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Marine Drugs
Volume 14
Issue 7
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Mar. Drugs, Volume 14, Issue 7 (July 2016) – 19 articles

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4545 KiB  
Article
APO-9′-Fucoxanthinone Extracted from Undariopsis peteseniana Protects Oxidative Stress-Mediated Apoptosis in Cigarette Smoke-Exposed Human Airway Epithelial Cells
by Jun-Ho Jang, Ji-Hyeok Lee, Hitendra S. Chand, Jong-Soo Lee, Yong Lin, Nathaniel Weathington, Rama Mallampalli, You-Jin Jeon and Toru Nyunoya
Mar. Drugs 2016, 14(7), 140; https://doi.org/10.3390/md14070140 - 21 Jul 2016
Cited by 11 | Viewed by 6280
Abstract
Long-term cigarette smoking increases the risk for chronic obstructive pulmonary disease (COPD), characterized by irreversible expiratory airflow limitation. The pathogenesis of COPD involves oxidative stress and chronic inflammation. Various natural marine compounds possess both anti-oxidant and anti-inflammatory properties, but few have been tested [...] Read more.
Long-term cigarette smoking increases the risk for chronic obstructive pulmonary disease (COPD), characterized by irreversible expiratory airflow limitation. The pathogenesis of COPD involves oxidative stress and chronic inflammation. Various natural marine compounds possess both anti-oxidant and anti-inflammatory properties, but few have been tested for their efficacy in COPD models. In this study, we conducted an in vitro screening test to identify natural compounds isolated from various brown algae species that might provide protection against cigarette smoke extract (CSE)-induced cytotoxicity. Among nine selected natural compounds, apo-9′-fucoxanthinone (Apo9F) exhibited the highest protection against CSE-induced cytotoxicity in immortalized human bronchial epithelial cells (HBEC2). Furthermore, the protective effects of Apo9F were observed to be associated with a significant reduction in apoptotic cell death, DNA damage, and the levels of mitochondrial reactive oxygen species (ROS) released from CSE-exposed HBEC2 cells. These results suggest that Apo9F protects against CSE-induced DNA damage and apoptosis by regulating mitochondrial ROS production. Full article
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Full article ">Figure 1
<p>Screening of nine marine compounds for protection against cigarette smoke-induced cytotoxicity in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide)-based cell viability after treatment with various concentrations of the nine individual marine compounds (0, 5, 10, 25, and 50 µM in DMSO (dimethyl sulfoxide)) in the presence or absence of 5% CSE (cigarette smoke extract) for 24 h. Single measurements for each data point with <span class="html-italic">R</span> values greater than 0.5 are shown for toxicity (0% CSE) or rescue (5% CSE); (<b>B</b>) BEAS-2B cells were cultured with 50 μM Apo9F in the presence or absence of 5% CSE for 24 h and assayed for viability. Data are expressed as mean ± SEM (** <span class="html-italic">p</span> &lt; 0.01) cytotoxicity in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 MTT-based cell viability after treatment with various concentrations of the nine individual marine compounds (0, 5, 10, 25, and 50 µM in DMSO) in the presence or absence of 5% CSE for 24 h. Single measurements for each data point with <span class="html-italic">R</span> values greater than 0.5 are shown for toxicity (0% CSE) or rescue (5% CSE); (<b>B</b>) BEAS-2B cells were cultured with 50 μM Apo9F in the presence or absence of 5% CSE for 24 h and assayed for viability. Data are expressed as mean ± SEM (** <span class="html-italic">p</span> &lt; 0.01).</p> Full article ">Figure 1 Cont.
<p>Screening of nine marine compounds for protection against cigarette smoke-induced cytotoxicity in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 MTT (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide)-based cell viability after treatment with various concentrations of the nine individual marine compounds (0, 5, 10, 25, and 50 µM in DMSO (dimethyl sulfoxide)) in the presence or absence of 5% CSE (cigarette smoke extract) for 24 h. Single measurements for each data point with <span class="html-italic">R</span> values greater than 0.5 are shown for toxicity (0% CSE) or rescue (5% CSE); (<b>B</b>) BEAS-2B cells were cultured with 50 μM Apo9F in the presence or absence of 5% CSE for 24 h and assayed for viability. Data are expressed as mean ± SEM (** <span class="html-italic">p</span> &lt; 0.01) cytotoxicity in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 MTT-based cell viability after treatment with various concentrations of the nine individual marine compounds (0, 5, 10, 25, and 50 µM in DMSO) in the presence or absence of 5% CSE for 24 h. Single measurements for each data point with <span class="html-italic">R</span> values greater than 0.5 are shown for toxicity (0% CSE) or rescue (5% CSE); (<b>B</b>) BEAS-2B cells were cultured with 50 μM Apo9F in the presence or absence of 5% CSE for 24 h and assayed for viability. Data are expressed as mean ± SEM (** <span class="html-italic">p</span> &lt; 0.01).</p> Full article ">Figure 2
<p>Apo9F suppresses apoptotic cell death in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 cells were cultured with 50 µM Apo9F in the presence or absence of 5% CSE for 24 h. Cell death was analyzed by Annexin Vand propidium iodide (PI) staining 24 h after CSE exposure. The percentage of Annexin V positive cells/total cell number was expressed as percentage apoptosis. Data are expressed as mean ± SEM for three independentexperiments (** <span class="html-italic">p</span> &lt; 0.01); (<b>B</b>) representative flow cytometry data are shown.</p> Full article ">Figure 2 Cont.
<p>Apo9F suppresses apoptotic cell death in cultured immortalized human bronchial epithelial cells. (<b>A</b>) HBEC2 cells were cultured with 50 µM Apo9F in the presence or absence of 5% CSE for 24 h. Cell death was analyzed by Annexin Vand propidium iodide (PI) staining 24 h after CSE exposure. The percentage of Annexin V positive cells/total cell number was expressed as percentage apoptosis. Data are expressed as mean ± SEM for three independentexperiments (** <span class="html-italic">p</span> &lt; 0.01); (<b>B</b>) representative flow cytometry data are shown.</p> Full article ">Figure 3
<p>Apo9F decreases mitochondria-derived ROS in cigarette smoke-exposed HBEC2 cells. (<b>A</b>) HBEC2 cells were cultured with Apo9F (50 µM) in the presence or absence of 2% CSE for 24 h and were determined mitochondrial ROS levels. Data are expressed as mean ± SEM for three independent experiments (** <span class="html-italic">p</span> &lt; 0.01); (<b>B</b>) HBEC2 cells were treated as in (<b>A</b>). Representative pictures are shown (Bars = 50 µm).</p> Full article ">Figure 3 Cont.
<p>Apo9F decreases mitochondria-derived ROS in cigarette smoke-exposed HBEC2 cells. (<b>A</b>) HBEC2 cells were cultured with Apo9F (50 µM) in the presence or absence of 2% CSE for 24 h and were determined mitochondrial ROS levels. Data are expressed as mean ± SEM for three independent experiments (** <span class="html-italic">p</span> &lt; 0.01); (<b>B</b>) HBEC2 cells were treated as in (<b>A</b>). Representative pictures are shown (Bars = 50 µm).</p> Full article ">Figure 4
<p>Apo9F attenuates cigarette smoke-induced DNA damage in HBEC2 cells. (<b>A</b>) HBEC2 cells were cultured with Apo9F (50 µM) in the presence or absence of 2% CSE for 24 h. Immunoblot analysis was performed for phosphorylation of ATM. Immunoblotting data are representative of three experiments; (<b>B</b>) HBEC2 cells were treated as in (<b>A</b>) and ICF (immunocytofluorescence) analysis was performed for phosphorylation of ATM. Representative pictures are shown (Bars = 50 µm).</p> Full article ">Figure 4 Cont.
<p>Apo9F attenuates cigarette smoke-induced DNA damage in HBEC2 cells. (<b>A</b>) HBEC2 cells were cultured with Apo9F (50 µM) in the presence or absence of 2% CSE for 24 h. Immunoblot analysis was performed for phosphorylation of ATM. Immunoblotting data are representative of three experiments; (<b>B</b>) HBEC2 cells were treated as in (<b>A</b>) and ICF (immunocytofluorescence) analysis was performed for phosphorylation of ATM. Representative pictures are shown (Bars = 50 µm).</p> Full article ">Figure 5
<p>Apo9F attenuates cigarette smoke-induced DNA damage in HBEC2 cells. HBEC2 cells were cultured with Apo9F (50 µM) in the presence or absence of 5% CSE for 4 h. (<b>A</b>) Representative images from the comet assay performed to measure DNA fragmentation by loss of nuclear DNA cohesion in the “tail moment” (black bars) with fluorescent microscopic imaging; (<b>B</b>) quantitative analysis of tail moment from at least 50 individual cells from each of the three groups (** <span class="html-italic">p</span> &lt; 0.01). (white scale bar, 50 µm).</p> Full article ">
1353 KiB  
Review
Blue-Print Autophagy: Potential for Cancer Treatment
by Nadia Ruocco, Susan Costantini and Maria Costantini
Mar. Drugs 2016, 14(7), 138; https://doi.org/10.3390/md14070138 - 21 Jul 2016
Cited by 30 | Viewed by 8722
Abstract
The marine environment represents a very rich source of biologically active compounds with pharmacological applications. This is due to its chemical richness, which is claiming considerable attention from the health science communities. In this review we give a general overview on the marine [...] Read more.
