of cyanotoxins, such as microcystins, lyngbyatoxins and aplysiatoxins, that are associated with public health issues. In this pilot study, an approach combining LC-MS/MS and molecular networking was employed as a rapid analytical method to detect aplysiatoxins present in four environmental marine cyanobacterial samples collected from intertidal areas in Singapore. Based on 16S-ITS rRNA gene sequences, these filamentous cyanobacterial samples collected from Pulau Hantu were determined as Trichodesmium erythraeum, Oscillatoria sp. PAB-2 and Okeania sp. PNG05-4. Organic extracts were prepared and analyzed on LC-HRMS/MS and Global Natural Product Social Molecular Networking (GNPS) for the presence of aplysiatoxin-related molecules. From the molecular networking, six known compounds, debromoaplysiatoxin (1), anhydrodebromoaplysiatoxin (2), 3-methoxydebromoaplysiatoxin (3), aplysiatoxin (4), oscillatoxin A (5) and 31-noroscillatoxin B (6), as well as potential new analogues, were detected in these samples. In addition, differences and similarities in molecular networking clusters related to the aplysiatoxin molecular family were observed in extracts of Trichodesmium erythraeum collected from two different locations and from different cyanobacterial species found at Pulau Hantu, respectively. Full article
(This article belongs to the Special Issue “Harmful Algae: Natural Products Research and Medical Application Exploration”―Selected Papers from the 18th International Conference on Harmful Algae (ICHA 2018))
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19 pages, 2361 KiB  
Article
Pro-Apoptotic Activity of French Polynesian Padina pavonica Extract on Human Osteosarcoma Cells
by Giulia Bernardini, Mariagiulia Minetti, Giuseppe Polizzotto, Manuele Biazzo and Annalisa Santucci
Mar. Drugs 2018, 16(12), 504; https://doi.org/10.3390/md16120504 - 13 Dec 2018
Cited by 25 | Viewed by 5893
Abstract
Recently, seaweeds and their extracts have attracted great interest in the pharmaceutical industry as a source of bioactive compounds. Studies have demonstrated the cytotoxic activity of macroalgae towards different types of cancer cell models, and their consumption has been suggested as a chemo-preventive [...] Read more.
Recently, seaweeds and their extracts have attracted great interest in the pharmaceutical industry as a source of bioactive compounds. Studies have demonstrated the cytotoxic activity of macroalgae towards different types of cancer cell models, and their consumption has been suggested as a chemo-preventive agent against several cancers such as breast, cervix and colon cancers. Reports relevant to the chemical properties of brown algae Padina sp. are limited and those accompanied to a comprehensive evaluation of the biological activity on osteosarcoma (OS) are non existent. In this report, we explored the chemical composition of French Polynesian Padina pavonica extract (EPP) by spectrophotometric assays (total phenolic, flavonoid and tannin content, and antioxidant activity) and by gas chromatography-mass spectrometry (GC-MS) analysis, and provided EPP lipid and sterols profiles. Several compounds with relevant biological activity were also identified that suggest interesting pharmacological and health-protecting effects for EPP. Moreover, we demonstrated that EPP presents good anti-proliferative and pro-apoptotic activities against two OS cell lines, SaOS-2 and MNNG, with different cancer-related phenotypes. Finally, our data suggest that EPP might target different properties associated with cancer development and aggressiveness. Full article
(This article belongs to the Special Issue Seaweeds Secondary Metabolites: Successes in and/or Probable Therapeutic Applications)
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28 pages, 2725 KiB  
Article
Seasonal Variations in the Metabolome and Bioactivity Profile of Fucus vesiculosus Extracted by an Optimised, Pressurised Liquid Extraction Protocol
by Edwin Heavisides, Caroline Rouger, Anna F. Reichel, Cornelia Ulrich, Arlette Wenzel-Storjohann, Susanne Sebens and Deniz Tasdemir
Mar. Drugs 2018, 16(12), 503; https://doi.org/10.3390/md16120503 - 13 Dec 2018
Cited by 42 | Viewed by 6840
Abstract
The metabolism of seaweeds depends on environmental parameters, the availability of nutrients, and biotic/abiotic stresses; therefore, their chemical composition fluctuates throughout the year. This study investigated seasonal variations in the metabolome of the Baltic Sea brown alga Fucus vesiculosus and its potential relation [...] Read more.
