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Mar. Drugs, Volume 14, Issue 11 (November 2016)

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Open AccessArticle Macrolactins from Marine-Derived Bacillus subtilis B5 Bacteria as Inhibitors of Inducible Nitric Oxide and Cytokines Expression
Mar. Drugs 2016, 14(11), 195; doi:10.3390/md14110195
Received: 25 June 2016 / Revised: 26 September 2016 / Accepted: 11 October 2016 / Published: 26 October 2016
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Abstract
In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence
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In order to find new natural products with anti-inflammatory activity, chemical investigation of a 3000-meter deep-sea sediment derived bacteria Bacillus subtilis B5 was carried out. A new macrolactin derivative was isolated and identified as 7,13-epoxyl-macrolactin A (1). Owing to the existence of the epoxy ring, 1 exhibited a significant inhibitory effect on the expression of inducible nitric oxide and cytokines, compared with previously isolated known macrolactins (25). Real-time Polymerase Chain Reaction (PCR) analysis showed that the new compound significantly inhibited the mRNA expressions of inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Reverse transcription-PCR analysis demonstrated that the new compound reduced the mRNA expression level of IL-1β in a concentration-dependent manner. Full article
(This article belongs to the Special Issue Deep-Sea Natural Products)
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Open AccessArticle Enzymatic Pre-Treatment Increases the Protein Bioaccessibility and Extractability in Dulse (Palmaria palmata)
Mar. Drugs 2016, 14(11), 196; doi:10.3390/md14110196
Received: 21 September 2016 / Revised: 13 October 2016 / Accepted: 21 October 2016 / Published: 26 October 2016
Cited by 1 | PDF Full-text (868 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Several common protein extraction protocols have been applied on seaweeds, but extraction yields have been limited. The aims of this study were to further develop and optimize existing extraction protocols and to examine the effect of enzymatic pre-treatment on bioaccessibility and extractability of
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Several common protein extraction protocols have been applied on seaweeds, but extraction yields have been limited. The aims of this study were to further develop and optimize existing extraction protocols and to examine the effect of enzymatic pre-treatment on bioaccessibility and extractability of seaweed proteins. Enzymatic pre-treatment of seaweed samples resulted in a three-fold increase in amino acids available for extraction. Combining enzymatic pre-treatment with alkaline extraction resulted in a 1.6-fold increase in the protein extraction yield compared to a standard alkaline extraction protocol. A simulated in vitro gastrointestinal digestion model showed that enzymatic pre-treatment of seaweed increased the amount of amino acids available for intestinal absorption 3.2-fold. In conclusion, enzymatic pre-treatment of seaweeds is effective for increasing the amount of amino acids available for utilization and may thus be an effective means for increasing the utilization potential of seaweed proteins. However, both the enzymatic pre-treatment protocol and the protein extraction protocol need further optimization in order to obtain optimal cost-benefit and results from the in vitro gastrointestinal digestion model need to be confirmed in clinical models. Full article
(This article belongs to the Special Issue Marine Proteins and Peptides)
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Open AccessArticle Evaluation of the Antioxidant Activity of the Marine Pyrroloiminoquinone Makaluvamines
Mar. Drugs 2016, 14(11), 197; doi:10.3390/md14110197
Received: 26 September 2016 / Revised: 19 October 2016 / Accepted: 20 October 2016 / Published: 27 October 2016
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Abstract
Makaluvamines are pyrroloiminoquinones isolated from Zyzzya sponges. Until now, they have been described as topoisomerase II inhibitors with cytotoxic effects in diverse tumor cell lines. In the present work, seven makaluvamines were tested in several antioxidant assays in primary cortical neurons and neuroblastoma
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Makaluvamines are pyrroloiminoquinones isolated from Zyzzya sponges. Until now, they have been described as topoisomerase II inhibitors with cytotoxic effects in diverse tumor cell lines. In the present work, seven makaluvamines were tested in several antioxidant assays in primary cortical neurons and neuroblastoma cells. Among the alkaloids studied, makaluvamine J was the most active in all the assays. This compound was able to reduce the mitochondrial damage elicited by the well-known stressor H2O2. The antioxidant properties of makaluvamine J are related to an improvement of the endogenous antioxidant defenses of glutathione and catalase. SHSY5Y assays proved that this compound acts as a Nrf2 activator leading to an improvement of antioxidant defenses. A low concentration of 10 nM is able to reduce the reactive oxygen species release and maintain a correct mitochondrial function. Based on these results, non-substituted nitrogen in the pyrrole plus the presence of a p-hydroxystyryl without a double bond seems to be the most active structure with a complete antioxidant effect in neuronal cells. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle The Sequestration of Oxy-Polybrominated Diphenyl Ethers in the Nudibranchs Miamira magnifica and Miamira miamirana
Mar. Drugs 2016, 14(11), 198; doi:10.3390/md14110198
Received: 25 August 2016 / Revised: 16 October 2016 / Accepted: 18 October 2016 / Published: 27 October 2016
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Abstract
A series of oxy-polybrominated diphenyl ethers (O-PBDEs) has been isolated from the extracts of Miamira magnifica and Miamira miamirana collected from Queensland, Australia. M. magnifica sequesters the new OH-PBDE 1 and six known OH-PBDEs containing four to six bromines (27
[...] Read more.