The marine environment represents a very rich source of biologically active compounds with pharmacological applications. This is due to its chemical richness, which is claiming considerable attention from the health science communities. In this review we give a general overview on the marine natural products involved in stimulation and inhibition of autophagy (a type of programmed cell death) linked to pharmacological and pathological conditions. Autophagy represents a complex multistep cellular process, wherein a double membrane vesicle (the autophagosome) captures organelles and proteins and delivers them to the lysosome. This natural and destructive mechanism allows the cells to degrade and recycle its cellular components, such as amino acids, monosaccharides, and lipids. Autophagy is an important mechanism used by cells to clear pathogenic organism and deal with stresses. Therefore, it has also been implicated in several diseases, predominantly in cancer. In fact, pharmacological stimulation or inhibition of autophagy have been proposed as approaches to develop new therapeutic treatments of cancers. In conclusion, this blue-print autophagy (so defined because it is induced and/or inhibited by marine natural products) represents a new strategy for the future of biomedicine and of biotechnology in cancer treatment. Full article
(This article belongs to the Special Issue Marine Compounds as Modulators of Autophagy and Lysosomal Activity)
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Full article ">Figure 1
<p>Schematic diagram of the steps of autophagy. Autophagy begins with the formation of the phagophore (vesicle nucleation step), which leads to the expansion of the phagophore into an autophagosome (vesicle elongation) with the helping of specific proteins. The autophagosome contains some different damaged organelles (shown by different colors), which can fuse with a lysosome (docking and fusion steps) forming an autolysosome.</p> Full article ">Figure 2
<p>Involvement of autophagy in different pathological and physiological processes.</p> Full article ">Figure 3
<p>Chemical structure of different autophagy-inducers, natural products from marine organisms.</p> Full article ">Figure 3 Cont.
<p>Chemical structure of different autophagy-inducers, natural products from marine organisms.</p> Full article ">Figure 4
<p>Chemical structure of different autophagy-inhibitors, natural products from marine organisms.</p> Full article ">
6280 KiB  
Review
From Discovery to Production: Biotechnology of Marine Fungi for the Production of New Antibiotics
by Johanna Silber, Annemarie Kramer, Antje Labes and Deniz Tasdemir
Mar. Drugs 2016, 14(7), 137; https://doi.org/10.3390/md14070137 - 21 Jul 2016
Cited by 68 | Viewed by 20370
Abstract
Filamentous fungi are well known for their capability of producing antibiotic natural products. Recent studies have demonstrated the potential of antimicrobials with vast chemodiversity from marine fungi. Development of such natural products into lead compounds requires sustainable supply. Marine biotechnology can significantly contribute [...] Read more.
Filamentous fungi are well known for their capability of producing antibiotic natural products. Recent studies have demonstrated the potential of antimicrobials with vast chemodiversity from marine fungi. Development of such natural products into lead compounds requires sustainable supply. Marine biotechnology can significantly contribute to the production of new antibiotics at various levels of the process chain including discovery, production, downstream processing, and lead development. However, the number of biotechnological processes described for large-scale production from marine fungi is far from the sum of the newly-discovered natural antibiotics. Methods and technologies applied in marine fungal biotechnology largely derive from analogous terrestrial processes and rarely reflect the specific demands of the marine fungi. The current developments in metabolic engineering and marine microbiology are not yet transferred into processes, but offer numerous options for improvement of production processes and establishment of new process chains. This review summarises the current state in biotechnological production of marine fungal antibiotics and points out the enormous potential of biotechnology in all stages of the discovery-to-development pipeline. At the same time, the literature survey reveals that more biotechnology transfer and method developments are needed for a sustainable and innovative production of marine fungal antibiotics. Full article
(This article belongs to the Special Issue Selected Papers from the 1st Congress of Marine Fungal Natural Products Consortium)
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<p>Biotechnological approaches at different steps of the process chain for developing antibiotics from marine fungi. Abbreviations: SAR, structure-activity relationship; DSP, downstream processing.</p> Full article ">
1713 KiB  
Article
New Cyclotetrapeptides and a New Diketopiperzine Derivative from the Marine Sponge-Associated Fungus Neosartorya glabra KUFA 0702
by War War May Zin, Suradet Buttachon, Tida Dethoup, Carla Fernandes, Sara Cravo, Madalena M. M. Pinto, Luís Gales, José A. Pereira, Artur M. S. Silva, Nazim Sekeroglu and Anake Kijjoa
Mar. Drugs 2016, 14(7), 136; https://doi.org/10.3390/md14070136 - 20 Jul 2016
Cited by 44 | Viewed by 7673
Abstract
Two new cyclotetrapeptides, sartoryglabramides A (5) and B (6), and a new analog of fellutanine A (8) were isolated, together with six known compounds including ergosta-4, 6, 8 (14), 22-tetraen-3-one, ergosterol 5, 8-endoperoxide, helvolic acid, aszonalenin ( [...] Read more.
Two new cyclotetrapeptides, sartoryglabramides A (5) and B (6), and a new analog of fellutanine A (8) were isolated, together with six known compounds including ergosta-4, 6, 8 (14), 22-tetraen-3-one, ergosterol 5, 8-endoperoxide, helvolic acid, aszonalenin (1), (3R)-3-(1H-indol-3-ylmethyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (2), takakiamide (3), (11aR)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione (4), and fellutanine A (7), from the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya glabra KUFA 0702. The structures of the new compounds were established based on extensive 1D and 2D spectral analysis. X-ray analysis was also used to confirm the relative configuration of the amino acid constituents of sartoryglabramide A (5), and the absolute stereochemistry of the amino acid constituents of sartoryglabramide A (5) and sartoryglabramides B (6) was determined by chiral HPLC analysis of their hydrolysates by co-injection with the d- and l- amino acids standards. Compounds 1–8 were tested for their antibacterial activity against Gram-positive (Escherichia coli ATCC 25922) and Gram-negative (Staphyllococus aureus ATCC 25923) bacteria, as well as for their antifungal activity against filamentous (Aspergillus fumigatus ATCC 46645), dermatophyte (Trichophyton rubrum ATCC FF5) and yeast (Candida albicans ATCC 10231). None of the tested compounds exhibited either antibacterial (MIC > 256 μg/mL) or antifungal activities (MIC > 512 μg/mL). Full article
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Graphical abstract
Full article ">Figure 1
<p>Secondary metabolites isolated from the ethyl acetate extract of the culture of <span class="html-italic">N. glabra</span> KUFA 0702.</p> Full article ">Figure 2
<p>Key COSY (—) and HMBC (→) correlations of compound <b>5</b>.</p> Full article ">Figure 3
<p>Ortep view of compound <b>5</b>.</p> Full article ">Figure 4
<p>Key COSY (—) and HMBC (→) correlations of compound <b>6</b>.</p> Full article ">Figure 5
<p>Key COSY (—) and HMBC (→) correlations of compound <b>8</b>.</p> Full article ">Figure 6
<p>Key NOESY (↔) correlations of compound <b>8</b>.</p> Full article ">Figure 7
<p>The two possible epoxide configurations for <b>8</b> in their lowest RHF/6-21G total energy conformation. Solid lines indicate direct NOESY correlations, explained by the <span class="html-italic">S</span>/<span class="html-italic">S</span> stereoisomer and not by the <span class="html-italic">R</span>/<span class="html-italic">R</span>. The discontinuous line shows how spin diffusion gives rise to an H-2′/NH-13 NOESY cross-peak.</p> Full article ">
4343 KiB  
Article
Transcriptome of the Australian Mollusc Dicathais orbita Provides Insights into the Biosynthesis of Indoles and Choline Esters
by Abdul Baten, Ajit Kumar Ngangbam, Daniel L. E. Waters and Kirsten Benkendorff
Mar. Drugs 2016, 14(7), 135; https://doi.org/10.3390/md14070135 - 20 Jul 2016
Cited by 6 | Viewed by 8309
Abstract
Dicathais orbita is a mollusc of the Muricidae family and is well known for the production of the expensive dye Tyrian purple and its brominated precursors that have anticancer properties, in addition to choline esters with muscle-relaxing properties. However, the biosynthetic pathways that [...] Read more.