The metabolism of seaweeds depends on environmental parameters, the availability of nutrients, and biotic/abiotic stresses; therefore, their chemical composition fluctuates throughout the year. This study investigated seasonal variations in the metabolome of the Baltic Sea brown alga Fucus vesiculosus and its potential relation to the bioactivity profile. By using a definitive screening design (DSD) combined with pressurised liquid extraction (PLE), an optimised protocol was developed to extract algal biomass monthly for a full calendar year. An untargeted metabolomics approach using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MSn)-based molecular networking and manual dereplication was employed. The extracts were simultaneously screened for their in vitro antimicrobial, anticancer/apoptotic, and free radical scavenging activities. 44 compounds were putatively dereplicated in the metabolome. Many compounds were found to vary with the sampling month; phlorotannin total ion count (TIC) was highest in summer, whilst chlorophylls, lipids, and carotenoids peaked in winter and spring. The greatest radical scavenging and apoptotic activities against pancreas cancer cells observed in the summer months were attributed to high phlorotannin TIC. Methicillin-resistant Staphylococcus aureus (MRSA) inhibitory activity was produced year-round without a clear seasonal trend. This is the first study applying DSD-based optimised PLE extraction combined with a metabolome analysis of F. vesiculosus for the identification of seasonal variations in both metabolome and bioactivity. Full article
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11 pages, 1722 KiB  
Article
The Marine Dinoflagellate Alexandrium minutum Activates a Mitophagic Pathway in Human Lung Cancer Cells
by Christian Galasso, Genoveffa Nuzzo, Christophe Brunet, Adrianna Ianora, Angela Sardo, Angelo Fontana and Clementina Sansone
Mar. Drugs 2018, 16(12), 502; https://doi.org/10.3390/md16120502 - 12 Dec 2018
Cited by 23 | Viewed by 3708
Abstract
Marine dinoflagellates are a valuable source of bioactive molecules. Many species produce cytotoxic compounds and some of these compounds have also been investigated for their anticancer potential. Here, we report the first investigation of the toxic dinoflagellate Alexandrium minutum as source of water-soluble [...] Read more.
Marine dinoflagellates are a valuable source of bioactive molecules. Many species produce cytotoxic compounds and some of these compounds have also been investigated for their anticancer potential. Here, we report the first investigation of the toxic dinoflagellate Alexandrium minutum as source of water-soluble compounds with antiproliferative activity against human lung cancer cells. A multi-step enrichment of the phenol–water extract yielded a bioactive fraction with specific antiproliferative effect (IC50 = 0.4 µg·mL−1) against the human lung adenocarcinoma cells (A549 cell line). Preliminary characterization of this material suggested the presence of glycoprotein with molecular weight above 20 kDa. Interestingly, this fraction did not exhibit any cytotoxicity against human normal lung fibroblasts (WI38). Differential gene expression analysis in A549 cancer cells suggested that the active fraction induces specific cell death, triggered by mitochondrial autophagy (mitophagy). In agreement with the cell viability results, gene expression data also showed that no mitophagic event was activated in normal cells WI38. Full article
(This article belongs to the Special Issue Marine Glycoconjugates: Trends and Perspectives)
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15 pages, 2562 KiB  
Article
A Strategy to Replace the Mouse Bioassay for Detecting and Identifying Lipophilic Marine Biotoxins by Combining the Neuro-2a Bioassay and LC-MS/MS Analysis
by Marcia Bodero, Arjen Gerssen, Liza Portier, Mirjam D. Klijnstra, Ron L. A. P. Hoogenboom, Leonardo Guzmán, Peter J. M. Hendriksen and Toine F. H. Bovee
Mar. Drugs 2018, 16(12), 501; https://doi.org/10.3390/md16120501 - 12 Dec 2018
Cited by 13 | Viewed by 4791
Abstract
Marine biotoxins in fish and shellfish can cause several symptoms in consumers, such as diarrhea, amnesia, or even death by paralysis. Monitoring programs are in place for testing shellfish on a regular basis. In some countries testing is performed using the so-called mouse [...] Read more.