A series of oxy-polybrominated diphenyl ethers (O-PBDEs) has been isolated from the extracts of Miamira magnifica and Miamira miamirana collected from Queensland, Australia. M. magnifica sequesters the new OH-PBDE 1 and six known OH-PBDEs containing four to six bromines (27). M. miamirana also accumulates known tribromo- and tetrabromo OMe-PBDEs 810 in both mantle and viscera tissues. To date, Miamira is the only genus of the family Chromodorididae that is known to incorporate O-PBDEs, rather than terpenes, in the mantle where the metabolites may play a putative role in chemical defense. The extract of M. magnifica was tested in a brine shrimp lethality assay and exhibited an LD50 of 58 μg/mL. Full article
(This article belongs to the Special Issue Marine Organohalides)
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Open AccessArticle Novel Conopeptides of Largely Unexplored Indo Pacific Conus sp.
Mar. Drugs 2016, 14(11), 199; doi:10.3390/md14110199
Received: 18 August 2016 / Revised: 13 September 2016 / Accepted: 15 October 2016 / Published: 27 October 2016
Cited by 3 | PDF Full-text (4441 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Cone snails are predatory creatures using venom as a weapon for prey capture and defense. Since this venom is neurotoxic, the venom gland is considered as an enormous collection of pharmacologically interesting compounds having a broad spectrum of targets. As such, cone snail
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Cone snails are predatory creatures using venom as a weapon for prey capture and defense. Since this venom is neurotoxic, the venom gland is considered as an enormous collection of pharmacologically interesting compounds having a broad spectrum of targets. As such, cone snail peptides represent an interesting treasure for drug development. Here, we report five novel peptides isolated from the venom of Conus longurionis, Conus asiaticus and Conus australis. Lo6/7a and Lo6/7b were retrieved from C. longurionis and have a cysteine framework VI/VII. Lo6/7b has an exceptional amino acid sequence because no similar conopeptide has been described to date (similarity percentage <50%). A third peptide, Asi3a from C. asiaticus, has a typical framework III Cys arrangement, classifying the peptide in the M-superfamily. Asi14a, another peptide of C. asiaticus, belongs to framework XIV peptides and has a unique amino acid sequence. Finally, AusB is a novel conopeptide from C. australis. The peptide has only one disulfide bond, but is structurally very different as compared to other disulfide-poor peptides. The peptides were screened on nAChRs, NaV and KV channels depending on their cysteine framework and proposed classification. No targets could be attributed to the peptides, pointing to novel functionalities. Moreover, in the quest of identifying novel pharmacological targets, the peptides were tested for antagonistic activity against a broad panel of Gram-negative and Gram-positive bacteria, as well as two yeast strains. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Marine Fungi as Producers of Benzocoumarins, a New Class of Inhibitors of Glycogen-Synthase-Kinase 3β
Mar. Drugs 2016, 14(11), 200; doi:10.3390/md14110200
Received: 12 August 2016 / Revised: 17 October 2016 / Accepted: 22 October 2016 / Published: 28 October 2016
Cited by 5 | PDF Full-text (959 KB) | HTML Full-text | XML Full-text
Abstract
The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad
[...] Read more.
