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Mar. Drugs, Volume 17, Issue 3 (March 2019)

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Cover Story (view full-size image) Though in many cases bioactive metabolites have been attributed to marine sponges and other [...] Read more.
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Open AccessArticle High-Throughput Identification and Analysis of Novel Conotoxins from Three Vermivorous Cone Snails by Transcriptome Sequencing
Mar. Drugs 2019, 17(3), 193; https://doi.org/10.3390/md17030193
Received: 21 February 2019 / Revised: 19 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
The venom of each Conus species consists of a diverse array of neurophysiologically active peptides, which are mostly unique to the examined species. In this study, we performed high-throughput transcriptome sequencing to extract and analyze putative conotoxin transcripts from the venom ducts of [...] Read more.
The venom of each Conus species consists of a diverse array of neurophysiologically active peptides, which are mostly unique to the examined species. In this study, we performed high-throughput transcriptome sequencing to extract and analyze putative conotoxin transcripts from the venom ducts of 3 vermivorous cone snails (C. caracteristicus, C. generalis, and C. quercinus), which are resident in offshore waters of the South China Sea. In total, 118, 61, and 48 putative conotoxins (across 22 superfamilies) were identified from the 3 Conus species, respectively; most of them are novel, and some possess new cysteine patterns. Interestingly, a series of 45 unassigned conotoxins presented with a new framework of C-C-C-C-C-C, and their mature regions were sufficiently distinct from any other known conotoxins, most likely representing a new superfamily. O- and M-superfamily conotoxins were the most abundant in transcript number and transcription level, suggesting their critical roles in the venom functions of these vermivorous cone snails. In addition, we identified numerous functional proteins with potential involvement in the biosynthesis, modification, and delivery process of conotoxins, which may shed light on the fundamental mechanisms for the generation of these important conotoxins within the venom duct of cone snails. Full article
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Open AccessArticle Spiralyde A, an Antikinetoplastid Dolabellane from the Brown Alga Dictyota spiralis
Mar. Drugs 2019, 17(3), 192; https://doi.org/10.3390/md17030192
Received: 4 March 2019 / Revised: 18 March 2019 / Accepted: 21 March 2019 / Published: 25 March 2019
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Abstract
Bioassay-guided fractionation of the antikinetoplastid extract of the brown alga Dictyota spiralis has led to the isolation of spiralyde A (1), a new dolabellane aldehyde, along with other five known related diterpenes (26). Their structures were determined [...] Read more.
Bioassay-guided fractionation of the antikinetoplastid extract of the brown alga Dictyota spiralis has led to the isolation of spiralyde A (1), a new dolabellane aldehyde, along with other five known related diterpenes (26). Their structures were determined by HRESIMS, 1D and 2D NMR spectroscopy, and comparison with data reported in the literature. The antiparasitic activity of all compounds was evaluated. Spiralyde A (1) and the known compound 3,4-epoxy-7,18-dolabelladiene (2) were the most active compounds against Leishmania amazonensis and Trypanosoma cruzi. Spiralyde A (1) was the most potent compound, comparable to benznidazole, the reference drug for trypanocidal activity. Full article
(This article belongs to the Special Issue Marine Natural Products with Antiprotozoal Activity)
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Open AccessReview Saline Environments as a Source of Potential Quorum Sensing Disruptors to Control Bacterial Infections: A Review
Mar. Drugs 2019, 17(3), 191; https://doi.org/10.3390/md17030191
Received: 27 February 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 25 March 2019
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Abstract
Saline environments, such as marine and hypersaline habitats, are widely distributed around the world. They include sea waters, saline lakes, solar salterns, or hypersaline soils. The bacteria that live in these habitats produce and develop unique bioactive molecules and physiological pathways to cope [...] Read more.