Dicathais orbita is a mollusc of the Muricidae family and is well known for the production of the expensive dye Tyrian purple and its brominated precursors that have anticancer properties, in addition to choline esters with muscle-relaxing properties. However, the biosynthetic pathways that produce these secondary metabolites in D. orbita are not known. Illumina HiSeq 2000 transcriptome sequencing of hypobranchial glands, prostate glands, albumen glands, capsule glands, and mantle and foot tissues of D. orbita generated over 201 million high quality reads that were de novo assembled into 219,437 contigs. Annotation with reference to the Nr, Swiss-Prot and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases identified candidate-coding regions in 76,152 of these contigs, with transcripts for many enzymes in various metabolic pathways associated with secondary metabolite biosynthesis represented. This study revealed that D. orbita expresses a number of genes associated with indole, sulfur and histidine metabolism pathways that are relevant to Tyrian purple precursor biosynthesis, and many of which were not found in the fully annotated genomes of three other molluscs in the KEGG database. However, there were no matches to known bromoperoxidase enzymes within the D. orbita transcripts. These transcriptome data provide a significant molecular resource for gastropod research in general and Tyrian purple producing Muricidae in particular. Full article
(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)
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Graphical abstract
Full article ">Figure 1
<p>Tyrindoxyl sulfate (<b>A</b>), the ultimate Tyrian purple precursor in <span class="html-italic">Dictahais orbita</span>, is held as a salt of the choline ester murexine (<b>B</b>).</p> Full article ">Figure 2
<p>The proportion and number of <span class="html-italic">Dicathais orbita</span> contigs assigned to gene ontology (GO) terms from biological process, cellular component and molecular function. Biological process was the most highly represented GO category followed by cellular component and molecular function.</p> Full article ">Figure 3
<p>Tryptophan metabolism pathway with matches to <span class="html-italic">Dicathais orbita</span> contigs filled in green. The match to a tryptophanase relevant to indole biosynthesis is highlighted by the red box, whereas the tryptophan 5-monoxygenase that was not detected in our transcriptome is highlighted in a blue box.</p> Full article ">Figure 4
<p>Phenylalanine, tyrosine and tryptophan biosynthetic pathways showing matches to <span class="html-italic">Dicathais orbita</span> contigs highlighted in green, with tryptophan synthase highlighted in the red box.</p> Full article ">Figure 5
<p>Sulfur metabolism pathway with matches to <span class="html-italic">Dicathais orbita</span> contigs highlighted in green; there was no match to dimethyl-sulfide monooxygenase in our transcriptome (<b>blue</b> box).</p> Full article ">Figure 6
<p>Cysteine and methionine metabolism pathways showing matches to <span class="html-italic">Dicathais orbita</span> contigs highlighted in green, including tyrosine aminotransferase (<b>red</b> box), but no match was found to methionine-gamma-lyase (<b>blue</b> box).</p> Full article ">Figure 7
<p>Glycerophospholipid metabolism pathway with matches to <span class="html-italic">D. orbita</span> contigs highlighted in green including choline kinase, choline <span class="html-italic">O</span>-acetyltransferase and acetylcholinesterase (<b>red</b> boxes) used to generate the acetyl choline moiety found in murexine.</p> Full article ">Figure 8
<p>Histidine metabolism pathway showing matches to <span class="html-italic">Dicathais orbita</span> contigs highlighted in green, including several enzymes that convert histidine into imidazole (<b>red</b> boxes) and imidazoleglycerol-phosphate dehydratase (<b>red</b> box <b>top</b> pathway).</p> Full article ">Figure 9
<p><span class="html-italic">Dicathais orbita</span> male (<b>A</b>) and female (<b>B</b>) tissues used for RNA extraction to generate the transcriptome.</p> Full article ">
8291 KiB  
Article
New Polyketides and New Benzoic Acid Derivatives from the Marine Sponge-Associated Fungus Neosartorya quadricincta KUFA 0081
by Chadaporn Prompanya, Tida Dethoup, Luís Gales, Michael Lee, José A. C. Pereira, Artur M. S. Silva, Madalena M. M. Pinto and Anake Kijjoa
Mar. Drugs 2016, 14(7), 134; https://doi.org/10.3390/md14070134 - 16 Jul 2016
Cited by 26 | Viewed by 7485
Abstract
Two new pentaketides, including a new benzofuran-1-one derivative (1) and a new isochromen-1-one (5), and seven new benzoic acid derivatives, including two new benzopyran derivatives (2a, b), a new benzoxepine derivative (3), two new [...] Read more.
Two new pentaketides, including a new benzofuran-1-one derivative (1) and a new isochromen-1-one (5), and seven new benzoic acid derivatives, including two new benzopyran derivatives (2a, b), a new benzoxepine derivative (3), two new chromen-4-one derivatives (4b, 7) and two new benzofuran derivatives (6a, b), were isolated, together with the previously reported 2,3-dihydro-6-hydroxy-2,2-dimethyl-4H-1-benzopyran-4-one (4a), from the culture of the marine sponge-associated fungus Neosartorya quadricincta KUFA 0081. The structures of the new compounds were established based on 1D and 2D NMR spectral analysis, and in the case of compounds 1, 2a, 4b, 5, 6a and 7, the absolute configurations of their stereogenic carbons were determined by an X-ray crystallographic analysis. None of the isolated compounds were active in the tests for antibacterial activity against Gram-positive and Gram-negative bacteria, as well as multidrug-resistant isolates from the environment (MIC > 256 μg/mL), antifungal activity against yeast (Candida albicans ATTC 10231), filamentous fungus (Aspergillus fumigatus ATTC 46645) and dermatophyte (Trichophyton rubrum FF5) (MIC > 512 µg/mL) and in vitro growth inhibitory activity against the MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma) cell lines (GI50 > 150 µM) by the protein binding dye SRB method. Full article
(This article belongs to the Special Issue Marine Fungal Natural Products)
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Full article ">Figure 1
<p>Secondary metabolites of <span class="html-italic">N. quadricincta</span> KUFA0081.</p> Full article ">Figure 1 Cont.
<p>Secondary metabolites of <span class="html-italic">N. quadricincta</span> KUFA0081.</p> Full article ">Figure 2
<p>Key HMBC (<b>→</b>) (<b>a</b>) and NOESY (<b>↔</b>) (<b>b</b>) correlations for compound <b>1</b>.</p> Full article ">Figure 3
<p>ORTEP diagram of compound <b>1</b>.</p> Full article ">Figure 4
<p>Key COSY (–), HMBC (→) (<b>a</b>) and NOESY (↔) (<b>b</b>) correlations for compound <b>2a</b>.</p> Full article ">Figure 5
<p>ORTEP diagram of compound <b>2a</b>.</p> Full article ">Figure 6
<p>Key COSY (–), HMBC (→) (<b>a</b>) and NOESY (↔) (<b>b</b>) correlations for compound <b>2b</b>.</p> Full article ">Figure 7
<p>Key COSY (–), HMBC (→) (<b>a</b>) and NOESY (↔) (<b>b</b>) correlations for compound <b>3</b>.</p> Full article ">Figure 8
<p>The two minimal energy conformations, C1 and C2, for the structure of <b>3</b>, with <span class="html-italic">R</span> configuration for C-3. All calculated distances and energies are exactly the same for the pairs 3<span class="html-italic">R</span>-C1/3<span class="html-italic">S</span>-C2 and 3<span class="html-italic">R</span>-C2/3<span class="html-italic">S</span>-C1. The shorter predicted inter-hydrogen distances H-2/H-11 are presented; for a discussion of the average, NOE effective distances, please refer to the main text.</p> Full article ">Figure 9
<p>Key COSY (<b>–</b>) and HMBC (<b>→</b>) correlations for compound <b>4b</b>.</p> Full article ">Figure 10
<p>ORTEP diagram of compound <b>4b</b>.</p> Full article ">Figure 11
<p>Key HMBC (→) correlations for compound <b>5</b>.</p> Full article ">Figure 12
<p>ORTEP diagram of compound <b>5</b>.</p> Full article ">Figure 13
<p>Key COSY (–), HMBC (→) (<b>a</b>) and NOESY (↔) (<b>b</b>) correlations for compound <b>6a</b>.</p> Full article ">Figure 14
<p>ORTEP diagram of <b>6a</b>.</p> Full article ">Figure 15
<p>Key COSY (<b>–</b>) and HMBC (<b>→</b>) correlations for compound <b>6b</b>.</p> Full article ">Figure 16
<p>Key COSY (–), HMBC (→) (<b>a</b>) and NOESY C-2 (↔) (<b>b</b>) C-2 for compound <b>7</b>.</p> Full article ">Figure 17
<p>ORTEP diagram of compound <b>7</b>.</p> Full article ">Figure 18
<p>Proposed biosynthetic pathways for compounds <b>1</b> and <b>5</b>.</p> Full article ">Figure 19
<p>Proposed biosynthetic pathway for compounds <b>2a</b>, <b>2b</b>, <b>4a</b>, <b>4b</b>, <b>6a</b>, <b>6b</b> and <b>7</b>.</p> Full article ">Figure 20
<p>Proposed biosynthetic pathway for compound <b>3</b>.</p> Full article ">
4244 KiB  
Article
Guanidine Alkaloids from the Marine Sponge Monanchora pulchra Show Cytotoxic Properties and Prevent EGF-Induced Neoplastic Transformation in Vitro
by Sergey A. Dyshlovoy, Kseniya M. Tabakmakher, Jessica Hauschild, Regina K. Shchekaleva, Katharina Otte, Alla G. Guzii, Tatyana N. Makarieva, Ekaterina K. Kudryashova, Sergey N. Fedorov, Larisa K. Shubina, Carsten Bokemeyer, Friedemann Honecker, Valentin A. Stonik and Gunhild Von Amsberg
Mar. Drugs 2016, 14(7), 133; https://doi.org/10.3390/md14070133 - 15 Jul 2016
Cited by 48 | Viewed by 8318
Abstract
Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight [...] Read more.
Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight rare guanidine alkaloids, recently isolated from the marine sponge Monanchora pulchra, namely: monanchocidin A (1), monanchocidin B (2), monanchomycalin C (3), ptilomycalin A (4), monanchomycalin B (5), normonanchocidin D (6), urupocidin A (7), and pulchranin A (8). All of the compounds induced cell cycle arrest (apart from 8) and programmed death of cancer cells. Ptilomycalin A-like compounds 1–6 activated JNK1/2 and ERK1/2, following AP-1 activation and caused p53-independent programmed cell death. Compound 7 induced p53-independent cell death without activation of AP-1 or caspase-3/7, and the observed JNK1/2 activation did not contribute to the cytotoxic effect of the compound. Alkaloid 8 induced JNK1/2 (but not ERK1/2) activation leading to p53-independent cell death and strong suppression of AP-1 activity. Alkaloids 1–4, 7, and 8 were able to inhibit the EGF-induced neoplastic transformation of JB6 P+ Cl41 cells. Our results suggest that investigated guanidine marine alkaloids hold potential to eliminate human cancer cells and prevent cancer cell formation and spreading. Full article
(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)
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<p>Alkaloids <b>1</b>–<b>8</b> and their effect on EGF-induced neoplastic transformation of JB6 P<sup>+</sup> Cl41 cells. (<b>A</b>) Structures of guanidine alkaloids <b>1</b>–<b>8</b> isolated from the marine sponge <span class="html-italic">Monanchora pulchra</span>; (<b>B</b>) representative pictures of microscopic fields of EGF-induced colonies of JB6 P<sup>+</sup> Cl41 cells in soft agar treated with urupocidin A (<b>6</b>) at the indicated concentrations; (<b>C</b>) Inhibition of EGF-induced neoplastic transformation of JB6 P<sup>+</sup> Cl41 cells by compounds <b>1</b>–<b>4</b>, <b>7</b>, and <b>8</b>. INCC<sub>50</sub>—concentration leading to a 50% inhibition of colonies formation. Ratios of IC<sub>50</sub>/INCC<sub>50</sub> were calculated using the IC<sub>50</sub> values from <a href="#marinedrugs-14-00133-t001" class="html-table">Table 1</a> generated by using the MTT assay. * indicates a statistically significant difference (<span class="html-italic">p</span> &lt; 0.05) from the control value.</p> Full article ">Figure 2
<p>Effect of alkaloids <b>1</b>–<b>8</b> on MAPK/AP-1 signaling. (<b>A</b>) Effect on basal AP-1-dependent transcriptional activity (<b>○</b>) and viability (□) of JB6 Cl41 cells stably expressing a luciferase reporter gene controlled by the AP-1 DNA binding sequence after 12 h of treatment. Cell viability was measured using MTT assay; (<b>B</b>) effect on the activation of JNK1/2 and ERK1/2. JB6 P<sup>+</sup> Cl41 cells were treated with the compounds <b>1</b>–<b>8</b> at the indicated concentrations for 48 h, and the level of protein expression was assessed by Western blotting. The intensities of p-JNK1/2 and p-ERK1/2 signals were quantified with Quantity One 4.6 software (Bio-Rad, Hercules, CA, USA) and normalized against the signals of total JNK1/2 and ERK1/2, correspondently; and (<b>C</b>) the effect of SP600125 (specific JNK1/2 inhibitor) on the survival of JB6 P<sup>+</sup> Cl41 cells treated with compounds <b>1</b>–<b>8</b>. Cells were co-treated with different concentrations of the individual drugs or their combination for 48 h. Cell viability was measured by MTT assay and the combinational index (CI) values were calculated with CompuSyn software (v.1.0., ComboSyn Inc., Paramus, NJ, USA) using the Chou-Talalay method. The ratio of the substances and the effects are presented in the <a href="#app1-marinedrugs-14-00133" class="html-app">Supplementary Materials</a>. * indicates a statistically significant difference (<span class="html-italic">p</span> &lt; 0.05) from the control value.</p> Full article ">Figure 2 Cont.
<p>Effect of alkaloids <b>1</b>–<b>8</b> on MAPK/AP-1 signaling. (<b>A</b>) Effect on basal AP-1-dependent transcriptional activity (<b>○</b>) and viability (□) of JB6 Cl41 cells stably expressing a luciferase reporter gene controlled by the AP-1 DNA binding sequence after 12 h of treatment. Cell viability was measured using MTT assay; (<b>B</b>) effect on the activation of JNK1/2 and ERK1/2. JB6 P<sup>+</sup> Cl41 cells were treated with the compounds <b>1</b>–<b>8</b> at the indicated concentrations for 48 h, and the level of protein expression was assessed by Western blotting. The intensities of p-JNK1/2 and p-ERK1/2 signals were quantified with Quantity One 4.6 software (Bio-Rad, Hercules, CA, USA) and normalized against the signals of total JNK1/2 and ERK1/2, correspondently; and (<b>C</b>) the effect of SP600125 (specific JNK1/2 inhibitor) on the survival of JB6 P<sup>+</sup> Cl41 cells treated with compounds <b>1</b>–<b>8</b>. Cells were co-treated with different concentrations of the individual drugs or their combination for 48 h. Cell viability was measured by MTT assay and the combinational index (CI) values were calculated with CompuSyn software (v.1.0., ComboSyn Inc., Paramus, NJ, USA) using the Chou-Talalay method. The ratio of the substances and the effects are presented in the <a href="#app1-marinedrugs-14-00133" class="html-app">Supplementary Materials</a>. * indicates a statistically significant difference (<span class="html-italic">p</span> &lt; 0.05) from the control value.</p> Full article ">Figure 3
<p>Effect alkaloids <b>1</b>–<b>8</b> on basal p53-dependent transcriptional activity (<b>○</b>) and viability (□) of JB6 Cl41 cells stably expressing a luciferase reporter gene controlled by the p53 DNA binding sequence after 12 h of treatment. Cell viability was measured using MTT assay. * indicates a statistically significant difference (<span class="html-italic">p</span> &lt; 0.05) from the control value.</p> Full article ">Figure 4
<p>Pro-apoptotic activity of alkaloids <b>1</b>–<b>8</b> in human cancer cells. (<b>A</b>) Analysis of DNA fragmentation in HeLa cells treated with compounds <b>1</b>–<b>8</b> for 48 h at the concentrations of IC<sub>50</sub>. The number of cells with fragmented DNA was assessed with flow cytometry and assumed as the sub-G1 population in cycle analysis; and (<b>B</b>) analysis of caspase-3/7 activity in HeLa cells under the treatment with the compounds <b>1</b>–<b>8</b> at the concentrations of IC<sub>50</sub> for 48 h. Cisplatin was used as a positive control. Concentrations used corresponded to IC<sub>50</sub> for HeLa cells as presented in <a href="#marinedrugs-14-00133-t001" class="html-table">Table 1</a>. * indicates a statistically significant difference (<span class="html-italic">p</span> &lt; 0.05) from the control value.</p> Full article ">Figure 5
<p>Suggested modes of action of the compounds <b>1</b>–<b>4</b> (<b>A</b>); <b>7</b> (<b>B</b>); and <b>8</b> (<b>C</b>).</p> Full article ">
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Article
Chamigrane Sesquiterpenes from a Basidiomycetous Endophytic Fungus XG8D Associated with Thai Mangrove Xylocarpus granatum
by Siwattra Choodej, Thapong Teerawatananond, Tohru Mitsunaga and Khanitha Pudhom
Mar. Drugs 2016, 14(7), 132; https://doi.org/10.3390/md14070132 - 15 Jul 2016
Cited by 23 | Viewed by 6559
Abstract
Six new chamigrane sesquiterpenes, merulinols A‒F (1‒6), and four known metabolites (7‒10) were isolated from the culture of the basidiomycetous fungus XG8D, a mangrove-derived endophyte. Their structures were elucidated mainly by 1D and 2D NMR, [...] Read more.
Six new chamigrane sesquiterpenes, merulinols A‒F (1‒6), and four known metabolites (7‒10) were isolated from the culture of the basidiomycetous fungus XG8D, a mangrove-derived endophyte. Their structures were elucidated mainly by 1D and 2D NMR, while the structures of 1 and 2 were further confirmed by single-crystal X-ray diffraction analysis. The in vitro cytotoxicity of all compounds was evaluated against three human cancer cell lines, MCF-7, Hep-G2, and KATO-3. Compounds 3 and 4 selectively displayed cytotoxicity against KATO-3 cells with IC50 values of 35.0 and 25.3 μM, respectively. Full article
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<p>Structures of metabolites <b>1</b>–<b>10</b> isolated from the basidiomycetous fungus XG8D.</p> Full article ">Figure 2
<p><sup>1</sup>H‒<sup>1</sup>H COSY and selected HMBC correlations of <b>1</b>, <b>5</b>, and <b>6</b>.</p> Full article ">Figure 3
<p>ORTEP plot of <b>1</b>.</p> Full article ">Figure 4
<p>ORTEP plot of <b>2</b>.</p> Full article ">Figure 5
<p>Selected NOESY correlations of <b>3</b> and <b>4</b>.</p> Full article ">
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Article
Austalides S-U, New Meroterpenoids from the Sponge-Derived Fungus Aspergillus aureolatus HDN14-107
by Jixing Peng, Xiaomin Zhang, Wei Wang, Tianjiao Zhu, Qianqun Gu and Dehai Li
Mar. Drugs 2016, 14(7), 131; https://doi.org/10.3390/md14070131 - 14 Jul 2016
Cited by 31 | Viewed by 7251
Abstract
Three new meroterpenoids, named austalides S-U (1–3), were isolated from the culture of a sponge-derived fungus Aspergillus aureolatus HDN14-107, together with eleven known austalides derivates (4–14). Their structures, including absolute configurations, were assigned on the [...] Read more.