The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin (1), alternariol (2), and alternariol-9-methylether (3) to be promising inhibitors of the isoform GSK-3β showing sub-μM IC50 values. The in vitro inhibition is in the range of the known highly active GSK-3β inhibitor TDZD-8. Compounds 13 have a highly oxygenated benzocoumarin core structure in common, which suggests that this may be a new structural feature for efficient GSK-3β inhibition. Full article
(This article belongs to the Special Issue Marine Fungal Natural Products)
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Open AccessArticle Chemistry and Bioactivity of Briaranes from the South China Sea Gorgonian Dichotella gemmacea
Mar. Drugs 2016, 14(11), 201; doi:10.3390/md14110201
Received: 29 August 2016 / Revised: 11 October 2016 / Accepted: 12 October 2016 / Published: 28 October 2016
Cited by 1 | PDF Full-text (834 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Seven new briarane diterpenoids, gemmacolides AZ–BF (17), were isolated together with eight known analogues (815) from the South China gorgonian Dichotella gemmacea. Their structures were elucidated based on detailed spectroscopic analysis and a comparison
[...] Read more.
Seven new briarane diterpenoids, gemmacolides AZ–BF (17), were isolated together with eight known analogues (815) from the South China gorgonian Dichotella gemmacea. Their structures were elucidated based on detailed spectroscopic analysis and a comparison with reported data. In an in vitro bioassay, these compounds exhibited different levels of growth inhibition activity against A549 and MG63 cells, giving continuous evidences about the biological contribution of functional groups at C-2, C-12, C-13, and C-16. These compounds were also evaluated for their antibacterial and antifungal activities. Compound 8 exhibited a potential antibacterial activity against both Gram-positive bacterium Bacillus megaterium and Gram-negative bacterium Escherichia coli. Full article
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Open AccessArticle New Typical Vector of Neurotoxin β-N-Methylamino-l-Alanine (BMAA) in the Marine Benthic Ecosystem
Mar. Drugs 2016, 14(11), 202; doi:10.3390/md14110202
Received: 4 September 2016 / Revised: 1 October 2016 / Accepted: 27 October 2016 / Published: 4 November 2016
Cited by 6 | PDF Full-text (1598 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The neurotoxin β-N-methylamino-l-alanine (BMAA) has been identified as an environmental factor triggering neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD). We investigated the possible vectors of BMAA and its isomers 2,4-diaminobutyric acid (DAB) and N
[...] Read more.
The neurotoxin β-N-methylamino-l-alanine (BMAA) has been identified as an environmental factor triggering neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD). We investigated the possible vectors of BMAA and its isomers 2,4-diaminobutyric acid (DAB) and N-2(aminoethyl)glycine (AEG) in marine mollusks collected from the Chinese coast. Sixty-eight samples of marine mollusks were collected along the Chinese coast in 2016, and were analyzed by an HILIC-MS/MS (hydrophilic interaction liquid chromatography with tandem quadrupole mass spectrometer) method without derivatization. BMAA was detected in a total of five samples from three species: Neverita didyma, Solen strictus, and Mytilus coruscus. The top three concentrations of free-form BMAA (0.99~3.97 μg·g−1 wet weight) were detected in N. didyma. DAB was universally detected in most of the mollusk samples (53/68) with no species-specific or regional differences (0.051~2.65 μg·g−1 wet weight). No AEG was detected in any mollusk samples tested here. The results indicate that the gastropod N. didyma might be an important vector of the neurotoxin BMAA in the Chinese marine ecosystem. The neurotoxin DAB was universally present in marine bivalve and gastropod mollusks. Since N. didyma is consumed by humans, we suggest that the origin and risk of BMAA and DAB toxins in the marine ecosystem should be further investigated in the future. Full article
(This article belongs to the Special Issue Marine Neurotoxins)
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Open AccessArticle Natural Products from Microalgae with Potential against Alzheimer’s Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors
Mar. Drugs 2016, 14(11), 203; doi:10.3390/md14110203
Received: 16 September 2016 / Revised: 20 October 2016 / Accepted: 25 October 2016 / Published: 2 November 2016
