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Mar. Drugs, Volume 17, Issue 10 (October 2019)

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Cover Story (view full-size image) A growing body of evidence suggest that C1q-domain-containing (C1qDC) proteins are involved in the [...] Read more.
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Open AccessArticle
Biological Effects of the Azaspiracid-Producing Dinoflagellate Azadinium dexteroporum in Mytilus galloprovincialis from the Mediterranean Sea
Mar. Drugs 2019, 17(10), 595; https://doi.org/10.3390/md17100595 (registering DOI) - 22 Oct 2019
Abstract
Azaspiracids (AZAs) are marine biotoxins including a variety of analogues. Recently, novel AZAs produced by the Mediterranean dinoflagellate Azadinium dexteroporum were discovered (AZA-54, AZA-55, 3-epi-AZA-7, AZA-56, AZA-57 and AZA-58) and their biological effects have not been investigated yet. This study aimed to identify [...] Read more.
Azaspiracids (AZAs) are marine biotoxins including a variety of analogues. Recently, novel AZAs produced by the Mediterranean dinoflagellate Azadinium dexteroporum were discovered (AZA-54, AZA-55, 3-epi-AZA-7, AZA-56, AZA-57 and AZA-58) and their biological effects have not been investigated yet. This study aimed to identify the biological responses (biomarkers) induced in mussels Mytilus galloprovincialis after the bioaccumulation of AZAs from A. dexteroporum. Organisms were fed with A. dexteroporum for 21 days and subsequently subjected to a recovery period (normal diet) of 21 days. Exposed organisms accumulated AZA-54, 3-epi-AZA-7 and AZA-55, predominantly in the digestive gland. Mussels’ haemocytes showed inhibition of phagocytosis activity, modulation of the composition of haemocytic subpopulation and damage to lysosomal membranes; the digestive tissue displayed thinned tubule walls, consumption of storage lipids and accumulation of lipofuscin. Slight genotoxic damage was also observed. No clear occurrence of oxidative stress and alteration of nervous activity was detected in AZA-accumulating mussels. Most of the altered parameters returned to control levels after the recovery phase. The toxic effects detected in M. galloprovincialis demonstrate a clear biological impact of the AZAs produced by A. dexteroporum, and could be used as early indicators of contamination associated with the ingestion of seafood. Full article
(This article belongs to the collection Bioactive Compounds from Marine Plankton)
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Open AccessReview
Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins
Mar. Drugs 2019, 17(10), 594; https://doi.org/10.3390/md17100594 (registering DOI) - 22 Oct 2019
Viewed by 42
Abstract
Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new [...] Read more.
Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new drugs, marine polyether toxins have been extensively studied, in terms of toxicology, pharmacology, detection, and analysis, structural identification, as well as their biosynthetic mechanisms. Although the biosynthetic mechanisms of marine polyether toxins are still unclear, certain progress has been made. In this review, research progress and current knowledge on the biosynthetic mechanisms of polyether toxins are summarized, including the mechanisms of carbon skeleton deletion, pendant alkylation, and polyether ring formation, along with providing a summary of mined biosynthesis-related genes. Finally, future research directions and applications of marine polyether toxins are discussed. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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Open AccessCommunication
Genome Sequencing of Streptomyces olivaceus SCSIO T05 and Activated Production of Lobophorin CR4 via Metabolic Engineering and Genome Mining
Mar. Drugs 2019, 17(10), 593; https://doi.org/10.3390/md17100593 - 20 Oct 2019
Viewed by 186
Abstract
Marine-sourced actinomycete genus Streptomyces continues to be an important source of new natural products. Here we report the complete genome sequence of deep-sea-derived Streptomyces olivaceus SCSIO T05, harboring 37 putative biosynthetic gene clusters (BGCs). A cryptic BGC for type I polyketides was activated [...] Read more.
Marine-sourced actinomycete genus Streptomyces continues to be an important source of new natural products. Here we report the complete genome sequence of deep-sea-derived Streptomyces olivaceus SCSIO T05, harboring 37 putative biosynthetic gene clusters (BGCs). A cryptic BGC for type I polyketides was activated by metabolic engineering methods, enabling the discovery of a known compound, lobophorin CR4 (1). Genome mining yielded a putative lobophorin BGC (lbp) that missed the functional FAD-dependent oxidoreductase to generate the d-kijanose, leading to the production of lobophorin CR4 without the attachment of d-kijanose to C17-OH. Using the gene-disruption method, we confirmed that the lbp BGC accounts for lobophorin biosynthesis. We conclude that metabolic engineering and genome mining provide an effective approach to activate cryptic BGCs. Full article
(This article belongs to the Special Issue Bioactive Marine Heterocyclic Compounds)
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Open AccessArticle
The Marine Catenovulum agarivorans MNH15 and Dextranase: Removing Dental Plaque
Mar. Drugs 2019, 17(10), 592; https://doi.org/10.3390/md17100592 - 18 Oct 2019
Viewed by 190
Abstract
Dextranase, a hydrolase that specifically hydrolyzes α-1,6-glucosidic bonds, has been used in the pharmaceutical, food, and biotechnology industries. In this study, the strain of Catenovulum agarivorans MNH15 was screened from marine samples. When the temperature, initial pH, NaCl concentration, and inducer concentration were [...] Read more.