Marine biotoxins in fish and shellfish can cause several symptoms in consumers, such as diarrhea, amnesia, or even death by paralysis. Monitoring programs are in place for testing shellfish on a regular basis. In some countries testing is performed using the so-called mouse bioassay, an assay that faces ethical concerns not only because of animal distress, but also because it lacks specificity and results in high amounts of false positives. In Europe, for lipophilic marine biotoxins (LMBs), a chemical analytical method using LC-MS/MS was developed as an alternative and is now the reference method. However, safety is often questioned when relying solely on such a method, and as a result, the mouse bioassay might still be used. In this study the use of a cell-based assay for screening, i.e., the neuro-2a assay, in combination with the official LC-MS/MS method was investigated as a new alternative strategy for the detection and quantification of LMBs. To this end, samples that had been tested previously with the mouse bioassay were analyzed in the neuro-2a bioassay and the LC-MS/MS method. The neuro-2a bioassay was able to detect all LMBs at the regulatory levels and all samples that tested positive in the mouse bioassay were also suspect in the neuro-2a bioassay. In most cases, these samples contained toxin levels (yessotoxins) that explain the outcome of the bioassay but did not exceed the established maximum permitted levels. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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15 pages, 8355 KiB  
Article
Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIС3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds
by Yaroslav A. Andreev, Dmitry I. Osmakov, Sergey G. Koshelev, Ekaterina E. Maleeva, Yulia A. Logashina, Victor A. Palikov, Yulia A. Palikova, Igor A. Dyachenko and Sergey A. Kozlov
Mar. Drugs 2018, 16(12), 500; https://doi.org/10.3390/md16120500 - 12 Dec 2018
Cited by 27 | Viewed by 4252
Abstract
Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. [...] Read more.
Acid-sensing ion channel 3 (ASIC3) makes an important contribution to the development and maintenance of inflammatory and acid-induced pain. We compared different ASIC3 inhibitors (peptides from sea anemones (APETx2 and Ugr9-1) and nonpeptide molecules (sevanol and diclofenac)) in anti-inflammatory action and analgesic effects. All tested compounds had distinct effects on pH-induced ASIC3 current. APETx2 inhibited only transient current, whereas Ugr9-1 and sevanol decreased transient and sustained components of the current. The effect on mice was evaluated after administering an intramuscular injection in the acetic acid writhing pain model and the complete Freund’s adjuvant-induced thermal hyperalgesia/inflammation test. The bell-shaped dependence of the analgesic effect was observed for APETx2 in the acetic acid-induced writhing test, as well as for sevanol and peptide Ugr9-1 in the thermal hyperalgesia test. This dependence could be evidence of the nonspecific action of compounds in high doses. Compounds reducing both components of ASIC3 current produced more significant pain relief than APETx2, which is an effective inhibitor of a transient current only. Therefore, the comparison of the efficacy of ASIC3 inhibitors revealed the importance of ASIC3-sustained currents’ inhibition for promotion of acidosis-related pain relief. Full article
(This article belongs to the Special Issue Marine Bioactive Peptides: Structure, Function, and Therapeutic Potential)
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16 pages, 3642 KiB  
Article
The Pseudoalteromonas luteoviolacea L-amino Acid Oxidase with Antimicrobial Activity Is a Flavoenzyme
by Andrés Andreo-Vidal, Antonio Sanchez-Amat and Jonatan C. Campillo-Brocal
Mar. Drugs 2018, 16(12), 499; https://doi.org/10.3390/md16120499 - 12 Dec 2018
Cited by 10 | Viewed by 4767
Abstract
The marine environment is a rich source of antimicrobial compounds with promising pharmaceutical and biotechnological applications. The Pseudoalteromonas genus harbors one of the highest proportions of bacterial species producing antimicrobial molecules. For decades, the presence of proteins with L-amino acid oxidase (LAAO) and [...] Read more.