Three new meroterpenoids, named austalides S-U (1–3), were isolated from the culture of a sponge-derived fungus Aspergillus aureolatus HDN14-107, together with eleven known austalides derivates (4–14). Their structures, including absolute configurations, were assigned on the basis of NMR, MS data, and TDDFT ECD calculations. Compound 1 is the first case of austalides with the terpene ring fused to the chroman ring in trans configuration. Compounds 3 and 5 exhibited activities against influenza virus A (H1N1), with IC50 values of 90 and 99 μM, respectively. Full article
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<p>Structures of compounds <b>1</b>–<b>14</b>.</p> Full article ">Figure 2
<p>Key COSY and HMBC correlations of <b>1</b>–<b>3</b>.</p> Full article ">Figure 3
<p>Key NOESY and NOE correlations of <b>1</b>–<b>3</b>.</p> Full article ">Figure 4
<p>B3LYP/6-31+G(d)-calculated ECD spectra of (11<span class="html-italic">R</span>, 14<span class="html-italic">R</span>, 17<span class="html-italic">R</span>, 20<span class="html-italic">S</span>, 21<span class="html-italic">R</span>)-<b>1</b> (<b>red</b>), and the experimental ECD spectrum of <b>1</b> (<b>black</b>). (σ = 0.20 eV).</p> Full article ">Figure 5
<p>Experimental ECD spectra of compounds <b>2</b>, <b>3</b>, <b>4</b> and <b>9</b>.</p> Full article ">Scheme 1
<p>A possible biosynthetic route to <b>1</b>–<b>3</b>.</p> Full article ">
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Article
Antiproliferative Scalarane-Based Metabolites from the Red Sea Sponge Hyrtios erectus
by Sameh S. Elhady, Ahmed M. Al-Abd, Ali M. El-Halawany, Abdulrahman M. Alahdal, Hashim A. Hassanean and Safwat A. Ahmed
Mar. Drugs 2016, 14(7), 130; https://doi.org/10.3390/md14070130 - 8 Jul 2016
Cited by 28 | Viewed by 7300
Abstract
Two new sesterterpenes analogs, namely, 12-acetoxy,16-epi-hyrtiolide (1) and 12β-acetoxy,16β-methoxy,20α-hydroxy-17-scalaren-19,20-olide (2), containing a scalarane-based framework along with seven previously reported scalarane-type sesterterpenes (3–9) have been isolated from the sponge Hyrtios erectus (order Dictyoceratida) collected [...] Read more.
Two new sesterterpenes analogs, namely, 12-acetoxy,16-epi-hyrtiolide (1) and 12β-acetoxy,16β-methoxy,20α-hydroxy-17-scalaren-19,20-olide (2), containing a scalarane-based framework along with seven previously reported scalarane-type sesterterpenes (3–9) have been isolated from the sponge Hyrtios erectus (order Dictyoceratida) collected from the Red Sea, Egypt. The structures of the isolated compounds were elucidated on the basis of their spectroscopic data and comparison with reported NMR data. Compounds 1–9 exhibited considerable antiproliferative activity against breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116) and hepatocellular carcinoma cells (HepG2). Compounds 3, 5 and 9 were selected for subsequent investigations regarding their mechanism of cell death induction (differential apoptosis/necrosis assessment) and their influence on cell cycle distribution. Full article
(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)
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<p>Red Sea sponge <span class="html-italic">Hyrtios erectus</span> (Underwater photograph).</p> Full article ">Figure 2
<p>Structure of isolated compounds <b>1</b>–<b>9</b>.</p> Full article ">Figure 3
<p>Selected COSY (correlation spectroscopy) and HMBC correlations of compounds <b>1</b> and <b>2</b>.</p> Full article ">Figure 4
<p>Important NOESY NMR correlations of compound <b>1</b>.</p> Full article ">Figure 5
<p>Important NOESY NMR correlations of compound <b>2</b>.</p> Full article ">Figure 6
<p>Apoptosis/necrosis analysis was assessed using annexin-V FITC/PI differential staining. HCT-116 cells were exposed to 5 µM of compounds <b>3</b> (<b>B</b>), <b>5</b> (<b>C</b>) and <b>9</b> (<b>D</b>) for 24 h and compared to control cells (<b>A</b>). Cells positive FITC, PI or FITC/PI were determined using quadrant analysis and plotted as percent of total population (<b>E</b>). Data are expressed as Mean ± SEM, <span class="html-italic">n</span> = 3; * significantly different from corresponding control at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 7
<p>Effect of Compounds <b>3</b>, <b>5</b> and <b>9</b> on the cell cycle distribution of HCT-116 cells. The cells were exposed to Compounds <b>3</b> (<b>B</b>), <b>5</b> (<b>C</b>), and <b>9</b> (<b>D</b>) for 24 h and compared to control cells (<b>A</b>). Cell cycle distribution was determined using DNA cytometry analysis and different cell phases were plotted (<b>E</b>) as percentage of total events. Sub-G cell population was taken as representative of total cell death and was plotted as percent of total events (<b>F</b>). Data are presented as mean ± SD; <span class="html-italic">n</span> = 3. *: significantly different from control group.</p> Full article ">
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Review
Spotlight on Antimicrobial Metabolites from the Marine Bacteria Pseudoalteromonas: Chemodiversity and Ecological Significance
by Clément Offret, Florie Desriac, Patrick Le Chevalier, Jérôme Mounier, Camille Jégou and Yannick Fleury
Mar. Drugs 2016, 14(7), 129; https://doi.org/10.3390/md14070129 - 8 Jul 2016
Cited by 130 | Viewed by 11753
Abstract
This review is dedicated to the antimicrobial metabolite-producing Pseudoalteromonas strains. The genus Pseudoalteromonas hosts 41 species, among which 16 are antimicrobial metabolite producers. To date, a total of 69 antimicrobial compounds belonging to 18 different families have been documented. They are classified into [...] Read more.
This review is dedicated to the antimicrobial metabolite-producing Pseudoalteromonas strains. The genus Pseudoalteromonas hosts 41 species, among which 16 are antimicrobial metabolite producers. To date, a total of 69 antimicrobial compounds belonging to 18 different families have been documented. They are classified into alkaloids, polyketides, and peptides. Finally as Pseudoalteromonas strains are frequently associated with macroorganisms, we can discuss the ecological significance of antimicrobial Pseudoalteromonas as part of the resident microbiota. Full article
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<p>Neighbor-joining tree indicating the phylogenetic relationships inferred from partial 16S rDNA gene sequences (1196 nt) of <span class="html-italic">Pseudoalteromonas</span> strains producing either alkaloids (<b>green</b>), polyketides (<b>red</b>), or peptides (<b>blue</b>). Empty circles represent strains producing unidentified antimicrobial compounds. Bootstrap values (expressed as percentage of 1000 replications) &gt; 50% are shown at branching points. The proteobacteria <span class="html-italic">Escherichia coli</span> 2012K11 (position 167-1356) was used as outgroup. Bar, 0.01 substitutions per nucleotide.</p> Full article ">
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Review
To Pee, or Not to Pee: A Review on Envenomation and Treatment in European Jellyfish Species
by Louise Montgomery, Jan Seys and Jan Mees
Mar. Drugs 2016, 14(7), 127; https://doi.org/10.3390/md14070127 - 8 Jul 2016
Cited by 40 | Viewed by 24465
Abstract
There is a growing cause for concern on envenoming European species because of jellyfish blooms, climate change and globalization displacing species. Treatment of envenomation involves the prevention of further nematocyst release and relieving local and systemic symptoms. Many anecdotal treatments are available but [...] Read more.