Dextranase, a hydrolase that specifically hydrolyzes α-1,6-glucosidic bonds, has been used in the pharmaceutical, food, and biotechnology industries. In this study, the strain of Catenovulum agarivorans MNH15 was screened from marine samples. When the temperature, initial pH, NaCl concentration, and inducer concentration were 30 °C, 8.0, 5 g/L, and 8 g/L, respectively, it yielded more dextranase. The molecular weight of the dextranase was approximately 110 kDa. The maximum enzyme activity was achieved at 40 °C and a pH of 8.0. The enzyme was stable at 30 °C and a pH of 5–9. The metal ion Sr2+ enhanced its activity, whereas NH4+, Co2+, Cu2+, and Li+ had the opposite effect. The dextranase effectively inhibited the formation of biofilm by Streptococcus mutans. Moreover, sodium fluoride, xylitol, and sodium benzoate, all used in dental care products, had no significant effect on dextranase activity. In addition, high-performance liquid chromatography (HPLC) showed that dextran was mainly hydrolyzed to glucose, maltose, and maltoheptaose. The results indicated that dextranase has high application potential in dental products such as toothpaste and mouthwash. Full article
Open AccessArticle
Fucoidan-Rich Substances from Ecklonia cava Improve Trimethyltin-Induced Cognitive Dysfunction via Down-Regulation of Amyloid β Production/Tau Hyperphosphorylation
Mar. Drugs 2019, 17(10), 591; https://doi.org/10.3390/md17100591 - 17 Oct 2019
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Abstract
Ecklonia cava (E. cava) was investigated to compare the effect of polyphenol and fucoidan extract and mixture (polyphenol:fucoidan = 4:6) on cognitive function. The ameliorating effect of E. cava was evaluated using the Y-maze, passive avoidance and Morris water maze tests [...] Read more.
Ecklonia cava (E. cava) was investigated to compare the effect of polyphenol and fucoidan extract and mixture (polyphenol:fucoidan = 4:6) on cognitive function. The ameliorating effect of E. cava was evaluated using the Y-maze, passive avoidance and Morris water maze tests with a trimethyltin (TMT)-induced cognitive dysfunction model, and the results showed that the fucoidan extract and mixture (4:6) had relatively higher learning and memory function effects than the polyphenol extract. After a behavioral test, the inhibitory effect of lipid peroxidation and cholinergic system activity were examined in mouse brain tissue, and the fucoidan extract and mixture (4:6) also showed greater improvements than the polyphenol extract. Mitochondrial activity was evaluated using mitochondrial reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP, ΔΨm), adenosine triphosphate (ATP) content, and mitochondria-mediated protein (BAX, cytochrome C) analysis, and these results were similar to the results of the behavioral tests. Finally, to confirm the cognitive function-related mechanism of E. cava, the amyloid-β production and tau hyperphosphorylation-medicated proteins were analyzed. Based on these results, the improvement effect of E. cava was more influenced by fucoidan than polyphenol. Therefore, our study suggests that the fucoidan-rich substances in E. cava could be a potential material for improving cognitive function by down-regulating amyloid-β production and tau hyperphosphorylation. Full article
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Open AccessReview
Sargassum Seaweed as a Source of Anti-Inflammatory Substances and the Potential Insight of the Tropical Species: A Review
Mar. Drugs 2019, 17(10), 590; https://doi.org/10.3390/md17100590 - 17 Oct 2019
Viewed by 164
Abstract
Sargassum is recognized both empirically and scientifically as a potential anti-inflammatory agent. Inflammation is an important response in the body that helps to overcome various challenges to body homeostasis such as microbial infections, tissue stress, and certain injuries. Excessive and uncontrolled inflammatory conditions [...] Read more.
Sargassum is recognized both empirically and scientifically as a potential anti-inflammatory agent. Inflammation is an important response in the body that helps to overcome various challenges to body homeostasis such as microbial infections, tissue stress, and certain injuries. Excessive and uncontrolled inflammatory conditions can affect the pathogenesis of various diseases. This review aims to explore the potential of Sargassum’s anti-inflammatory activity, not only in crude extracts but also in sulfated polysaccharides and purified compounds. The tropical region has a promising availability of Sargassum biomass because its climate allows for the optimal growth of seaweed throughout the year. This is important for its commercial utilization as functional ingredients for both food and non-food applications. To the best of our knowledge, studies related to Sargassum’s anti-inflammatory activity are still dominated by subtropical species. Studies on tropical Sargassum are mainly focused on the polysaccharides group, though there are some other potentially bioactive compounds such as polyphenols, terpenoids, fucoxanthin, fatty acids and their derivatives, typical polar lipids, and other groups. Information on the modulation mechanism of Sargassum’s bioactive compounds on the inflammatory response is also discussed here, but specific mechanisms related to the interaction between bioactive compounds and targets in cells still need to be further studied. Full article
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Open AccessArticle
Physicochemical and Biological Properties of Gelatin Extracted from Marine Snail Rapana venosa
Mar. Drugs 2019, 17(10), 589; https://doi.org/10.3390/md17100589 - 17 Oct 2019
Viewed by 154
Abstract
In this study, we aimed to obtain gelatin from the marine snail Rapana venosa using acidic and enzymatic extraction methods and to characterize these natural products for cosmetic and pharmaceutical applications. Marine gelatins presented protein values and hydroxyproline content similar to those of [...] Read more.
In this study, we aimed to obtain gelatin from the marine snail Rapana venosa using acidic and enzymatic extraction methods and to characterize these natural products for cosmetic and pharmaceutical applications. Marine gelatins presented protein values and hydroxyproline content similar to those of commercial mammalian gelatin, but with higher melting temperatures. Their electrophoretic profile and Fourier transform infrared (FTIR) spectra revealed protein and absorption bands situated in the amide region, specific for gelatin molecule. Scanning electron microscopy (SEM) analysis showed significant differences in the structure of the lyophilized samples, depending on the type of gelatin. In vitro studies performed on human keratinocytes showed no cytotoxic effect of acid-extracted gelatin at all tested concentrations and moderate cytotoxicity of enzymatic extracted gelatin at concentrations higher than 0.5 mg/mL. Also, both marine gelatins favored keratinocyte cell adhesion. No irritant potential was recorded as the level of IL-1α and IL-6 proinflammatory cytokines released by HaCaT cells cultivated in the presence of marine gelatins was significantly reduced. Together, these data suggest that marine snails are an alternative source of gelatins with potential use in pharmaceutical and skincare products. Full article
Open AccessArticle
Antiamoebic Activities of Indolocarbazole Metabolites Isolated from Streptomyces sanyensis Cultures
Mar. Drugs 2019, 17(10), 588; https://doi.org/10.3390/md17100588 - 17 Oct 2019
Viewed by 174
Abstract
Indolocarbazoles are a family of natural alkaloids characterized by their potent protein kinase and topoisomerase I inhibitory activity. Among them, staurosporine (1) has exhibited promising inhibitory activity against parasites. Based on new insights on the activity and mechanism of action of [...] Read more.