Cited by 3 | PDF Full-text (1067 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, many new enzymes, like glutaminyl cyclase (QC), could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme-inhibiting properties of natural substances are becoming increasingly important. In different studies, the pathophysiology connection of QC to various
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In recent years, many new enzymes, like glutaminyl cyclase (QC), could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme-inhibiting properties of natural substances are becoming increasingly important. In different studies, the pathophysiology connection of QC to various diseases including Alzheimer’s disease (AD) was described. Algae are known for the ability to synthesize complex and highly-diverse compounds with specific enzyme inhibition properties. Therefore, we screened different algae species for the presence of QC inhibiting metabolites using a new “Reverse Metabolomics” technique including an Activity-correlation Analysis (AcorA), which is based on the correlation of bioactivities to mass spectral data with the aid of mathematic informatics deconvolution. Thus, three QC inhibiting compounds from microalgae belonging to the family of sulfolipids were identified. The compounds showed a QC inhibition of 81% and 76% at concentrations of 0.25 mg/mL and 0.025 mg/mL, respectively. Thus, for the first time, sulfolipids are identified as QC inhibiting compounds and possess substructures with the required pharmacophore qualities. They represent a new lead structure for QC inhibitors. Full article
(This article belongs to the Special Issue Enzyme Inhibitors of Marine Origin)
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Open AccessArticle Biscogniauxone, a New Isopyrrolonaphthoquinone Compound from the Fungus Biscogniauxia mediterranea Isolated from Deep-Sea Sediments
Mar. Drugs 2016, 14(11), 204; doi:10.3390/md14110204
Received: 29 September 2016 / Revised: 24 October 2016 / Accepted: 26 October 2016 / Published: 2 November 2016
Cited by 2 | PDF Full-text (901 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The properties and the production of new metabolites from the fungal strain LF657 isolated from the Herodotes Deep (2800 m depth) in the Mediterranean Sea are reported in this study. The new isolate was identified as Biscogniauxia mediterranea based on ITS1-5.8S-ITS2 and 28S
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The properties and the production of new metabolites from the fungal strain LF657 isolated from the Herodotes Deep (2800 m depth) in the Mediterranean Sea are reported in this study. The new isolate was identified as Biscogniauxia mediterranea based on ITS1-5.8S-ITS2 and 28S rRNA gene sequences. A new isopyrrolonaphthoquinone with inhibitory activity against glycogen synthase kinase (GSK-3β) was isolated from this fungus. This is the first report of this class of compounds from a fungus isolated from a deep-sea sediment, as well as from a Biscogniauxia species. Full article
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Open AccessArticle Structure–Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins
Mar. Drugs 2016, 14(11), 207; doi:10.3390/md14110207
Received: 9 July 2016 / Revised: 7 August 2016 / Accepted: 31 October 2016 / Published: 4 November 2016
Cited by 1 | PDF Full-text (831 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins
[...] Read more.
Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure–activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2-epi-DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ≥ DTX2 >> 2-epi-DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs’ activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors. Full article
(This article belongs to the collection Bioactive Compounds from Marine Plankton)
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Open AccessArticle Astaxanthin and Docosahexaenoic Acid Reverse the Toxicity of the Maxi-K (BK) Channel Antagonist Mycotoxin Penitrem A
Mar. Drugs 2016, 14(11), 208; doi:10.3390/md14110208
Received: 1 September 2016 / Revised: 15 October 2016 / Accepted: 1 November 2016 / Published: 9 November 2016
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Abstract
Penitrem A (PA) is a food mycotoxin produced by several terrestrial and few marine Penicillium species. PA is a potent tremorgen through selective antagonism of the calcium-dependent potassium BK (Maxi-K) channels. Discovery of natural products that can prevent the toxic effects of PA