The marine environment is a rich source of antimicrobial compounds with promising pharmaceutical and biotechnological applications. The Pseudoalteromonas genus harbors one of the highest proportions of bacterial species producing antimicrobial molecules. For decades, the presence of proteins with L-amino acid oxidase (LAAO) and antimicrobial activity in Pseudoalteromonas luteoviolacea has been known. Here, we present for the first time the identification, cloning, characterization and phylogenetic analysis of Pl-LAAO, the enzyme responsible for both LAAO and antimicrobial activity in P. luteoviolacea strain CPMOR-2. Pl-LAAO is a flavoprotein of a broad substrate range, in which the hydrogen peroxide generated in the LAAO reaction is responsible for the antimicrobial activity. So far, no protein with a sequence similarity to Pl-LAAO has been cloned or characterized, with this being the first report on a flavin adenine dinucleotide (FAD)-containing LAAO with antimicrobial activity from a marine microorganism. Our results revealed that 20.4% of the sequenced Pseudoalteromonas strains (specifically, 66.6% of P. luteoviolacea strains) contain Pl-laao similar genes, which constitutes a well-defined phylogenetic group. In summary, this work provides insights into the biological significance of antimicrobial LAAOs in the Pseudoalteromonas genus and shows an effective approach for the detection of novel LAAOs, whose study may be useful for biotechnological applications. Full article
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14 pages, 3366 KiB  
Article
Effect of Marine Microalga Chlorella pyrenoidosa Ethanol Extract on Lipid Metabolism and Gut Microbiota Composition in High-Fat Diet-Fed Rats
by Xuzhi Wan, Tiantian Li, Dan Liu, Yihan Chen, Yuanyuan Liu, Bin Liu, Huiying Zhang and Chao Zhao
Mar. Drugs 2018, 16(12), 498; https://doi.org/10.3390/md16120498 - 9 Dec 2018
Cited by 54 | Viewed by 5847
Abstract
Effects of marine microalga Chlorella pyrenoidosa 55% ethanol extract (CPE55) on lipid metabolism, gut microbiota and regulation mechanism in high fat diet-fed induced hyperlipidaemia rats were investigated. Structure characterizations of major compounds in CPE55 were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass [...] Read more.
Effects of marine microalga Chlorella pyrenoidosa 55% ethanol extract (CPE55) on lipid metabolism, gut microbiota and regulation mechanism in high fat diet-fed induced hyperlipidaemia rats were investigated. Structure characterizations of major compounds in CPE55 were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass spectrometry (UPLC-Q-TOF-MS/MS). The compositions of gut microbiota in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Oral administration with CPE55 markedly alleviated dyslipidemia through improving adverse blood lipid profile and inhibiting hepatic lipid accumulation and steatosis. CPE55 has downregulated the gene expression levels of acetyl CoA carboxylase, sterol regulatory element-binding transcription factor-1c, and 3-hydroxy-3-methyl glutaryl coenzyme A reductase and upregulated adenosine 5′-monophosphate-activated protein kinase-α. It has also improved the abundance of bacteria Alistipes, Prevotella, Alloprevotella, and Ruminococcus1 and decreased the abundances of Turicibacter and Lachnospira. Turicibacter and Lachnospira were both positive correlations of metabolic phenotypes. The findings above illustrated that CPE55 might be developed as food ingredients to ameliorate lipid metabolic disorders and hyperlipidaemia. Full article
(This article belongs to the Collection Marine Drugs in the Management of Metabolic Diseases)
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14 pages, 2733 KiB  
Article
Pyropia yezoensis Protein Prevents Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes
by Min-Kyeong Lee, Jeong-Wook Choi, Youn Hee Choi and Taek-Jeong Nam
Mar. Drugs 2018, 16(12), 497; https://doi.org/10.3390/md16120497 - 8 Dec 2018
Cited by 16 | Viewed by 5912
Abstract
Glucocorticoids (GCs), which are endocrine hormones released under stress conditions, can cause skeletal muscle atrophy. This study investigated whether Pyropia yezoensis crude protein (PYCP) inhibits synthetic GCs dexamethasone (DEX)-induced myotube atrophy associated with proteolytic systems. Mouse skeletal muscle C2C12 myotubes were treated with [...] Read more.