There is a growing cause for concern on envenoming European species because of jellyfish blooms, climate change and globalization displacing species. Treatment of envenomation involves the prevention of further nematocyst release and relieving local and systemic symptoms. Many anecdotal treatments are available but species-specific first aid response is essential for effective treatment. However, species identification is difficult in most cases. There is evidence that oral analgesics, seawater, baking soda slurry and 42–45 °C hot water are effective against nematocyst inhibition and giving pain relief. The application of topical vinegar for 30 s is effective on stings of specific species. Treatments, which produce osmotic or pressure changes can exacerbate the initial sting and aggravate symptoms, common among many anecdotal treatments. Most available therapies are based on weak evidence and thus it is strongly recommended that randomized clinical trials are undertaken. We recommend a vital increase in directed research on the effect of environmental factors on envenoming mechanisms and to establish a species-specific treatment. Adequate signage on jellyfish stings and standardized first aid protocols with emphasis on protective equipment and avoidance of jellyfish to minimize cases should be implemented in areas at risk. Full article
(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)
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<p>Nematocyst structure and mechanism.</p> Full article ">Figure 2
<p>Schematic diagram of cross-reacting jellyfish species mentioned in publications. The species in grey are currently located outside European waters.</p> Full article ">Figure 3
<p>Number of publications on envenomation symptoms and treatments found on European jellyfish species.</p> Full article ">Figure 4
<p>Comparison of the percentage of 63 papers investigating a given treatment, compared to the percentage of papers that concluded beneficial use of the given treatment.</p> Full article ">Figure 5
<p>The number of conclusions drawn from reviewed papers displaying beneficial (positive effect), ineffective (no effect), or worsening treatments (negative effect) on the jellyfish sting of treatments found in 5% of papers (3 papers) and above.</p> Full article ">Figure 6
<p>(<b>a</b>) Obis, E. <span class="html-italic">Carybdea marsupialis</span> are small transparent box jellyfish with a tentacle on each of the four corners. Photograph reproduced with permission from LIFE CUBOMED project (LIFE08 NAT/ES/0064) and the photographer Eduardo Obis [<a href="#B67-marinedrugs-14-00127" class="html-bibr">67</a>]; (<b>b</b>) de Wulf, L. <span class="html-italic">Chrysaora hysoscella</span> is white-yellow with 16 brown paired bands on the bell surface.</p> Full article ">
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Article
Screening of Diatom Strains and Characterization of Cyclotella cryptica as A Potential Fucoxanthin Producer
by Bingbing Guo, Bin Liu, Bo Yang, Peipei Sun, Xue Lu, Jin Liu and Feng Chen
Mar. Drugs 2016, 14(7), 125; https://doi.org/10.3390/md14070125 - 8 Jul 2016
Cited by 99 | Viewed by 11723
Abstract
Fucoxanthin has been receiving ever-increasing interest due to its broad health beneficial effects. Currently, seaweeds are the predominant source of natural fucoxanthin. However, the disappointingly low fucoxanthin content has impeded their use, driving the exploration of alternative fucoxanthin producers. In the present study, [...] Read more.
Fucoxanthin has been receiving ever-increasing interest due to its broad health beneficial effects. Currently, seaweeds are the predominant source of natural fucoxanthin. However, the disappointingly low fucoxanthin content has impeded their use, driving the exploration of alternative fucoxanthin producers. In the present study, thirteen diatom strains were evaluated with respect to growth and fucoxanthin production potential. Cyclotella cryptica (CCMP 333), which grew well for fucoxanthin production under both photoautotrophic and heterotrophic growth conditions, was selected for further investigation. The supply of nitrate and light individually or in combination were all found to promote growth and fucoxanthin accumulation. When transferring heterotrophic cultures to light, fucoxanthin responded differentially to light intensities and was impaired by higher light intensity with a concomitant increase in diadinoxanthin and diatoxanthin, indicative of the modulation of Diadinoxanthin Cycle to cope with the light stress. Taken together, we, for the first time, performed the screening of diatom strains for fucoxanthin production potential and investigated in detail the effect of nutritional and environmental factors on C. cryptica growth and fucoxanthin accumulation. These results provide valuable implications into future engineering of C. cryptica culture parameters for improved fucoxanthin production and C. cryptica may emerge as a promising microalgal source of fucoxanthin. Full article
(This article belongs to the Collection Bioactive Compounds from Marine Plankton)
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<p>Proposed fucoxanthin biosynthetic steps in diatoms. LCYB: lycopene β-cyclase; VDE: violaxanthin de-epoxidases; ZEP: zeaxanthin epoxidases; DEP: diatoxanthin epoxidases; DDE: diadinoxanthin de-epoxidases. Solid arrows indicate steps that have been validated, while dotted arrows designate the steps to be defined.</p> Full article ">Figure 2
<p>Fucoxanthin content and productivity of thirteen diatom strains under photoautotrophic conditions. Cells on Day 14 were harvested for analysis. Dark bars represent the fucoxanthin content and grey ones represent the fucoxanthin productivity. The fucoxanthin productivity was expressed as fucoxanthin yield divided by culture days. Data are means of three replicates and error bars indicate standard deviations.</p> Full article ">Figure 3
<p>Fucoxanthin content (<b>black</b> column) and biomass concentration (<b>gray</b> column) of diatom strains capable of growing on glucose without light. Cells on Day 6 were collected for analysis. The solid black bar and grey bar represent the fucoxanthin content and biomass concentration, respectively. Data are means of three replicates and error bars indicate standard deviations.</p> Full article ">Figure 4
<p>Biomass concentration (<b>a</b>); Fucoxanthin contents (<b>b</b>); Fucoxanthin yield (<b>c</b>); and Fucoxanthin productivity (<b>d</b>) of <span class="html-italic">C. cryptica</span>. Solid circle and empty circle represent the culture with or without nitrate in the light, and solid triangle down and empty triangle up represent the culture with or without nitrate under dark, respectively. The nitrate concentration is 1.00 g·L<sup>−1</sup> and the light intensity is 30 μmol·m<sup>−2</sup>·s<sup>−1</sup>. Data are means of three replicates and error bars indicate standard deviations.</p> Full article ">Figure 5
<p>Biomass concentration (<b>a</b>); Fucoxanthin contents (<b>b</b>); and Fucoxanthin yield (<b>c</b>) under different light intensity. Solid circle, empty cycle, solid triangle down and empty triangle up represent an illumination intensity condition of 10, 20, 30, and 40 μmol·m<sup>−2</sup>·s<sup>−1</sup>, respectively, with solid square as the dark-growing control. Data are means of three replicates and error bars indicate standard deviations.</p> Full article ">Figure 6
<p>HPLC (High Performance Liquid Chromatography) chromatograms of fucoxanthin standard (<b>a</b>) and the crude extract of <span class="html-italic">C. cryptica</span> (<b>b</b>). Mass spectroscopy (<b>c</b>) of peak 1 in (<b>b</b>) and its visible absorption spectra (<b>d</b>). Absorbance in (<b>a</b>) and (<b>b</b>) was recorded at 449 nm. Peaks were identified as follows: 1, fucoxanthin; 2, diadinoxanthin; and 3, diatoxanthin.</p> Full article ">Figure 7
<p>Fucoxanthin content (<b>blue</b> bar), Diadinoxanthin content (<b>orange</b> bar) and Diatoxanthin content (<b>grey</b> bar) under different light intensity. Bars from the bottom up in every group represent the light intensity of 10, 20, 30, and 40 μmol·m<sup>−2</sup>·s<sup>−1</sup>, respectively. Diadinoxanthin and diatoxanthin contents were quantified as fucoxanthin equivalents with the same method.</p> Full article ">
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Article
Electrospinning of Nanodiamond-Modified Polysaccharide Nanofibers with Physico-Mechanical Properties Close to Natural Skins
by Mina Mahdavi, Nafiseh Mahmoudi, Farzad Rezaie Anaran and Abdolreza Simchi
Mar. Drugs 2016, 14(7), 128; https://doi.org/10.3390/md14070128 - 7 Jul 2016
Cited by 55 | Viewed by 8030
Abstract
Electrospinning of biopolymers has gained significant interest for the fabrication of fibrous mats for potential applications in tissue engineering, particularly for wound dressing and skin regeneration. In this study, for the first time, we report successful electrospinning of chitosan-based biopolymers containing bacterial cellulous [...] Read more.