Saline environments, such as marine and hypersaline habitats, are widely distributed around the world. They include sea waters, saline lakes, solar salterns, or hypersaline soils. The bacteria that live in these habitats produce and develop unique bioactive molecules and physiological pathways to cope with the stress conditions generated by these environments. They have been described to produce compounds with properties that differ from those found in non-saline habitats. In the last decades, the ability to disrupt quorum-sensing (QS) intercellular communication systems has been identified in many marine organisms, including bacteria. The two main mechanisms of QS interference, i.e., quorum sensing inhibition (QSI) and quorum quenching (QQ), appear to be a more frequent phenomenon in marine aquatic environments than in soils. However, data concerning bacteria from hypersaline habitats is scarce. Salt-tolerant QSI compounds and QQ enzymes may be of interest to interfere with QS-regulated bacterial functions, including virulence, in sectors such as aquaculture or agriculture where salinity is a serious environmental issue. This review provides a global overview of the main works related to QS interruption in saline environments as well as the derived biotechnological applications. Full article
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Open AccessArticle In Silico Analysis of Relationship between Proteins from Plastid Genome of Red Alga Palmaria sp. (Japan) and Angiotensin I Converting Enzyme Inhibitory Peptides
Mar. Drugs 2019, 17(3), 190; https://doi.org/10.3390/md17030190
Received: 20 February 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 25 March 2019
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Abstract
Plastid proteins are one of the main components in red algae. In order to clarify the angiotensin I converting enzyme (ACE) inhibitory peptides from red alga Palmaria sp. (Japan), we determined the plastid genome sequence. The genome possesses 205 protein coding genes, which [...] Read more.
Plastid proteins are one of the main components in red algae. In order to clarify the angiotensin I converting enzyme (ACE) inhibitory peptides from red alga Palmaria sp. (Japan), we determined the plastid genome sequence. The genome possesses 205 protein coding genes, which were classified as genetic systems, ribosomal proteins, photosystems, adenosine triphosphate (ATP) synthesis, metabolism, transport, or unknown. After comparing ACE inhibitory peptides between protein sequences and a database, photosystems (177 ACE inhibitory peptides) were found to be the major source of ACE inhibitory peptides (total of 751). Photosystems consist of phycobilisomes, photosystem I, photosystem II, cytochrome complex, and a redox system. Among them, photosystem I (53) and II (51) were the major source of ACE inhibitory peptides. We found that the amino acid sequence of apcE (14) in phycobilisomes, psaA (18) and psaB (13) in photosystem I, and psbB (11) and psbC (10) in photosystem II covered a majority of bioactive peptide sequences. These results are useful for evaluating the bioactive peptides from red algae. Full article
(This article belongs to the Special Issue Bioinformatics of Marine Natural Products)
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Open AccessArticle Rat Glioma Cell-Based Functional Characterization of Anti-Stress and Protein Deaggregation Activities in the Marine Carotenoids, Astaxanthin and Fucoxanthin
Mar. Drugs 2019, 17(3), 189; https://doi.org/10.3390/md17030189
Received: 18 January 2019 / Revised: 13 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
Stress, protein aggregation, and loss of functional properties of cells have been shown to contribute to several deleterious pathologies including cancer and neurodegeneration. The incidence of these pathologies has also been shown to increase with age and are often presented as evidence to [...] Read more.
Stress, protein aggregation, and loss of functional properties of cells have been shown to contribute to several deleterious pathologies including cancer and neurodegeneration. The incidence of these pathologies has also been shown to increase with age and are often presented as evidence to the cumulative effect of stress and protein aggregation. Prevention or delay of onset of these diseases may prove to be unprecedentedly beneficial. In this study, we explored the anti-stress and differentiation-inducing potential of two marine bioactive carotenoids (astaxanthin and fucoxanthin) using rat glioma cells as a model. We found that the low (nontoxic) doses of both protected cells against UV-induced DNA damage, heavy metal, and heat-induced protein misfolding and aggregation of proteins. Their long-term treatment in glioma cells caused the induction of physiological differentiation into astrocytes. These phenotypes were supported by upregulation of proteins that regulate cell proliferation, DNA damage repair mechanism, and glial differentiation, suggesting their potential for prevention and treatment of stress, protein aggregation, and age-related pathologies. Full article
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Open AccessArticle Structure and Neuroprotective Effect of Polysaccharide from Viscera Autolysates of Squid Ommastrephes bartrami
Mar. Drugs 2019, 17(3), 188; https://doi.org/10.3390/md17030188
Received: 6 February 2019 / Revised: 5 March 2019 / Accepted: 15 March 2019 / Published: 22 March 2019
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Abstract
To explore bioactive polysaccharides from the byproducts of squid processing, a heteropolysaccharide, named SV2-1, was isolated from the viscera of squid Ommastrephes bartrami by autolysis, anion-exchange and gel-permeation chromatography and measured for its neuroprotective activity. It was a homogeneous polysaccharide with a molecular [...] Read more.