Glucocorticoids (GCs), which are endocrine hormones released under stress conditions, can cause skeletal muscle atrophy. This study investigated whether Pyropia yezoensis crude protein (PYCP) inhibits synthetic GCs dexamethasone (DEX)-induced myotube atrophy associated with proteolytic systems. Mouse skeletal muscle C2C12 myotubes were treated with DEX in the presence or absence of PYCP. DEX exposure (100 μM) for 24 h significantly decreased myotube diameter and myogenin expression, which were all increased by treatment with 20 and 40 μg/mL PYCP. Additionally, PYCP significantly reduced the nuclear expression of the forkhead box transcription factors, FoxO1 and FoxO3a, and ubiquitin-proteasome pathway activation. Further mechanistic research revealed that PYCP inhibited the autophagy-lysosome pathway in DEX-induced C2C12 myotubes. These findings indicate that PYCP prevents DEX-induced myotube atrophy through the regulation of FoxO transcription factors, followed by the inhibition of the ubiquitin-proteasome and autophagy-lysosome pathways. Therefore, we suggest that inhibiting these two proteolytic processes with FoxO transcription factors is a promising strategy for preventing DEX-related myotube atrophy. Full article
(This article belongs to the Special Issue The Pharmacological Potential of Marine-Derived Peptides and Proteins)
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13 pages, 743 KiB  
Article
Spirulina maxima Decreases Endothelial Damage and Oxidative Stress Indicators in Patients with Systemic Arterial Hypertension: Results from Exploratory Controlled Clinical Trial
by Jesús Martínez-Sámano, Adriana Torres-Montes de Oca, Oscar Ivan Luqueño-Bocardo, Patricia V. Torres-Durán and Marco A. Juárez-Oropeza
Mar. Drugs 2018, 16(12), 496; https://doi.org/10.3390/md16120496 - 8 Dec 2018
Cited by 36 | Viewed by 6299
Abstract
(1) Background: Spirulina (Arthrospira) maxima has shown beneficial effects such as being anti-dyslipidemic, antiviral, antioxidant and antihypertensive. However, there are few and limited clinical studies. (2) Methods: a prospective, randomized, parallel pilot study of 4.5 g administration of Spirulina maxima or [...] Read more.
(1) Background: Spirulina (Arthrospira) maxima has shown beneficial effects such as being anti-dyslipidemic, antiviral, antioxidant and antihypertensive. However, there are few and limited clinical studies. (2) Methods: a prospective, randomized, parallel pilot study of 4.5 g administration of Spirulina maxima or placebo for 12 weeks in 16 patients with systemic arterial hypertension (SAH) undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors was performed to assess the effects on endothelial damage and oxidative stress indicators. The blood levels of sICAM-1, sVCAM-1, endothelin-1, and sE-selectin were quantified; the activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and concentrations of reduced glutathione, oxidized glutathione, and thiobarbituric acid reactive substances, were also quantified before and after the treatment period. (3) Results: There were statistically significant (p < 0.05) decreases in systolic blood pressure, sVCAM-1, sE-selectin and endothelin-1 levels, and increases in glutathione peroxidase activity and oxidized glutathione levels. (4) Conclusion: The effects found in the present study agree with antihypertensive and antioxidant effects previously reported for Spirulina maxima. However, this is the first report about the effects on indicators of endothelial damage. More research in this field is necessary to gain an insight into the effects of Spirulina on these indicators. Full article
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14 pages, 1471 KiB  
Article
Evaluation of the Potential of Collagen from Codfish Skin as a Biomaterial for Biomedical Applications
by Ana M. Carvalho, Alexandra P. Marques, Tiago H. Silva and Rui L. Reis
Mar. Drugs 2018, 16(12), 495; https://doi.org/10.3390/md16120495 - 8 Dec 2018
Cited by 90 | Viewed by 7984
Abstract
Collagen is one of the most widely used biomaterials, not only due its biocompatibility, biodegradability and weak antigenic potential, but also due to its role in the structure and function of tissues. Searching for alternative collagen sources, the aim of this study was [...] Read more.