Electrospinning of biopolymers has gained significant interest for the fabrication of fibrous mats for potential applications in tissue engineering, particularly for wound dressing and skin regeneration. In this study, for the first time, we report successful electrospinning of chitosan-based biopolymers containing bacterial cellulous (33 wt %) and medical grade nanodiamonds (MND) (3 nm; up to 3 wt %). Morphological studies by scanning electron microscopy showed that long and uniform fibers with controllable diameters from 80 to 170 nm were prepared. Introducing diamond nanoparticles facilitated the electrospinning process with a decrease in the size of fibers. Fourier transform infrared spectroscopy determined hydrogen bonding between the polymeric matrix and functional groups of MND. It was also found that beyond 1 wt % MND, percolation networks of nanoparticles were formed which affected the properties of the nanofibrous mats. Uniaxial tensile testing of the woven mats determined significant enhancement of the strength (from 13 MPa to 25 MP) by dispersion of 1 wt % MND. The hydrophilicity of the mats was also remarkably improved, which was favorable for cell attachment. The water vapor permeability was tailorable in the range of 342 to 423 µg·Pa−1·s−1·m−1. The nanodiamond-modified mats are potentially suitable for wound healing applications. Full article
(This article belongs to the Collection Marine Polysaccharides)
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<p>Effect of medical grade nanodiamonds (MND) on the morphology and size distribution of electrospun fibers: (<b>a</b>) chitosan/bacterial cellulose (CS/BC) without MND; (<b>c</b>) contain 1%; (<b>e</b>) 2% and (<b>g</b>) 3% MND particles, respectively. (<b>b</b>), (<b>d</b>), (<b>f</b>) and (<b>h</b>) show the fiber diameter distribution diagrams of each specimen.</p> Full article ">Figure 2
<p>Formation of large nanoparticle clusters upon electrospinning. The concentration of MND (%) is (<b>a</b>) 2 and (<b>b</b>) 3.</p> Full article ">Figure 3
<p>Fourier transform infrared (FT-IR) spectrum of (<b>a</b>) CS/BC polymer; (<b>b</b>) the nanocomposite fiber containing 3% MND; and (<b>c</b>) pristine MND.</p> Full article ">Figure 4
<p>Effect of diamond particles on the hydrophilicity of electrospun CS/BC mats.</p> Full article ">Figure 5
<p>Stress-strain curves of electrospun mats containing different amounts of diamond nanoparticles.</p> Full article ">Figure 6
<p>Weight change per unit of area of the mats versus time for CS/BC mats containing different amounts of MND.</p> Full article ">Figure 7
<p>Cell viability of CS/BC mats dependent on the MND content at two incubated times.</p> Full article ">
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Article
Anticancer Effect of Fucoidan on DU-145 Prostate Cancer Cells through Inhibition of PI3K/Akt and MAPK Pathway Expression
by Gang-Sik Choo, Hae-Nim Lee, Seong-Ah Shin, Hyeong-Jin Kim and Ji-Youn Jung
Mar. Drugs 2016, 14(7), 126; https://doi.org/10.3390/md14070126 - 7 Jul 2016
Cited by 55 | Viewed by 8640
Abstract
In this study, we showed that PI3K/Akt signaling mediates fucoidan’s anticancer effects on prostate cancer cells, including suppression of proliferation. Fucoidan significantly decreased viability of DU-145 cancer cells in a concentration-dependent manner as shown by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The drug also significantly [...] Read more.
In this study, we showed that PI3K/Akt signaling mediates fucoidan’s anticancer effects on prostate cancer cells, including suppression of proliferation. Fucoidan significantly decreased viability of DU-145 cancer cells in a concentration-dependent manner as shown by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The drug also significantly increased chromatin condensation, which indicates apoptosis, in a concentration-dependent manner as shown by DAPI (4′,6-diamidino-2-phenylindole) staining. Fucoidan increased expression of Bax, cleaved poly-ADP ribose polymerase and cleaved caspase-9, and decreased of the Bcl-2, p-Akt, p-PI3K, p-P38, and p-ERK in a concentration-dependent manner. In vivo, fucoidan (at 5 and 10 mg/kg) significantly decreased tumor volume, and increased apoptosis as assessed by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, confirming the tumor inhibitory effect. The drug also increased expression of p-Akt and p-ERK as shown by immunohistochemistry staining. Therefore, fucoidan may be a promising cancer preventive medicine due to its growth inhibitory effects and induction of apoptosis in human prostate cancer cells. Full article
(This article belongs to the Collection Marine Polysaccharides)
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<p>Effect of fucoidan on the cell viability of DU-145 cells. DU-145 cells (2 × 10<sup>4</sup> cells/mL) were treated with 0, 250, 500, 750, 1000 μg/mL fucoidan in RPMI-1640 medium containing 5% FBS for 24 h. The growth inhibition was measured by the MTT assay. Data are mean standard deviation (SD) for three samples. The significance was determined by Student’s <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> &lt; 0.05 compared with untreated control).</p> Full article ">Figure 2
<p>Effect of fucoidan on the chromatin condensation in DU-145 cells. (<b>A</b>) DU-145 cells were treated with 0, 500, 1000 μg/mL fucoidan or vehicle in RPMI-1640 medium containing 5% FBS for 24 h, and cell were stained with DAPI. The arrows indicate chromatin condensation in the cancer cell. (<b>B</b>) DU-145 cells were treated with fucoidan (0, 500, 1000 μg/mL) for 24 h. Apoptosis cells were counted under a light microscope and expressed as the average of five fields. Each bar represents the mean ± SD calculated from independent experiments. Significance was determined by Dunnett’s <span class="html-italic">t</span>-test with * <span class="html-italic">p</span> &lt; 0.05 compared as statistically significant compared with non-treated controls.</p> Full article ">Figure 3
<p>Effect of fucoidan on the apoptotic pathway in DU-145 cells. DU-145 cells were treated with fucoidan 0, 500, and 1000 μg/mL for 24 h and cell were harvested to measure protein levels of Bax, Bcl-2, cspase-9, and PARP by western blotting. The blots were also probed with β-actin antibodies to confirm equal sample loading.</p> Full article ">Figure 4
<p>Effect of fucoidan on the activation of PI3K/Akt pathway in DU-145 cells. Cells were treated with fucoidan 0, 500 and 1000 μg/mL for 24 h. Cell lysates were prepared as described in the materials and methods and analyzed by 12% SDS-PAGE followed by western blotting. (<b>A</b>) The membranes were incubated with PI3K/AKT pathway antibodies. (<b>B</b>) The membranes were incubated with MAPKs pathway antibodies. Each bar represents the mean ± SD calculated from independent experiments. Significance was determined by Dunnett’s <span class="html-italic">t</span>-test with * <span class="html-italic">p</span> &lt;0.05 compared as statistically significant compared with non-treated controls.</p> Full article ">Figure 5
<p>Inhibition of DU-145 prostate tumor growth and enhancement of apoptosis in DU-145 prostate tumors by the fucoidan. (<b>A</b>) To identify the effect of fucoidan in DU-145 prostate tumor growth, nude mice were treated with fucoidan (0, 5, 10 mg/kg) for 21 days (<span class="html-italic">n</span> = 5). (<b>B</b>) The graph expresses final tumor weight. (<b>C</b>) The graph is nude mice weight. Each value was expressed as mean ± SE of five mice. Significance was determined by Dunnett’s <span class="html-italic">t</span>-test with * <span class="html-italic">p</span> &lt;0.05 compared as statistically significant compared with non-treated controls.</p> Full article ">Figure 6
<p>Induction of apoptosis by fucoidan in DU-145 cells. Nude mice were treated with fucoidan for 21 days and apoptosis was assessed by terminal deoxynucleotidyltransferase-mediated Dutp nick-ned labeling (TUNEL) assay. Tumor tissues were observed under a microscope and photographed at a ×200 magnification. The percentage of labeled with TUNEL-positive apoptotic cells was calculated from 1,000 scored cells. Paraffin-embedded tumors were cut into 5 μm sections. Each bar represents the mean ± SD calculated from independent experiments. Significance was determined by Dunnett’s <span class="html-italic">t</span>-test with * <span class="html-italic">p</span> &lt;0.05 compared as statistically significant compared with non-treated controls. Scale bar, 10 µm.</p> Full article ">Figure 7
<p>Effect of fucoidan on p-Akt and p-ERK expression in DU-145 prostate tumors. Nude mice were administered fucoidan (0, 5 and 10 mg/kg) for three weeks and assayed by immunohistochemistry using p-Akt and p-ERK antibodes. Tumor tissues were observed under a microscope and photographed at a ×400 magnification. Paraffin-embedded tumors were sectioned to a thickness of 5 µm. Scale bar, 5 µm.</p> Full article ">Figure 8
<p>Histological observation of nude mice treated intraperitoneally with fucoidan. Fucoidan was administered at a dose of 5 or 10 mg/kg five times per week, for a total 21 injections. On day 21, mice were sacrificed, and tumors excised and evaluated by hematoxylin &amp; eosin (H &amp; E) staining (×200). The dose of fucoidan had no detectable toxicological effect on nude mice. Scale bar, 10 µm.</p> Full article ">
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Article
Production of the Marine Carotenoid Astaxanthin by Metabolically Engineered Corynebacterium glutamicum
by Nadja A. Henke, Sabine A. E. Heider, Petra Peters-Wendisch and Volker F. Wendisch
Mar. Drugs 2016, 14(7), 124; https://doi.org/10.3390/md14070124 - 30 Jun 2016
Cited by 88 | Viewed by 13410
Abstract
Astaxanthin, a red C40 carotenoid, is one of the most abundant marine carotenoids. It is currently used as a food and feed additive in a hundred-ton scale and is furthermore an attractive component for pharmaceutical and cosmetic applications with antioxidant activities. Corynebacterium glutamicum [...] Read more.