To explore bioactive polysaccharides from the byproducts of squid processing, a heteropolysaccharide, named SV2-1, was isolated from the viscera of squid Ommastrephes bartrami by autolysis, anion-exchange and gel-permeation chromatography and measured for its neuroprotective activity. It was a homogeneous polysaccharide with a molecular weight of 2.3 kDa by HPSEC analysis. SV2-1 contained glucuronic acid, galactosamine and fucose in the ratio of 1.0:1.1:1.2. Its structural characteristics were elucidated by methylation analysis, gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR). The backbone of SV2-1 was composed of alternant →4)-α-l-Fucp-(1→ and →3)-β-d-GlcUA-(1→ Most of →4)-α-l-Fucp-(1→ (90%) was substituted by single α-d-GlcNAc as the branches. SV2-1 can protect against the death of PC12 induced by 6-OHDA, and effectively improves cell viability and reduces extracellular LDH release in PC12 cells after injury. Moreover, SV2-1 significantly increases SOD activity but decreases MDA levels. Full article
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Open AccessArticle Phytoene Accumulation in the Novel Microalga Chlorococcum sp. Using the Pigment Synthesis Inhibitor Fluridone
Mar. Drugs 2019, 17(3), 187; https://doi.org/10.3390/md17030187
Received: 26 February 2019 / Revised: 19 March 2019 / Accepted: 19 March 2019 / Published: 22 March 2019
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Abstract
Carotenoids are lipophilic pigments found in plants and algae, as well as some bacteria, archaea, and fungi that serve two functions—(1) as light harvesting molecules—primary carotenoids, and (2) as antioxidants, acting against reactive oxygen species–secondary carotenoids. Because of their strong antioxidant properties, they [...] Read more.
Carotenoids are lipophilic pigments found in plants and algae, as well as some bacteria, archaea, and fungi that serve two functions—(1) as light harvesting molecules—primary carotenoids, and (2) as antioxidants, acting against reactive oxygen species–secondary carotenoids. Because of their strong antioxidant properties, they are also valuable for the development of anti-aging and photo-protective cosmetic applications. Of particular interest is the carotenoid phytoene, for its colorless and UV absorption characteristics. In this study, we targeted a reduction of phytoene desaturase (PDS) activity with the pigment-inhibiting herbicide 1-methyl-3-phenyl-5-[3-(trifluoromethyl)phenyl]pyridin-4-one (fluridone), which leads to the over-accumulation of phytoene in the recently characterized microalgal strain Chlorococcum sp. (UTEX B 3056). After post-incubation with fluridone, phytoene levels were measured at ~33 ug/mg cell tissue, as opposed to non-detectable levels in control cultures. Hence, the novel microalga Chlorococcum sp. is a viable candidate for the production of the high-value carotenoid phytoene and subsequent applications in cosmeceuticals, as well as more obvious nutraceutical and pharmaceutical applications. Full article
(This article belongs to the collection Marine Carotenoids)
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Open AccessArticle Two New Piperazine-Triones from a Marine-Derived Streptomycetes sp. Strain SMS636
Mar. Drugs 2019, 17(3), 186; https://doi.org/10.3390/md17030186
Received: 28 February 2019 / Revised: 14 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
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Abstract
Two new piperazine-triones lansai E and F (1, 2), together with four known secondary metabolites lansai D (3), 1-N-methyl-(E,Z)-albonoursin (4), imidazo[4,5-e]-1,2,4-triazine (5), and streptonigrin (6) were [...] Read more.
Two new piperazine-triones lansai E and F (1, 2), together with four known secondary metabolites lansai D (3), 1-N-methyl-(E,Z)-albonoursin (4), imidazo[4,5-e]-1,2,4-triazine (5), and streptonigrin (6) were isolated from a deep-sea-derived Streptomycetes sp. strain SMS636. The structures of the isolated compounds were confirmed by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR. Compound 4 exhibited moderate antibacterial activities against Staphylococcus aureus and methicillin resistant S. aureus (MRSA) with Minimum Inhibitory Concentration (MIC) values of 12.5 and 25 μg/mL, respectively. Compound 6 displayed significant antibacterial activities against S. aureus, MRSA and Bacillus Calmette-Guérin (BCG) with MIC values of 0.78, 0.78 and 1.25 μg/mL, respectively. Full article
(This article belongs to the Special Issue Natural Products from Marine Actinomycetes)
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Open AccessArticle Expression, Purification and Characterization of Chondroitinase AC II from Marine Bacterium Arthrobacter sp. CS01
Mar. Drugs 2019, 17(3), 185; https://doi.org/10.3390/md17030185
Received: 15 February 2019 / Revised: 12 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
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Abstract
Chondroitinase (ChSase), a type of glycosaminoglycan (GAG) lyase, can degrade chondroitin sulfate (CS) to unsaturate oligosaccharides, with various functional activities. In this study, ChSase AC II from a newly isolated marine bacterium Arthrobacter sp. CS01 was cloned, expressed in Pichia pastoris X33, purified, [...] Read more.