Collagen is one of the most widely used biomaterials, not only due its biocompatibility, biodegradability and weak antigenic potential, but also due to its role in the structure and function of tissues. Searching for alternative collagen sources, the aim of this study was to extract collagen from the skin of codfish, previously obtained as a by-product of fish industrial plants, and characterize it regarding its use as a biomaterial for biomedical application, according to American Society for Testing and Materials (ASTM) Guidelines. Collagen type I with a high degree of purity was obtained through acid-extraction, as confirmed by colorimetric assays, SDS-PAGE and amino acid composition. Thermal analysis revealed a denaturing temperature around 16 °C. Moreover, collagen showed a concentration-dependent effect in metabolism and on cell adhesion of lung fibroblast MRC-5 cells. In conclusion, this study shows that collagen can be obtained from marine-origin sources, while preserving its bioactivity, supporting its use in biomedical applications. Full article
(This article belongs to the Special Issue Collagen from Marine Biological Source and Medical Applications)
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13 pages, 622 KiB  
Article
Fatty Acid Composition and Thermotropic Behavior of Glycolipids and Other Membrane Lipids of Ulva lactuca (Chlorophyta) Inhabiting Different Climatic Zones
by Eduard Kostetsky, Natalia Chopenko, Maria Barkina, Peter Velansky and Nina Sanina
Mar. Drugs 2018, 16(12), 494; https://doi.org/10.3390/md16120494 - 7 Dec 2018
Cited by 23 | Viewed by 4630
Abstract
Increasing global temperatures are expected to increase the risk of extinction of various species due to acceleration in the pace of shifting climate zones. Nevertheless, there is no information on the physicochemical properties of membrane lipids that enable the adaptation of the algae [...] Read more.
Increasing global temperatures are expected to increase the risk of extinction of various species due to acceleration in the pace of shifting climate zones. Nevertheless, there is no information on the physicochemical properties of membrane lipids that enable the adaptation of the algae to different climatic zones. The present work aimed to compare fatty acid composition and thermal transitions of membrane lipids from green macroalgae Ulva lactuca harvested in the Sea of Japan and the Adriatic Sea in summer. U. lactuca inhabiting the Adriatic Sea had bleached parts of thalli which were completely devoid of chloroplast glycolipids. The adaptation to a warmer climatic zone was also accompanied by a significant decrease in the ratio between unsaturated and saturated fatty acids (UFA/SFA) of membrane lipids, especially in bleached thalli. Hence, bleaching of algae is probably associated with the significant decrease of the UFA/SFA ratio in glycolipids. The decreasing ratio of n-3/n-6 polyunsaturated fatty acids (PUFAs) was observed in extra-plastidial lipids and only in the major glycolipid, non-lamellar monogalactosyldiacylglycerol. The opposite thermotropic behavior of non-lamellar and lamellar glycolipids can contribute to maintenance of the highly dynamic structure of thylakoid membranes of algae in response to the increasing temperatures of climatic zones. Full article
(This article belongs to the Special Issue Marine Glycoconjugates: Trends and Perspectives)
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9 pages, 1362 KiB  
Article
Biosynthesis and Secretion of Human Tissue Kallikrein in Transgenic Chlamydomonas reinhardtii
by Jun Chen, Jinxia Wu, Qingyu Wu and Zhangli Hu
Mar. Drugs 2018, 16(12), 493; https://doi.org/10.3390/md16120493 - 7 Dec 2018
Cited by 3 | Viewed by 3821
Abstract
The green alga Chlamydomonas reinhardtii was recently been shown to be an effective bio-manufacturing platform for the production of recombinant proteins. The advantage of using C. reinhardtii is that it is fast to grow, inexpensive to culture, and relatively safe. However, the expression [...] Read more.