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Penitrem A (PA) is a food mycotoxin produced by several terrestrial and few marine Penicillium species. PA is a potent tremorgen through selective antagonism of the calcium-dependent potassium BK (Maxi-K) channels. Discovery of natural products that can prevent the toxic effects of PA is important for food safety. Astaxanthin (AST) is a marine natural xanthophyll carotenoid with documented antioxidant activity. Unlike other common antioxidants, AST can cross blood brain barriers (BBBs), inducing neuroprotective effects. Docosahexaenoic acid (DHA) is polyunsaturated ω-3 fatty acid naturally occurring in fish and algae. DHA is essential for normal neurological and cellular development. This study evaluated the protective activity of AST and DHA against PA-induced toxicity, in vitro on Schwann cells CRL-2765 and in vivo in the worm Caenorhbitidis elegans and Sprague Dawley rat models. PA inhibited the viability of Schwann cells, with an IC50 of 22.6 μM. Dose-dependent treatments with 10–100 μM DHA significantly reversed the PA toxicity at its IC50 dose, and improved the survival of Schwann cells to 70.5%–98.8%. Similarly, dose-dependent treatments with 10–20 μM AST reversed the PA toxicity at its IC50 dose and raised these cells’ survival to 61.7%–70.5%. BK channel inhibition in the nematode C. elegans is associated with abnormal reversal locomotion. DHA and AST counteracted the in vivo PA BK channel antagonistic activity in the C. elegans model. Rats fed a PA-contaminated diet showed high levels of glutamate (GLU), aspartate (ASP), and gamma amino butyric acid (GABA), with observed necrosis or absence of Purkinjie neurons, typical of PA-induced neurotoxicity. Dopamine (DA), serotonin (5-HT), and norepinephrine (NE) levels were abnormal, Nitric Oxide (NO) and Malondialdehyde (MDA) levels were significantly increased, and total antioxidant capacity (TAC) level in serum and brain homogenates was significantly decreased in PA-treated rats. DHA and AST treatments effectively counteracted the toxic effects of PA and normalized most biochemical parameters in rats. DHA and AST can be useful food additives to prevent and reverse PA food-induced toxicity. Full article
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Open AccessArticle Chemical and Genetic Diversity of Nodularia spumigena from the Baltic Sea
Mar. Drugs 2016, 14(11), 209; doi:10.3390/md14110209
Received: 29 September 2016 / Revised: 26 October 2016 / Accepted: 2 November 2016 / Published: 10 November 2016
Cited by 1 | PDF Full-text (859 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Nodularia spumigena is a toxic, filamentous cyanobacterium occurring in brackish waters worldwide, yet forms extensive recurrent blooms in the Baltic Sea. N. spumigena produces several classes of non-ribosomal peptides (NRPs) that are active against several key metabolic enzymes. Previously, strains from geographically distant
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Nodularia spumigena is a toxic, filamentous cyanobacterium occurring in brackish waters worldwide, yet forms extensive recurrent blooms in the Baltic Sea. N. spumigena produces several classes of non-ribosomal peptides (NRPs) that are active against several key metabolic enzymes. Previously, strains from geographically distant regions showed distinct NRP metabolic profiles. In this work, conspecific diversity in N. spumigena was studied using chemical and genetic approaches. NRP profiles were determined in 25 N. spumigena strains isolated in different years and from different locations in the Baltic Sea using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Genetic diversity was assessed by targeting the phycocyanin intergenic spacer and flanking regions (cpcBA-IGS). Overall, 14 spumigins, 5 aeruginosins, 2 pseudaeruginosins, 2 nodularins, 36 anabaenopeptins, and one new cyanopeptolin-like peptide were identified among the strains. Seven anabaenopeptins were new structures; one cyanopeptolin-like peptide was discovered in N. spumigena for the first time. Based on NRP profiles and cpcBA-IGS sequences, the strains were grouped into two main clusters without apparent influence of year and location, indicating persistent presence of these two subpopulations in the Baltic Sea. This study is a major step in using chemical profiling to explore conspecific diversity with a higher resolution than with a sole genetic approach. Full article
(This article belongs to the collection Bioactive Compounds from Marine Plankton)
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Open AccessArticle The Potential Exploitation of the Mediterranean Invasive Alga Caulerpa cylindracea: Can the Invasion Be Transformed into a Gain?