Indolocarbazoles are a family of natural alkaloids characterized by their potent protein kinase and topoisomerase I inhibitory activity. Among them, staurosporine (1) has exhibited promising inhibitory activity against parasites. Based on new insights on the activity and mechanism of action of STS in Acanthamoeba parasites, this work reports the isolation, identification, and the anti-Acanthamoeba activity of the minor metabolites 7-oxostaurosporine (2), 4′-demethylamino-4′-oxostaurosporine (3), and streptocarbazole B (4), isolated from cultures of the mangrove strain Streptomyces sanyensis. A clear correlation between the antiparasitic activities and the structural elements and conformations of the indolocarbazoles 14 was observed. Also, the study reveals that 7-oxostaurosporine (2) affects membrane permeability and causes mitochondrial damages on trophozoites of A. castellanii Neff. Full article
(This article belongs to the Special Issue Marine Natural Products with Antiprotozoal Activity)
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Open AccessArticle
Selective Inhibition of Liver Cancer Cells Using Venom Peptide
Mar. Drugs 2019, 17(10), 587; https://doi.org/10.3390/md17100587 - 17 Oct 2019
Viewed by 174
Abstract
Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that [...] Read more.
Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here we describe the selectivity and mechanism of action of terebrid snail venom peptide, Tv1, for treating the most common type of liver cancer, hepatocellular carcinoma (HCC). Tv1 inhibited the proliferation of murine HCC cells and significantly reduced tumor size in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to overexpressed transient receptor potential (TRP) channels leading to calcium dependent apoptosis resulting from down-regulation of cyclooxygenase-2 (COX-2). Our findings demonstrate the importance of modulating ion channels and the unique potential of venom peptides as tumor specific ligands in the quest for targeted cancer therapies. Full article
(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)
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Open AccessArticle
Anti-Inflammatory and Anti-Aging Evaluation of Pigment–Protein Complex Extracted from Chlorella Pyrenoidosa
Mar. Drugs 2019, 17(10), 586; https://doi.org/10.3390/md17100586 - 16 Oct 2019
Viewed by 211
Abstract
Oxidative stress contributes to chronic inflammatory processes implicated in aging, referred to as “inflamm-aging.” In this study, the potential anti-inflammatory and anti-aging effects of a pigment–protein complex (PPC) from Chlorella pyrenoidosa were investigated using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and D-galactose (D-gal)-induced aging [...] Read more.
Oxidative stress contributes to chronic inflammatory processes implicated in aging, referred to as “inflamm-aging.” In this study, the potential anti-inflammatory and anti-aging effects of a pigment–protein complex (PPC) from Chlorella pyrenoidosa were investigated using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and D-galactose (D-gal)-induced aging in a murine model. Results indicated that PPC inhibits the production of the inflammatory cytokines TNF-α and IL-6, and the inflammatory mediator nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. It also protected mice from D-gal induced informatory aging by increasing the activity of the antioxidant enzyme, such as superoxide dismutase (SOD), inhibiting D-gal-induced NF-κB upregulation, and increasing PPARs expression in the brain and gut. The findings indicated that PPC has favorable anti-inflammatory and anti-aging properties, and could be useful in the treatment of acute inflammation and senescence diseases. Full article
(This article belongs to the collection Marine Polysaccharides) Printed Edition available
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Open AccessArticle
A Potential Antineoplastic Peptide of Human Prostate Cancer Cells Derived from the Lesser Spotted Dogfish (Scyliorhinus canicula L.)
Mar. Drugs 2019, 17(10), 585; https://doi.org/10.3390/md17100585 - 16 Oct 2019
Viewed by 194
Abstract
The purpose of the present paper is to investigate the mechanism of action of a pyroglutamate-modified peptide (pE-K092D) on in vitro growth inhibition of MDA-Pca-2b prostate cancer cells. This peptide was derived from a peptide previously isolated from the testis of the lesser [...] Read more.
The purpose of the present paper is to investigate the mechanism of action of a pyroglutamate-modified peptide (pE-K092D) on in vitro growth inhibition of MDA-Pca-2b prostate cancer cells. This peptide was derived from a peptide previously isolated from the testis of the lesser spotted dogfish and identified as QLTPEALADEEEMNALAAR (K092D). The effect of the peptide on cell proliferation and cell death mechanisms was studied by flow cytometry. Cellular morphology and cytoskeleton integrity of peptide-treated cells were observed by immunofluorescence microscopy. Results showed the onset of peptide induced early cytoskeleton perturbation, inhibition of autophagy, inhibition of cell proliferation and, at the end, non-apoptotic cell death mechanisms (membrane destabilization and necrosis). All those mechanisms seem to contribute to MDA-Pca-2b growth inhibition by a main cytostatic fate. Full article
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Open AccessArticle
Bioactive Diketopiperazines and Nucleoside Derivatives from a Sponge-Derived Streptomyces Species
Mar. Drugs 2019, 17(10), 584; https://doi.org/10.3390/md17100584 - 16 Oct 2019
Viewed by 192
Abstract
Fractionation and purification of the ethyl acetate extract of the culture of a sponge-derived actinomycete, Streptomyces species Call-36, resulted in the isolation and identification of a new diketopiperazine, actinozine A (1), cyclo(2-OH-d-Pro-l-Leu) (2), two new [...] Read more.