The green alga Chlamydomonas reinhardtii was recently been shown to be an effective bio-manufacturing platform for the production of recombinant proteins. The advantage of using C. reinhardtii is that it is fast to grow, inexpensive to culture, and relatively safe. However, the expression of foreign proteins is always low and difficult to purify in C. reinhardtii. Human kallikrein has the potential to be developed into certain drugs, like insulin. Therefore, its biosynthesis is important to drug development. In this study, we synthesized the sg gene, a signal peptide sequence of alkaline phosphatase, and inserted it into a pH124 plasmid, which contains a HSP70A-RBCS2 promoter and a RBCS2 terminator. Then, we inserted the human kallikrein gene klk1 behind the sg sequence to make a pHsgk124 vector. The pHsgk124 were transferred into a cell-wall deficient strain of C. reinhardtii, cc-503, by using the glass bead method. Southern blot analysis showed that sg and klk1 were incorporated into genes of the transgenic C. reinhardtii. RT-PCR analysis showed that it had an active transcription and its expression increased three times under heat stress. Western blot analyses of proteins inside and outside cells (in the culture medium) showed that klk1 was expressed in the cell and the resulting protein was secreted into medium. An enzyme activity assay showed that the recombinant protein had the ability to hydrolyze the specific substrate H-D-Val-Leu-Arg-Pna. In conclusion, we successfully bioengineered C. reinhardtii to produce and secrete human kallikrein protein, which has important biomedical implications. Full article
(This article belongs to the Special Issue Pre-Clinical Marine Drug Discovery)
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21 pages, 2196 KiB  
Article
New Insights into the Culture Method and Antibacterial Potential of Gracilaria gracilis
by Gioele Capillo, Serena Savoca, Rosaria Costa, Marilena Sanfilippo, Carmen Rizzo, Angelina Lo Giudice, Ambrogina Albergamo, Rossana Rando, Giovanni Bartolomeo, Nunziacarla Spanò and Caterina Faggio
Mar. Drugs 2018, 16(12), 492; https://doi.org/10.3390/md16120492 - 7 Dec 2018
Cited by 64 | Viewed by 5451
Abstract
Enormous marine biodiversity offers an endless reservoir of chemicals for many applications. In this scenario, the extraction of seaweeds represents an interesting source of compounds displaying antimicrobial activity. In particular, among the different red algae, Gracilaria gracilis plays an important role due to [...] Read more.
Enormous marine biodiversity offers an endless reservoir of chemicals for many applications. In this scenario, the extraction of seaweeds represents an interesting source of compounds displaying antimicrobial activity. In particular, among the different red algae, Gracilaria gracilis plays an important role due to the presence of important bioactives in its composition. In spite of these features, an efficient culture system is still absent. In the present study, a novel algal culture method was developed and compared to another more common cultural practice, widely reported in literature. A higher efficiency of the new method, both for daily growth rate and biomass, was assessed. Furthermore, the growth inhibitory activity of five extracts, obtained using ethanol, methanol, acetone, chloroform or diethyl ether as a solvent, from the cultured G. gracilis was tested against Gram-positive and Gram-negative pathogens. Algal extracts exhibited a considerable inhibitory activity against B. subtilis strains, while a slight inhibition was observed against V. fischeri. The different extracts showed significant differences in bacterial growth inhibition, with the highest activity that was recorded for the ethanol extract, followed by that of methanol. Based on the chemical characterization, these findings could be related to the antimicrobial activity played by the combination of total carbohydrates and polyphenols, which were determined at high levels in ethanol and methanol extracts, as well as by the highest number and levels of single polyphenols. Conversely, the lower growth inhibitory activities found in chloroform and diethyl ether extracts could be related to the isolation of minor lipid classes (e.g., neutral and medium polar lipids) composed by fatty acids, such as stearic, oleic and arachidonic acids, typically characterized by antimicrobial activity. In consideration of the results obtained, the present study has a double implication, involving both the field of cultural practices and the exploitation of natural sources for the isolation of antimicrobial agents useful both in pharmaceutical and food applications. Full article
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13 pages, 3675 KiB  
Article
iTRAQ-Based Quantitative Proteomic Analysis of a Toxigenic Dinoflagellate Alexandrium catenella at Different Stages of Toxin Biosynthesis during the Cell Cycle
by Shu-Fei Zhang, Yong Zhang, Lin Lin and Da-Zhi Wang
Mar. Drugs 2018, 16(12), 491; https://doi.org/10.3390/md16120491 - 7 Dec 2018
Cited by 20 | Viewed by 3759
Abstract
Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids that are produced mainly by marine dinoflagellates. PST biosynthesis in dinoflagellates is a discontinuous process that is coupled to the cell cycle. However, little is known about the molecular mechanism underlying this [...] Read more.