Mar. Drugs 2016, 14(11), 210; doi:10.3390/md14110210
Received: 29 July 2016 / Revised: 8 November 2016 / Accepted: 9 November 2016 / Published: 15 November 2016
Cited by 1 | PDF Full-text (527 KB) | HTML Full-text | XML Full-text
Abstract
Recently, there is a growing interest towards the development of strategies for invasive seaweed control and exploitation as source of secondary metabolites. Here, we investigated the potential of exploitation in biotechnology and recycling options in eradication programs of the lipidic extract of the
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Recently, there is a growing interest towards the development of strategies for invasive seaweed control and exploitation as source of secondary metabolites. Here, we investigated the potential of exploitation in biotechnology and recycling options in eradication programs of the lipidic extract of the Mediterranean invasive seaweed Caulerpa cylindracea (Chlorophyta). The chemical characterization was carried out by means of multinuclear and multidimensional NMR spectroscopy. The fatty acid profile of C. cylindracea assessed the presence of several types of molecules known for antioxidant activity such as carotenoids, chlorophylls, pheophytins, and sterols. The NMR spectroscopy showed also the characteristic signals of saturated, unsaturated, and free fatty acids as well as other metabolites including the biopolymer polyhydroxybutyrate. The lipidic extract exerted an antioxidant activity corresponding to 552.14 ± 69.13 mmol Trolox equivalent/g (ORAC) and to 70.3 ± 2.67 mmol Trolox equivalent/g (TEAC). The extract showed an antibacterial activity against several Vibrio species, suggesting its potential use in the control of diseases in mariculture. Our results show that C. cylindracea, representing a critical hazard in coastal areas, could be transformed into a gain supporting specific management actions to reduce the effects of human pressures. Full article
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Open AccessArticle Anti-Melanogenic Activity of Gagunin D, a Highly Oxygenated Diterpenoid from the Marine Sponge Phorbas sp., via Modulating Tyrosinase Expression and Degradation
Mar. Drugs 2016, 14(11), 212; doi:10.3390/md14110212
Received: 10 October 2016 / Revised: 10 November 2016 / Accepted: 14 November 2016 / Published: 17 November 2016
Cited by 1 | PDF Full-text (3539 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge
[...] Read more.
Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge Phorbas sp., has exhibited cytotoxicity toward human leukemia cells. However, the effect of GD on normal cells and the molecular mechanisms remain to be elucidated. In the present study, we identified for the first time the anti-melanogenic activity of GD and its precise underlying mechanisms in mouse melan-a cells. GD significantly inhibited melanin synthesis in the melan-a cells and a reconstructed human skin model. Further analysis revealed that GD suppressed the expression of tyrosinase and increased the rate of tyrosinase degradation. GD also inhibited tyrosinase enzymatic activity. In addition, GD effectively suppressed the expression of proteins associated with melanosome transfer. These findings suggest that GD is a potential candidate for cosmetic formulations due to its multi-functional properties. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle The Role of Individual Disulfide Bonds of μ-Conotoxin GIIIA in the Inhibition of NaV1.4
Mar. Drugs 2016, 14(11), 213; doi:10.3390/md14110213
Received: 28 September 2016 / Revised: 31 October 2016 / Accepted: 11 November 2016 / Published: 18 November 2016
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Abstract
μ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to
[...] Read more.
μ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of NaV1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against NaV1.4 was assayed by whole cell patch-clamp on rNaV1.4, heterologously expressed in HEK293 cells. The corresponding IC50 values were 0.069 ± 0.005 μM for GIIIA, 2.1 ± 0.3 μM for GIIIA-1, 3.3 ± 0.2 μM for GIIIA-2, and 15.8 ± 0.8 μM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3–Cys15, Cys4–Cys20 and Cys10–Cys21, respectively). Other analogues were not active enough for IC50 measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of NaV1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10–Cys21 is the most important for the NaV1.4 potency. Full article
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Open AccessArticle Phomopsichin A–D; Four New Chromone Derivatives from Mangrove Endophytic Fungus Phomopsis sp. 33#
Mar. Drugs 2016, 14(11), 215; doi:10.3390/md14110215
Received: 9 September 2016 / Revised: 20 October 2016 / Accepted: 8 November 2016 / Published: 22 November 2016
Cited by 4 | PDF Full-text (2253 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Four new chromone derivatives, phomopsichins A–D (14), along with a known compound, phomoxanthone A (5), were isolated from the fermentation products of mangrove endophytic fungus Phomopsis sp. 33#. Their structures were elucidated based on comprehensive spectroscopic analysis
[...] Read more.