Fractionation and purification of the ethyl acetate extract of the culture of a sponge-derived actinomycete, Streptomyces species Call-36, resulted in the isolation and identification of a new diketopiperazine, actinozine A (1), cyclo(2-OH-d-Pro-l-Leu) (2), two new nucleosides, thymidine-3-mercaptocarbamic acid (3) and thymidine-3-thioamine (4), together with cyclo(d-Pro-l-Phe) (5) and cyclo(l-Pro-l-Phe) (6). The structure assignments of the compounds were carried out by interpretation of 1D and 2D NMR data and mass spectral determinations. The absolute configurations of 1 and 2 were determined by Marfey’s method and by comparison of the experimental and TDDFT-calculated ECD spectra. Actinozine A possesses an unprecedented hydroperoxy moiety at C-2 of the proline moiety, while 3 and 4 possess unusual mercaptocarbamic acid and thiohydroxylamine functionalities at N-3 of the thymine moiety. The isolated compounds displayed variable cytotoxic and antimicrobial activities. Full article
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Open AccessFeature PaperArticle
Extensive Tandem Duplication Events Drive the Expansion of the C1q-Domain-Containing Gene Family in Bivalves
Mar. Drugs 2019, 17(10), 583; https://doi.org/10.3390/md17100583 - 14 Oct 2019
Viewed by 175
Abstract
C1q-domain-containing (C1qDC) proteins are rapidly emerging as key players in the innate immune response of bivalve mollusks. Growing experimental evidence suggests that these highly abundant secretory proteins are involved in the recognition of microbe-associated molecular patterns, serving as lectin-like molecules in the bivalve [...] Read more.
C1q-domain-containing (C1qDC) proteins are rapidly emerging as key players in the innate immune response of bivalve mollusks. Growing experimental evidence suggests that these highly abundant secretory proteins are involved in the recognition of microbe-associated molecular patterns, serving as lectin-like molecules in the bivalve proto-complement system. While a large amount of functional data concerning the binding specificity of the globular head C1q domain and on the regulation of these molecules in response to infection are quickly accumulating, the genetic mechanisms that have led to the extraordinary lineage-specific expansion of the C1qDC gene family in bivalves are still largely unknown. The analysis of the chromosome-scale genome assembly of the Eastern oyster Crassostrea virginica revealed that the 476 oyster C1qDC genes, far from being uniformly distributed along the genome, are located in large clusters of tandemly duplicated paralogs, mostly found on chromosomes 7 and 8. Our observations point out that the evolutionary process behind the development of a large arsenal of C1qDC lectin-like molecules in marine bivalves is still ongoing and likely based on an unequal crossing over. Full article
(This article belongs to the Special Issue Marine Glycobiology, Glycomics and Lectins)
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Open AccessArticle
Anti-Inflammatory Activity of a Peptide from Skipjack (Katsuwonus pelamis)
Mar. Drugs 2019, 17(10), 582; https://doi.org/10.3390/md17100582 - 13 Oct 2019
Viewed by 247
Abstract
In this paper, the effect of skipjack (Katsuwonus pelamis) enzymatic peptide (SEP), which was prepared and purified from a byproduct of skipjack, on inflammation, ulcerative colitis and the regulation of intestinal flora was studied in a mouse ulcerative colitis model and [...] Read more.
In this paper, the effect of skipjack (Katsuwonus pelamis) enzymatic peptide (SEP), which was prepared and purified from a byproduct of skipjack, on inflammation, ulcerative colitis and the regulation of intestinal flora was studied in a mouse ulcerative colitis model and a transgenic zebrafish inflammation model. The aggregation of transgenic granulocyte neutrophils in zebrafish from a normal environment and from a sterile environment was calculated, and the anti-inflammatory activity of SEP was evaluated. To evaluate the anti-ulcerative colitis activity of SEP, DSS-induced colitis mice were given SEP, salicylazosulfapyridine (SASP), or SASP + SEP. Then, the concentrations of IL-6, IL-10 and TNF-α in the serum were detected, the HE-stained colon tissue was examined by microscopy the species composition and abundance distribution of the intestinal flora was analyzed. The results showed that 500 μg/mL SEP treatment significantly alleviated neutrophil granulocyte aggregation in the zebrafish inflammation model; Diarrhea, hematochezia and body weight loss were alleviated to a certain extent in mice gavaged with SEP and SASP, and the combination of SASP with SEP was the most effective in mice. The damage to villi in the intestine was completely repaired, and the levels of IL-6, IL-10 and TNF-α, which are associated with inflammation, were all reduced. In addition, the proportion of intestinal probiotics or harmless bacteria increased, while that of pathogenic bacteria decreased, and the effect of the combined treatment was the most pronounced. These results show that SEP could relieve inflammation, cure ulcerative colitis, regulate intestinal flora and enhance the therapeutic effect of the clinical drug SASP. This study provides a theoretical basis for the development of SEP as an anti-inflammatory adjuvant therapy and intestinal flora regulator. Full article
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Open AccessArticle
Glycol Chitosan-Docosahexaenoic Acid Liposomes for Drug Delivery: Synergistic Effect of Doxorubicin-Rapamycin in Drug-Resistant Breast Cancer
Mar. Drugs 2019, 17(10), 581; https://doi.org/10.3390/md17100581 - 12 Oct 2019
Viewed by 161
Abstract
Marine ecosystems are the most prevalent ecosystems on the planet, providing a diversity of living organisms and resources. The development of nanotechnology may provide solutions for utilizing these thousands of potential compounds as marine pharmaceuticals. Here, we designed a liposomal glycol chitosan formulation [...] Read more.