Paralytic shellfish toxins (PSTs) are a group of potent neurotoxic alkaloids that are produced mainly by marine dinoflagellates. PST biosynthesis in dinoflagellates is a discontinuous process that is coupled to the cell cycle. However, little is known about the molecular mechanism underlying this association. Here, we compared global protein expression profiles of a toxigenic dinoflagellate, Alexandrium catenella, collected at four different stages of toxin biosynthesis during the cell cycle, using an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic approach. The results showed that toxin biosynthesis occurred mainly in the G1 phase, especially the late G1 phase. In total, 7232 proteins were confidently identified, and 210 proteins exhibited differential expression among the four stages. Proteins involved in protein translation and photosynthetic pigment biosynthesis were significantly upregulated during toxin biosynthesis, indicating close associations among the three processes. Nine toxin-related proteins were detected, and two core toxin biosynthesis proteins, namely, sxtA and sxtI, were identified for the first time in dinoflagellates. Among these proteins, sxtI and ompR were significantly downregulated when toxin biosynthesis stopped, indicating that they played important roles in the regulation of PST biosynthesis. Our study provides new insights into toxin biosynthesis in marine dinoflagellates: nitrogen balance among different biological processes regulates toxin biosynthesis, and that glutamate might play a key modulatory role. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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13 pages, 1323 KiB  
Article
Analysis of the Transcriptome of the Red Seaweed Grateloupia imbricata with Emphasis on Reproductive Potential
by Pilar Garcia-Jimenez, Carlos Llorens, Francisco J. Roig and Rafael R. Robaina
Mar. Drugs 2018, 16(12), 490; https://doi.org/10.3390/md16120490 - 7 Dec 2018
Cited by 13 | Viewed by 4153
Abstract
Grateloupia imbricata is an intertidal marine seaweed and candidate model organism for both industry and academic research, owing to its ability to produce raw materials such as carrageenan. Here we report on the transcriptome of G. imbricata with the aim of providing new [...] Read more.
Grateloupia imbricata is an intertidal marine seaweed and candidate model organism for both industry and academic research, owing to its ability to produce raw materials such as carrageenan. Here we report on the transcriptome of G. imbricata with the aim of providing new insights into the metabolic pathways and other functional pathways related to the reproduction of Grateloupia species. Next-generation sequencing was carried out with subsequent de novo assembly and annotation using state-of-the-art bioinformatic protocols. The results show the presence of transcripts required for the uptake of glycerol, which is a specific carbon source for in vitro culture of G. imbricata and nucleotide sequences that are involved in polyamine-based biosynthesis, polyamine degradation, and metabolism of jasmonates and ethylene. Polyamines, ethylene and methyl jasmonate are plant growth regulators that elicit the development and maturation of cystocarps and the release of spores from seaweeds. Our results will inform studies of the mechanisms that control polysaccharide accumulation, cystocarp formation and spore release. Moreover, our transcriptome information clarifies aspects of red seaweed carposporogenesis with potential benefits for enhancing reproduction. Full article
(This article belongs to the Special Issue Discovery and Application of Macroalgae-Derived Natural Products)
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