Astaxanthin, a red C40 carotenoid, is one of the most abundant marine carotenoids. It is currently used as a food and feed additive in a hundred-ton scale and is furthermore an attractive component for pharmaceutical and cosmetic applications with antioxidant activities. Corynebacterium glutamicum, which naturally synthesizes the yellow C50 carotenoid decaprenoxanthin, is an industrially relevant microorganism used in the million-ton amino acid production. In this work, engineering of a genome-reduced C. glutamicum with optimized precursor supply for astaxanthin production is described. This involved expression of heterologous genes encoding for lycopene cyclase CrtY, β-carotene ketolase CrtW, and hydroxylase CrtZ. For balanced expression of crtW and crtZ their translation initiation rates were varied in a systematic approach using different ribosome binding sites, spacing, and translational start codons. Furthermore, β-carotene ketolases and hydroxylases from different marine bacteria were tested with regard to efficient astaxanthin production in C. glutamicum. In shaking flasks, the C. glutamicum strains developed here overproduced astaxanthin with volumetric productivities up to 0.4 mg·L−1·h−1 which are competitive with current algae-based production. Since C. glutamicum can grow to high cell densities of up to 100 g cell dry weight (CDW)·L−1, the recombinant strains developed here are a starting point for astaxanthin production by C. glutamicum. Full article
(This article belongs to the Special Issue Marine Carotenoids)
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<p>Scheme of C40 cyclic carotenoid biosynthesis in recombinant <span class="html-italic">C. glutamicum</span>. The biosynthesis of C40 cyclic carotenoids derived from precursor molecules dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP) is illustrated. Genes are shown next to the reaction catalyzed by the encoded enzyme (<span class="html-italic">crtE</span>: Prenyl transferase, <span class="html-italic">crtB</span>: Phytoene synthase, <span class="html-italic">crtI</span>: Phytoene desaturase, <span class="html-italic">crtEb</span>: Lycopene elongase, <span class="html-italic">crtYe/f</span>: C45/50 carotenoid ε-cyclase, <span class="html-italic">crtY</span>: Lycopene β-cyclase, <span class="html-italic">crtZ</span>: β-Carotene hydroxylase (3,3'-beta-ionone ring hydroxylase), <span class="html-italic">crtW</span>: β-Carotene ketolase (4,4'-beta-ionone ring ketolase). Endogenous genes are shown in grey boxes and their overexpression indicated by green arrows. Heterologous genes are highlighted in colored boxes.</p> Full article ">Figure 2
<p>Combinatorial gene assembly for varied translation initiation of β-carotene ketolase and hydroxylase genes. Combinations of different RBS sequences (differences given in red letters), translation start codons (ATG/GTG) and spacers (3, 6 or 8 bp in length) between them are highlighted in a green box.</p> Full article ">Figure 3
<p>COMB strains expressing <span class="html-italic">crtW</span> from <span class="html-italic">B. aurantiaca</span> and <span class="html-italic">crtZ</span> from <span class="html-italic">P. ananatis</span> with varied translation initiation signals after growth in the Biolector micro fermentation system. Color phenotypes of 46 different COMB strains and the parental strain BETA1 (bottom right) after 24 h of cultivation.</p> Full article ">Figure 4
<p>Carotenoid profiles and calculated translational initiation rates (TIRs) for <span class="html-italic">C. glutamicum</span> strains expressing <span class="html-italic">crtW</span> from <span class="html-italic">B. aurantiaca</span> and <span class="html-italic">crtZ</span> from <span class="html-italic">P. ananatis</span> with varied translation initiation signal. TIRs were calculated by applying the RBS calculator tool [<a href="#B46-marinedrugs-14-00124" class="html-bibr">46</a>] on the mRNA sequence. TIRs were classified as follows: TIRs &lt;200: low; 200 &lt; TIRs &lt; 2000: medium; TIRs &gt;2000: high. Production of β-carotene, zeaxanthin, canthaxanthin and astaxanthin was determined after 24 h of cultivation in CGXII + 100 mM glucose in Biolector micro fermenter.</p> Full article ">
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Article
Structural Features and Potent Antidepressant Effects of Total Sterols and β-sitosterol Extracted from Sargassum horneri
by Donghai Zhao, Lianwen Zheng, Ling Qi, Shuran Wang, Liping Guan, Yanan Xia and Jianhui Cai
Mar. Drugs 2016, 14(7), 123; https://doi.org/10.3390/md14070123 - 28 Jun 2016
Cited by 51 | Viewed by 11433
Abstract
The purified total sterols and β-sitosterol extracted from Sargassum horneri were evaluated for their antidepressant-like activity using the forced swim test (FST) and tail suspension test (TST) in mice. Total sterols and β-sitosterol significantly reduced the immobility time in the FST and TST. [...] Read more.
The purified total sterols and β-sitosterol extracted from Sargassum horneri were evaluated for their antidepressant-like activity using the forced swim test (FST) and tail suspension test (TST) in mice. Total sterols and β-sitosterol significantly reduced the immobility time in the FST and TST. Total sterols were administered orally for 7 days at doses of 50, 100, and 200 mg/kg, and β-sitosterol was administered intraperitoneally at doses of 10, 20, and 30 mg/kg. β-sitosterol had no effect on locomotor activity in the open field test. In addition, total sterols and β-sitosterol significantly increased NE, 5-HT, and the metabolite 5-HIAA in the mouse brain, suggesting that the antidepressant-like activity may be mediated through these neurotransmitters. Full article
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<p>Effects of β-sitosterol and the positive control fluoxetine (FLU) on the immobility time in the FST in mice. Data are expressed as the mean ± SEM (<span class="html-italic">n</span> = 8). * <span class="html-italic">P</span> &lt; 0.05, ** <span class="html-italic">P</span> &lt; 0.01, *** <span class="html-italic">P</span> &lt; 0.001 compared with vehicle control.</p> Full article ">Figure 2
<p>Effects of β-sitosterol and the positive control fluoxetine (FLU) on the immobility time in the TST in mice. Data are expressed as the mean ± SEM (<span class="html-italic">n</span> = 8). * <span class="html-italic">P</span> &lt; 0.05, ** <span class="html-italic">P</span> &lt; 0.01, *** <span class="html-italic">P</span> &lt; 0.001 compared with vehicle control.</p> Full article ">Figure 3
<p>Effects of β-sitosterol on exploratory activity in the open field test. Crossing: number of line crossings; rearing: number of times observed standing on hind legs; grooming: number of modifications. Values represent the mean ± SEM <span class="html-italic">n</span> = 8.</p> Full article ">Figure 4
<p>Chemical structure of β-sitosterol.</p> Full article ">
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Article
Pretrichodermamides D–F from a Marine Algicolous Fungus Penicillium sp. KMM 4672
by Anton N. Yurchenko, Olga F. Smetanina, Elena V. Ivanets, Anatoly I. Kalinovsky, Yuliya V. Khudyakova, Natalya N. Kirichuk, Roman S. Popov, Carsten Bokemeyer, Gunhild Von Amsberg, Ekaterina A. Chingizova, Shamil Sh. Afiyatullov and Sergey A. Dyshlovoy
Mar. Drugs 2016, 14(7), 122; https://doi.org/10.3390/md14070122 - 27 Jun 2016
Cited by 40 | Viewed by 7354
Abstract
Three new epidithiodiketopiperazines pretrichodermamides D–F (1–3), together with the known N-methylpretrichodermamide B (4) and pretrichodermamide С (5), were isolated from the lipophilic extract of the marine algae-derived fungus Penicillium sp. KMM 4672. The structures [...] Read more.
Three new epidithiodiketopiperazines pretrichodermamides D–F (1–3), together with the known N-methylpretrichodermamide B (4) and pretrichodermamide С (5), were isolated from the lipophilic extract of the marine algae-derived fungus Penicillium sp. KMM 4672. The structures of compounds 1–5 were determined based on spectroscopic methods. The absolute configuration of pretrichodermamide D (1) was established by a combination of modified Mosher′s method, NOESY data, and biogenetic considerations. N-Methylpretrichodermamide B (5) showed strong cytotoxicity against 22Rv1 human prostate cancer cells resistant to androgen receptor targeted therapies. Full article
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<p>Chemical structures of isolated compounds <b>1</b>–<b>5</b>.</p> Full article ">Figure 2
<p>∆δ (δ<sub>S</sub>−δ<sub>R</sub>) values (in Hz) for the MTPA ester of <b>1</b>.</p> Full article ">Figure 3
<p>Energy-minimized 3D models of <b>1</b>–<b>3</b> with selected ROESY correlations.</p> Full article ">
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Article
Toxicological Evaluation of Low Molecular Weight Fucoidan in Vitro and in Vivo
by Pai-An Hwang, Ming-De Yan, Hong-Ting Victor Lin, Kuan-Lun Li and Yen-Chang Lin
Mar. Drugs 2016, 14(7), 121; https://doi.org/10.3390/md14070121 - 24 Jun 2016
Cited by 46 | Viewed by 7840
Abstract
For a long time, fucoidan has been well known for its pharmacological activities, and recently low molecular weight fucoidan (LMF) has been used in food supplements and pharmaceutical products. In the present study, LMF was extracted from Laminaria japonica by enzyme hydrolysis. The [...] Read more.
For a long time, fucoidan has been well known for its pharmacological activities, and recently low molecular weight fucoidan (LMF) has been used in food supplements and pharmaceutical products. In the present study, LMF was extracted from Laminaria japonica by enzyme hydrolysis. The toxicity of LMF in mouse and rat models was determined by many methods, such as total arsenic content, bacterial reverse mutation assay, chromosome aberration assay, and in vivo micronucleus assay. The present findings showed that LMF at 5000 μg/mL exhibited no mutagenicity. It also produced no formatting disruption of red blood cells in vivo. At 2000 mg/kg BW/day there were no toxicological indications. LMF is expected to be used as a safe food supplement. Full article
(This article belongs to the Collection Marine Polysaccharides)
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<p>Growth curves for male (open symbols) and female (solid symbols) rats treated with LMF-LJ for 28 days. Values were expressed as mean ± SD, <span class="html-italic">n</span> = 10.</p> Full article ">
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