Marine ecosystems are the most prevalent ecosystems on the planet, providing a diversity of living organisms and resources. The development of nanotechnology may provide solutions for utilizing these thousands of potential compounds as marine pharmaceuticals. Here, we designed a liposomal glycol chitosan formulation to load both doxorubicin (DOX) and rapamycin (RAPA), and then evaluated its therapeutic potential in a prepared drug-resistant cell model. We explored the stability of the drug delivery system by changing the physiological conditions and characterized its physicochemical properties. The electrostatic complexation between DOX-glycol chitosan and docosahexaenoic acid RAPA-liposomes (GC-DOX/RAPA ω-liposomes) was precisely regulated, resulting in particle size of 131.3 nm and zeta potential of −14.5 mV. The well-characterized structure of GC-DOX/RAPA ω-liposomes led to high loading efficiencies of 4.1% for DOX and 6.2% for RAPA. Also, GC-DOX/RAPA ω-liposomes exhibited high colloidal stability under physiological conditions and synergistic anti-cancer effects on DOX-resistant MDA-MB-231 cells, while showing pH-sensitive drug release behavior. Our results provided a viable example of marine pharmaceuticals with therapeutic potential for treating drug-resistant tumors using an efficient and safe drug delivery system. Full article
(This article belongs to the Special Issue Nano-Marine Drugs: Relevance of Nanoformulations in Cancer Therapies)
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Open AccessArticle
Anti-Inflammatory Effects of Lipids Extracted from Arctoscopus japonicus Eggs on LPS-Stimulated RAW264.7 Cells
Mar. Drugs 2019, 17(10), 580; https://doi.org/10.3390/md17100580 - 11 Oct 2019
Viewed by 218
Abstract
Arctoscopus japonicus is a cold-water marine fish. The present study investigated the fatty acid composition of A. japonicus egg lipids and their anti-inflammatory effects on LPS-stimulated RAW246.7 macrophages. The results showed that A. japonicus egg lipids contained primarily polyunsaturated fatty acids (52.9% of [...] Read more.
Arctoscopus japonicus is a cold-water marine fish. The present study investigated the fatty acid composition of A. japonicus egg lipids and their anti-inflammatory effects on LPS-stimulated RAW246.7 macrophages. The results showed that A. japonicus egg lipids contained primarily polyunsaturated fatty acids (52.9% of the total fatty acid content; mostly eicosapentaenoic acid [EPA, 21.2 ± 0.5%] and docosahexaenoic acid [DHA, 25.9 ± 0.1%]), followed by monounsaturated fatty acids and saturated fatty acids (23.7% and 23.4%, respectively). A. japonicus egg lipids significantly decreased nitric oxide (NO) production and suppressed the expression of immune-associated genes such as iNOS, COX-2, IL-1β, IL-6, and TNF-α LPS-stimulated RAW246.7 macrophages in dose-dependent manner. A. japonicus egg lipids also reduced the phosphorylation levels of NF-κB p-65, p38, ERK1/2, and JNK, key components of the NF-κB and MAPK pathways, suggesting that the lipid-induced anti-inflammatory activity is related to these signaling pathways. These results indicate that the lipids extracted from A. japonicus eggs have potential biofunctions and might be useful for regulating inflammation in macrophages. Full article
(This article belongs to the Special Issue Marine Lipids with Biological Interest)
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Open AccessArticle
Biologically Active Metabolites from the Marine Sediment-Derived Fungus Aspergillus flocculosus
Mar. Drugs 2019, 17(10), 579; https://doi.org/10.3390/md17100579 - 11 Oct 2019
Viewed by 227
Abstract
Four new compounds were isolated from the Vietnamese marine sediment-derived fungus Aspergillus flocculosus, one aspyrone-related polyketide aspilactonol G (2), one meroterpenoid 12-epi-aspertetranone D (4), two drimane derivatives (7,9), together with five known metabolites ( [...] Read more.
Four new compounds were isolated from the Vietnamese marine sediment-derived fungus Aspergillus flocculosus, one aspyrone-related polyketide aspilactonol G (2), one meroterpenoid 12-epi-aspertetranone D (4), two drimane derivatives (7,9), together with five known metabolites (1,3,5,6,8,10). The structures of compounds 110 were established by NMR and MS techniques. The absolute stereoconfigurations of compounds 1 and 2 were determined by a modified Mosher’s method. The absolute configurations of compounds 4 and 7 were established by a combination of analysis of ROESY data and coupling constants as well as biogenetic considerations. Compounds 7 and 8 exhibited cytotoxic activity toward human prostate cancer 22Rv1, human breast cancer MCF-7, and murine neuroblastoma Neuro-2a cells. Full article
(This article belongs to the Special Issue Selected Papers from XVI MaNaPro and XI ECMNP)
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Open AccessArticle
Cultivation of Sponge-Associated Bacteria from Agelas sventres and Xestospongia muta Collected from Different Depths
Mar. Drugs 2019, 17(10), 578; https://doi.org/10.3390/md17100578 - 11 Oct 2019
Viewed by 199
Abstract
Sponge-associated bacteria have been mostly cultured from shallow water (≤30 m) sponges, whereas only few studies targeted specimens from below 30 m. This study assessed the cultivability of bacteria from two marine sponges Xestospongia muta and Agelas sventres collected from shallow (<30 m), [...] Read more.
Sponge-associated bacteria have been mostly cultured from shallow water (≤30 m) sponges, whereas only few studies targeted specimens from below 30 m. This study assessed the cultivability of bacteria from two marine sponges Xestospongia muta and Agelas sventres collected from shallow (<30 m), upper mesophotic (30–60 m), and lower mesophotic (60–90 m) reefs. Sponge-associated bacteria were cultivated on six different media, and replicate plates were used to pick individual colonies or to recover the entire biomass. Prokaryotic community analysis was conducted using Illumina MiSeq sequencing of 16S rRNA gene amplicons. A total of 144 bacterial isolates were picked following a colony morphology coding scheme and subsequently identified by 16S rRNA gene sequence analysis. Sponge individuals at each depth-range harboured specific cultivable bacteria that were not retrieved from specimens collected at other depths. However, there were substantial differences in the number of colonies obtained for replicate sponges of the same species. In addition, source of inoculum and cultivation medium had more impact on the cultured prokaryotic community than sample collection depth. This suggests that the “plate count anomaly” is larger than differences in sponge-associated prokaryotic community composition related to depth. Full article
(This article belongs to the Special Issue Marine Bacteria as Sources of Bioactive Compounds)
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Open AccessArticle
Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach
Mar. Drugs 2019, 17(10), 577; https://doi.org/10.3390/md17100577 - 11 Oct 2019
Viewed by 157
Abstract
A glycopeptide fraction (GPF) from internal organs of green sea urchins (Strongylocentrotus droebachiensis Müller, Strongylocentrotidae) has been reported to be an effective bronchitis treatment. In this study, we evaluated the pharmacokinetic and tissue distribution of GPF, following single and repeated intranasal (i/n) [...] Read more.