Four new chromone derivatives, phomopsichins A–D (14), along with a known compound, phomoxanthone A (5), were isolated from the fermentation products of mangrove endophytic fungus Phomopsis sp. 33#. Their structures were elucidated based on comprehensive spectroscopic analysis coupled with single-crystal X-ray diffraction or theoretical calculations of electronic circular dichroism (ECD). They feature a tricyclic framework, in which a dihydropyran ring is fused with the chromone ring. Compounds 15 showed weak inhibitory activities on acetylcholinesterase as well as α-glucosidase, weak radical scavenging effects on 1,1-diphenyl-2-picrylhydrazyl (DPPH) as well as OH, and weak antimicrobial activities. Compounds 14 showed no cytotoxic activity against MDA-MB-435 breast cancer cells. Their other bioactivities are worthy of further study, considering their unique molecular structures. Full article
(This article belongs to the Special Issue Marine Fungal Natural Products)
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Open AccessReview Natural Proline-Rich Cyclopolypeptides from Marine Organisms: Chemistry, Synthetic Methodologies and Biological Status
Mar. Drugs 2016, 14(11), 194; doi:10.3390/md14110194
Received: 11 September 2016 / Revised: 2 October 2016 / Accepted: 15 October 2016 / Published: 26 October 2016
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Abstract
Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success
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Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success is the potent and specific, yet safe, mode of action of peptides. Among the wide range of biologically-active peptides, naturally-occurring marine-derived cyclopolypeptides exhibit a broad range of unusual and potent pharmacological activities. Because of their size and complexity, proline-rich cyclic peptides (PRCPs) occupy a crucial chemical space in drug discovery that may provide useful scaffolds for modulating more challenging biological targets, such as protein-protein interactions and allosteric binding sites. Diverse pharmacological activities of natural cyclic peptides from marine sponges, tunicates and cyanobacteria have encouraged efforts to develop cyclic peptides with well-known synthetic methods, including solid-phase and solution-phase techniques of peptide synthesis. The present review highlights the natural resources, unique structural features and the most relevant biological properties of proline-rich peptides of marine-origin, focusing on the potential therapeutic role that the PRCPs may play as a promising source of new peptide-based novel drugs. Full article
(This article belongs to the Special Issue Marine Proteins and Peptides)
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Open AccessReview Ceramide as a Target of Marine Triterpene Glycosides for Treatment of Human Myeloid Leukemia
Mar. Drugs 2016, 14(11), 205; doi:10.3390/md14110205
Received: 13 September 2016 / Revised: 19 October 2016 / Accepted: 28 October 2016 / Published: 3 November 2016
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Abstract
Acute myeloid leukemia (AML) is a heterogeneous myeloid clonal disorder exhibiting the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Standard AML therapy requires intensive combination chemotherapy, which leads to significant treatment-related toxicity. The search for new, low toxic
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Acute myeloid leukemia (AML) is a heterogeneous myeloid clonal disorder exhibiting the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Standard AML therapy requires intensive combination chemotherapy, which leads to significant treatment-related toxicity. The search for new, low toxic marine agents, inducing the generation of ceramide in leukemic cells is a new approach to improve the therapy of leukemia. This review focuses on the metabolism of sphingolipids, the role of ceramide in treating leukemia, and the antitumor activity, related to ceramide metabolism, of some marine metabolites, particularly stichoposides, triterpene glycosides extracted from sea cucumbers of the family Stichopodiidae. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessReview Chiral Alkyl Halides: Underexplored Motifs in Medicine
Mar. Drugs 2016, 14(11), 206; doi:10.3390/md14110206
Received: 24 September 2016 / Revised: 21 October 2016 / Accepted: 31 October 2016 / Published: 4 November 2016
Cited by 2 | PDF Full-text (2501 KB) | HTML Full-text | XML Full-text
Abstract
While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems.