A glycopeptide fraction (GPF) from internal organs of green sea urchins (Strongylocentrotus droebachiensis Müller, Strongylocentrotidae) has been reported to be an effective bronchitis treatment. In this study, we evaluated the pharmacokinetic and tissue distribution of GPF, following single and repeated intranasal (i/n) administration over the course of seven days in rats. The method measuring lactate dehydrogenase as biomarker was used to analyse the plasma and tissue concentrations of GPF. GPF appears in the plasma 15 min after single i/n administration (100 µg/kg) and reaches its maximum at 45 min. The area under the curve (AUC)0–24 and Cmax were similar using both i/n and intravenous administration, while mean residence time (MRT) and T1/2 after i/n administration were significantly higher compared with intravenous (i/v) administration. The absolute bioavailability of GPF after i/n administration was 89%. The values of tissue availability (ft) provided evidence about the highest concentration of GPF in the nose mucosa (ft = 34.9), followed by spleen (ft = 4.1), adrenal glands (ft = 3.8), striated muscle (ft = 1.8), kidneys (ft = 0.5), and liver (ft = 0.3). After repeated dose administration, GPF exhibited significantly higher AUC0–24 and MRT, indicating its accumulation in the plasma. Full article
(This article belongs to the Special Issue Pharmacokinetic Research of Marine Drugs)
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Open AccessReview
Bioinformatics for Marine Products: An Overview of Resources, Bottlenecks, and Perspectives
Mar. Drugs 2019, 17(10), 576; https://doi.org/10.3390/md17100576 - 11 Oct 2019
Viewed by 177
Abstract
The sea represents a major source of biodiversity. It exhibits many different ecosystems in a huge variety of environmental conditions where marine organisms have evolved with extensive diversification of structures and functions, making the marine environment a treasure trove of molecules with potential [...] Read more.
The sea represents a major source of biodiversity. It exhibits many different ecosystems in a huge variety of environmental conditions where marine organisms have evolved with extensive diversification of structures and functions, making the marine environment a treasure trove of molecules with potential for biotechnological applications and innovation in many different areas. Rapid progress of the omics sciences has revealed novel opportunities to advance the knowledge of biological systems, paving the way for an unprecedented revolution in the field and expanding marine research from model organisms to an increasing number of marine species. Multi-level approaches based on molecular investigations at genomic, metagenomic, transcriptomic, metatranscriptomic, proteomic, and metabolomic levels are essential to discover marine resources and further explore key molecular processes involved in their production and action. As a consequence, omics approaches, accompanied by the associated bioinformatic resources and computational tools for molecular analyses and modeling, are boosting the rapid advancement of biotechnologies. In this review, we provide an overview of the most relevant bioinformatic resources and major approaches, highlighting perspectives and bottlenecks for an appropriate exploitation of these opportunities for biotechnology applications from marine resources. Full article
(This article belongs to the Special Issue Bioinformatics of Marine Natural Products)
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Open AccessArticle
Preparation and Properties of Minocycline-Loaded Carboxymethyl Chitosan Gel/Alginate Nonwovens Composite Wound Dressings
Mar. Drugs 2019, 17(10), 575; https://doi.org/10.3390/md17100575 - 11 Oct 2019
Viewed by 201
Abstract
As derivatives from marine natural biomaterials, alginate-based and chitosan-based biomaterials are commonly used in wound dressings. Calcium alginate fiber (CAF) dressings possess excellent absorption and unique gel forming performance, but the low bioactivity limits its application in wound healing. Carboxymethyl chitosan (CM-Chit) has [...] Read more.
As derivatives from marine natural biomaterials, alginate-based and chitosan-based biomaterials are commonly used in wound dressings. Calcium alginate fiber (CAF) dressings possess excellent absorption and unique gel forming performance, but the low bioactivity limits its application in wound healing. Carboxymethyl chitosan (CM-Chit) has excellent antibacterial activity, but the gel structure with weak mechanical properties restricts its application. In this study, minocycline (Mino)/CM-Chit solution was coated on the surface of plasma treated CAF needle-punched nonwovens, and then Mino loaded CM-Chit gel/CAF nonwovens composite dressings were fabricated by EDC/NHS (1-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide) crosslinking. The dressings had a porous composite structure, which allowed them to quickly absorb and store a large number of wound exudates. Skin-like tensile performance allowed the dressings to provide a better healing environment. Antibacterial assay against Escherichia coli and Staphylococcus aureus indicated that the addition of Mino significantly improved the antibacterial activity of the wound dressings. The tight structure of CM-Chit gel prevented the burst release of Mino so that the dressings had antibacterial activity in a certain period of release time. Cell culture assay showed that the dressings had excellent cell biocompatibility. As new functional dressings, the prepared composite dressings had excellent potential in the clinical healing of wounds. Full article
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Open AccessArticle
Naturally Drug-Loaded Chitin: Isolation and Applications
Mar. Drugs 2019, 17(10), 574; https://doi.org/10.3390/md17100574 - 10 Oct 2019
Viewed by 257
Abstract
Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are [...] Read more.
Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are typical examples of demosponges with well-developed chitinous skeletons. In particular, species belonging to the family Ianthellidae possess chitinous, flat, fan-like fibrous skeletons with a unique, microporous 3D architecture that makes them particularly interesting for applications. In this work, we focus our attention on the demosponge Ianthella flabelliformis (Linnaeus, 1759) for simultaneous extraction of both naturally occurring (“ready-to-use”) chitin scaffolds, and biologically active bromotyrosines which are recognized as potential antibiotic, antitumor, and marine antifouling substances. We show that selected bromotyrosines are located within pigmental cells which, however, are localized within chitinous skeletal fibers of I. flabelliformis. A two-step reaction provides two products: treatment with methanol extracts the bromotyrosine compounds bastadin 25 and araplysillin-I N20 sulfamate, and a subsequent treatment with acetic acid and sodium hydroxide exposes the 3D chitinous scaffold. This scaffold is a mesh-like structure, which retains its capillary network, and its use as a potential drug delivery biomaterial was examined for the first time. The results demonstrate that sponge-derived chitin scaffolds, impregnated with decamethoxine, effectively inhibit growth of the human pathogen Staphylococcus aureus in an agar diffusion assay. Full article
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Open AccessArticle
Entomotoxic Activity of Prasiola crispa (Antarctic Algae) in Nauphoeta cinerea Cockroaches: Identification of Main Steroidal Compounds
Mar. Drugs 2019, 17(10), 573; https://doi.org/10.3390/md17100573 - 10 Oct 2019
Viewed by 187
Abstract
Prasiola crispa is a macroscopic green algae found in abundance in Antarctica ice free areas. Prasiola crispan-hexaneextract (HPC) induced insecticidal activity in Nauphoeta cinerea cockroaches after 24 h of exposure. The chemical analysis of HPC revealed the presence of the followingphytosterols: β-sitosterol, [...] Read more.
Prasiola crispa is a macroscopic green algae found in abundance in Antarctica ice free areas. Prasiola crispan-hexaneextract (HPC) induced insecticidal activity in Nauphoeta cinerea cockroaches after 24 h of exposure. The chemical analysis of HPC revealed the presence of the followingphytosterols: β-sitosterol, campesterol and stigmasterol. The incubation of cockroach semi-isolated heart preparations with HPC caused a significant negative chronotropic activity in the heartbeats. HPC affected the insect neuromuscular function by inducing a complete inhibition of the cockroach leg-muscle twitch tension. When the isolated phytosterols were injected at in vivo cockroach neuromuscular preparations, there was a progressive inhibition of muscle twitches on the following order of potency: β-sitosterol > campesterol > stigmasterol. HPC also provoked significant behavioral alterations, characterized by the increase or decrease of cockroach grooming activity, depending on the dose assayed. Altogether, the results presented here corroborate the insecticide potential of Prasiola crispa Antarctic algae. They also revealed the presence of phytosterols and the involvement of these steroidal compounds in the entomotoxic activity of the algae, potentially by modulating octopaminergic-cholinergic pathways. Further phytochemical-combined bioguided analysis of the HPC will unveil novel bioactive compounds that might be an accessory to the insecticide activity of the algae. Full article
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
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Open AccessArticle
Actinomycin V Suppresses Human Non-Small-Cell Lung Carcinoma A549 Cells by Inducing G2/M Phase Arrest and Apoptosis via the p53-Dependent Pathway
Mar. Drugs 2019, 17(10), 572; https://doi.org/10.3390/md17100572 - 09 Oct 2019
Viewed by 248
Abstract
Actinomycin V, extracted and separated from marine-derived actinomycete Streptomyces sp., as the superior potential replacement of actinomycin D (which showed defect for its hepatotoxicity) has revealed an ideal effect in the suppression of migration and invasion in human breast cancer cells as [...] Read more.
Actinomycin V, extracted and separated from marine-derived actinomycete Streptomyces sp., as the superior potential replacement of actinomycin D (which showed defect for its hepatotoxicity) has revealed an ideal effect in the suppression of migration and invasion in human breast cancer cells as referred to in our previous study. In this study, the involvement of p53 in the cell cycle arrest and pro-apoptotic action of actinomycin V was investigated in human non-small-cell lung carcinoma A549 cells. Results from the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide assay showed that cytotoxic activity of actinomycin V on A549 cells (with wild-type p53) was stronger than the NCI-H1299 cells (p53-deficient). Actinomycin V upregulated both of the protein and mRNA expression levels of p53, p21Waf1/Cip1 and Bax in A549 cells. For this situation, actinomycin V decreased the M-phase related proteins (Cdc2, Cdc25A and Cyclin B1) expression, arrested cells in G2/M phase and subsequently triggered apoptosis by mediating the Bcl-2 family proteins’ expression (Bax and Bcl-2). Furthermore, the effects of cell cycle arrest and apoptosis in A549 cells which were induced by actinomycin V could be reversed by the pifithrin-α, a specific inhibitor of p53 transcriptional activity. Collectively, our results suggest that actinomycin V causes up-regulation of p53 by which the growth of A549 cells is suppressed for cell cycle arrest and apoptosis. Full article
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Open AccessReview
Therapies from Fucoidan: New Developments
Mar. Drugs 2019, 17(10), 571; https://doi.org/10.3390/md17100571 - 09 Oct 2019
Viewed by 263
Abstract
Since our last review in 2015, the study and use of fucoidan has extended in several research areas. Clinical use of fucoidan for the treatment of renal disease has become available and human safety studies have been undertaken on radiolabeled fucoidan for the [...] Read more.
Since our last review in 2015, the study and use of fucoidan has extended in several research areas. Clinical use of fucoidan for the treatment of renal disease has become available and human safety studies have been undertaken on radiolabeled fucoidan for the purpose of imaging thrombi. Fucoidan has been incorporated into an increasing number of commercially available supplements and topical treatments. In addition, new measuring techniques are now available to assess the biologically relevant uptake of fucoidans and to assist in production. Microbiome modulation and anti-pathogenic effects are increasingly promising applications for fucoidans, due to the need for alternative approaches to antibiotic use in the food chain. This review outlines promising new developments in fucoidan research, including potential future therapeutic use. Full article
Open AccessArticle
Phlorotannins from Ecklonia cava Attenuates Palmitate-Induced Endoplasmic Reticulum Stress and Leptin Resistance in Hypothalamic Neurons
Mar. Drugs 2019, 17(10), 570; https://doi.org/10.3390/md17100570 - 09 Oct 2019
Viewed by 238
Abstract
Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava [...] Read more.
Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)—had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia. Full article
(This article belongs to the collection Marine Drugs in the Management of Metabolic Diseases)
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Open AccessFeature PaperArticle
Kinase-Based Screening of Marine Natural Extracts Leads to the Identification of a Cytotoxic High Molecular Weight Metabolite from the Mediterranean Sponge Crambe tailliezi
Mar. Drugs 2019, 17(10), 569; https://doi.org/10.3390/md17100569 - 09 Oct 2019
Viewed by 284
Abstract
Regulated cell death (RCD) results from the activation of one or more signal transduction modules both in physiological or pathological conditions. It is now established that RCD is involved in numerous human diseases, including cancer. As regulated cell death processes can be modulated [...] Read more.
Regulated cell death (RCD) results from the activation of one or more signal transduction modules both in physiological or pathological conditions. It is now established that RCD is involved in numerous human diseases, including cancer. As regulated cell death processes can be modulated by pharmacological tools, the research reported here aims to characterize new marine compounds acting as RCD modulators. Protein kinases (PKs) are key signaling actors in various RCDs notably through the control of either mitosis (e.g., the PKs Aurora A and B) or necroptosis (e.g., RIPK1 and RIPK3). From the primary screening of 27 various extracts of marine organisms collected in the Mediterranean Sea, an extract and subsequently a purified high molecular weight compound dubbed P3, were isolated from the marine sponge Crambe tailliezi and characterized as a selective inhibitor of PKs Aurora A and B. Furthermore, P3 was shown to induce apoptosis and to decrease proliferation and mitotic index of human osteosarcoma U-2 OS cells. Full article
(This article belongs to the Special Issue High-Throughput Screening of Marine Resources)
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Open AccessArticle
Cloning, Expression, and Characterization of a New PL25 Family Ulvan Lyase from Marine Bacterium Alteromonas sp. A321
Mar. Drugs 2019, 17(10), 568; https://doi.org/10.3390/md17100568 - 08 Oct 2019
Viewed by 263
Abstract
Ulvan lyases can degrade ulvan to oligosaccharides with potent biological activity. A new ulvan lyase gene, ALT3695, was identified in Alteromonas sp. A321. Soluble expression of ALT3695 was achieved in Escherichia coli BL21 (DE3). The 1314-bp gene encoded a protein with 437 [...] Read more.
Ulvan lyases can degrade ulvan to oligosaccharides with potent biological activity. A new ulvan lyase gene, ALT3695, was identified in Alteromonas sp. A321. Soluble expression of ALT3695 was achieved in Escherichia coli BL21 (DE3). The 1314-bp gene encoded a protein with 437 amino acid residues. The amino acid sequence of ALT3695 exhibited low sequence identity with polysaccharide lyase family 25 (PL25) ulvan lyases from Pseudoalteromonas sp. PLSV (64.14% identity), Alteromonas sp. LOR (62.68% identity), and Nonlabens ulvanivorans PLR (57.37% identity). Recombinant ALT3695 was purified and the apparent molecular weight was about 53 kDa, which is different from that of other polysaccharide-degrading enzymes identified in Alteromonas sp. A321. ALT3695 exhibited maximal activity in 50 mM Tris-HCl buffer at pH 8.0 and 50 °C. ALT3695 was relatively thermostable, as 90% activity was observed after incubation at 40 °C for 3 h. The Km and Vmax values of ALT3695 towards ulvan were 0.43 mg·mL−1 and 0.11 μmol·min−1·mL−1, respectively. ESI-MS analysis showed that enzymatic products were mainly disaccharides and tetrasaccharides. This study reports a new PL25 family ulvan lyase, ALT3695, with properties that suggest its great potential for the preparation of ulvan oligosaccharides. Full article
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Open AccessReview
Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application
Mar. Drugs 2019, 17(10), 567; https://doi.org/10.3390/md17100567 - 06 Oct 2019
Viewed by 341
Abstract
Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. [...] Read more.
Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with minimum host toxicity against a variety of clinically relevant, enveloped viruses. This review examines the structural characteristics of GRFT, focusing on its carbohydrate-binding capability. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addition, its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale production and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clinical studies examining GRFT’s effects on viruses are presented. Full article
(This article belongs to the Special Issue Anti-Microbial Compounds from Marine Sources)
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Open AccessFeature PaperArticle
Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells
Mar. Drugs 2019, 17(10), 566; https://doi.org/10.3390/md17100566 - 04 Oct 2019
Viewed by 337
Abstract
Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural [...] Read more.
Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural stem cells (rNSC) as a model system, and used a well-known neurotoxin, domoic acid (DA), as a model test chemical to validate the assay. This assay was used to investigate the potential neurotoxic effects of Ochratoxin A (OTA), of which the main target organ is the kidney. However, limited information is available regarding its neurotoxic effects. The effects of DA and OTA on the cytotoxicity and on the degree of differentiation of rat rNSC into astrocytes, neurons, and oligodendrocytes were monitored using cell-specific immunofluorescence staining for undifferentiated rNSC (nestin), neurospheres (nestin and A2B5), neurons (MAP2 clone M13, MAP2 clone AP18, and Doublecortin), astrocytes (GFAP), and oligodendrocytes (A2B5 and mGalc). In the absence of any chemical exposure, approximately 46% of rNSC differentiated into astrocytes and neurons, while 40% of the rNSC differentiated into oligodendrocytes. Both non-cytotoxic and cytotoxic concentrations of DA and OTA reduced the differentiation of rNSC into astrocytes, neurons, and oligodendrocytes. Furthermore, a non-cytotoxic nanomolar (0.05 µM) concentration of DA and 0.2 µM of OTA reduced the percentage differentiation of rNSC into astrocytes and neurons. Morphometric analysis showed that the highest concentration (10 μM) of DA reduced axonal length. These indicate that low, non-cytotoxic concentrations of DA and OTA can interfere with the differentiation of rNSC. Full article
(This article belongs to the Special Issue Genetics of Marine Organisms Associated with Human Health)
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