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While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation. Full article
(This article belongs to the Special Issue Marine Organohalides)
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Open AccessReview Preclinical and Clinical Studies on Antioxidative, Antihypertensive and Cardioprotective Effect of Marine Proteins and Peptides—A Review
Mar. Drugs 2016, 14(11), 211; doi:10.3390/md14110211
Received: 3 October 2016 / Revised: 10 November 2016 / Accepted: 11 November 2016 / Published: 18 November 2016
Cited by 2 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
High seafood consumption has traditionally been linked to a reduced risk of cardiovascular diseases, mainly due to the lipid lowering effects of the long chained omega 3 fatty acids. However, fish and seafood are also excellent sources of good quality proteins and emerging
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High seafood consumption has traditionally been linked to a reduced risk of cardiovascular diseases, mainly due to the lipid lowering effects of the long chained omega 3 fatty acids. However, fish and seafood are also excellent sources of good quality proteins and emerging documentation show that, upon digestion, these proteins are sources for bioactive peptides with documented favorable physiological effects such as antioxidative, antihypertensive and other cardioprotective effects. This documentation is mainly from in vitro studies, but also animal studies are arising. Evidence from human studies evaluating the positive health effects of marine proteins and peptides are scarce. In one study, a reduction in oxidative stress after intake of cod has been documented and a few human clinical trials have been performed evaluating the effect on blood pressure. The results are, however, inconclusive. The majority of the human clinical trials performed to investigate positive health effects of marine protein and lean fish intake, has focused on blood lipids. While some studies have documented a reduction in triglycerides after intake of lean fish, others have documented no effects. Full article
(This article belongs to the Special Issue Marine Proteins and Peptides)
Open AccessReview Innovative Alternative Technologies to Extract Carotenoids from Microalgae and Seaweeds
Mar. Drugs 2016, 14(11), 214; doi:10.3390/md14110214
Received: 29 September 2016 / Revised: 7 November 2016 / Accepted: 11 November 2016 / Published: 22 November 2016
Cited by 7 | PDF Full-text (1522 KB) | HTML Full-text | XML Full-text
Abstract
Marine microalgae and seaweeds (microalgae) represent a sustainable source of various bioactive natural carotenoids, including β-carotene, lutein, astaxanthin, zeaxanthin, violaxanthin and fucoxanthin. Recently, the large-scale production of carotenoids from algal sources has gained significant interest with respect to commercial and industrial applications for
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Marine microalgae and seaweeds (microalgae) represent a sustainable source of various bioactive natural carotenoids, including β-carotene, lutein, astaxanthin, zeaxanthin, violaxanthin and fucoxanthin. Recently, the large-scale production of carotenoids from algal sources has gained significant interest with respect to commercial and industrial applications for health, nutrition, and cosmetic applications. Although conventional processing technologies, based on solvent extraction, offer a simple approach to isolating carotenoids, they suffer several, inherent limitations, including low efficiency (extraction yield), selectivity (purity), high solvent consumption, and long treatment times, which have led to advancements in the search for innovative extraction technologies. This comprehensive review summarizes the recent trends in the extraction of carotenoids from microalgae and seaweeds through the assistance of different innovative techniques, such as pulsed electric fields, liquid pressurization, supercritical fluids, subcritical fluids, microwaves, ultrasounds, and high-pressure homogenization. In particular, the review critically analyzes technologies, characteristics, advantages, and shortcomings of the different innovative processes, highlighting the differences in terms of yield, selectivity, and economic and environmental sustainability. Full article
(This article belongs to the collection Marine Carotenoids)
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Open AccessReview Alkynyl-Containing Peptides of Marine Origin: A Review
Mar. Drugs 2016, 14(11), 216; doi:10.3390/md14110216
Received: 19 September 2016 / Revised: 15 November 2016 / Accepted: 16 November 2016 / Published: 23 November 2016
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Abstract
Since the 1990s, a number of terminal alkynyl residue-containing cyclic/acyclic peptides have been identified from marine organisms, especially cyanobacteria and marine mollusks. This review has presented 66 peptides, which covers over 90% marine peptides with terminal alkynyl fatty acyl units. In fact, more
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Since the 1990s, a number of terminal alkynyl residue-containing cyclic/acyclic peptides have been identified from marine organisms, especially cyanobacteria and marine mollusks. This review has presented 66 peptides, which covers over 90% marine peptides with terminal alkynyl fatty acyl units. In fact, more than 90% of these peptides described in the literature are of cyanobacterial origin. Interestingly, all the linear peptides featured with terminal alkyne were solely discovered from marine cyanobacteria. The objective of this article is to provide an overview on the types, structural characterization of these unusual terminal alkynyl fatty acyl units, as well as the sources and biological functions of their composed peptides. Many of these peptides have a variety of biological activities, including antitumor, antibacterial, antimalarial, etc. Further, we have also discussed the evident biosynthetic origin responsible for formation of terminal alkynes of natural PKS (polyketide synthase)/NRPS (nonribosome peptide synthetase) hybrids. Full article
(This article belongs to the Special Issue Marine Proteins and Peptides)
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