Chondroitinase (ChSase), a type of glycosaminoglycan (GAG) lyase, can degrade chondroitin sulfate (CS) to unsaturate oligosaccharides, with various functional activities. In this study, ChSase AC II from a newly isolated marine bacterium Arthrobacter sp. CS01 was cloned, expressed in Pichia pastoris X33, purified, and characterized. ChSase AC II, with a molecular weight of approximately 100 kDa and a specific activity of 18.7 U/mg, showed the highest activity at 37 °C and pH 6.5 and maintained stability at a broad range of pH (5–7.5) and temperature (below 35 °C). The enzyme activity was increased in the presence of Mn2+ and was strongly inhibited by Hg2+. Moreover, the kinetic parameters of ChSase AC II against CS-A, CS-C, and HA were determined. TLC and ESI-MS analysis of the degradation products indicated that ChSase AC II displayed an exolytic action mode and completely hydrolyzed three substrates into oligosaccharides with low degrees of polymerization (DPs). All these features make ChSase AC II a promising candidate for the full use of GAG to produce oligosaccharides. Full article
(This article belongs to the Special Issue Marine Bacteria as Sources of Bioactive Compounds)
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Open AccessArticle Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells
Mar. Drugs 2019, 17(3), 184; https://doi.org/10.3390/md17030184
Received: 12 February 2019 / Revised: 14 March 2019 / Accepted: 17 March 2019 / Published: 20 March 2019
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Abstract
Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the [...] Read more.
Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells’ ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal. Full article
(This article belongs to the Special Issue Marine Immunomodulators)
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Open AccessReview Biological Activities of Fucoidan and the Factors Mediating Its Therapeutic Effects: A Review of Recent Studies
Mar. Drugs 2019, 17(3), 183; https://doi.org/10.3390/md17030183
Received: 1 March 2019 / Revised: 14 March 2019 / Accepted: 16 March 2019 / Published: 20 March 2019
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Abstract
The marine acid polysaccharide fucoidan has attracted attention from both the food and pharmaceutical industries due to its promising therapeutic effects. Fucoidan is a polysaccharide that mainly consists of L-fucose and sulphate groups. Its excellent biological function is attributed to its unique biological [...] Read more.
The marine acid polysaccharide fucoidan has attracted attention from both the food and pharmaceutical industries due to its promising therapeutic effects. Fucoidan is a polysaccharide that mainly consists of L-fucose and sulphate groups. Its excellent biological function is attributed to its unique biological structure. Classical activities include antitumor, antioxidant, anticoagulant, antithrombotic, immunoregulatory, antiviral and anti-inflammatory effects. More recently, fucoidan has been shown to alleviate metabolic syndrome, protect the gastrointestinal tract, benefit angiogenesis and bone health. This review focuses on the progress in our understanding of the biological activities of fucoidan, highlighting its benefits for the treatment of human disease. We hope that this review can provide some theoretical basis and inspiration for the product development of fucoidan. Full article
(This article belongs to the collection Marine Polysaccharides) Printed Edition available
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Open AccessArticle Chromone-Derived Polyketides from the Deep-Sea Fungus Diaporthe phaseolorum FS431
Mar. Drugs 2019, 17(3), 182; https://doi.org/10.3390/md17030182
Received: 28 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
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Abstract
Five new chromone-derived polyketides phaseolorins A-F (15), together with nine known compounds, were isolated from the deep-sea derived fungus Diaporthe phaseolorum FS431. The structures of new compounds were determined by analysis of their NMR and high-resolution electrospray ionization mass [...] Read more.
Five new chromone-derived polyketides phaseolorins A-F (15), together with nine known compounds, were isolated from the deep-sea derived fungus Diaporthe phaseolorum FS431. The structures of new compounds were determined by analysis of their NMR and high-resolution electrospray ionization mass spectroscopy (HRESIMS) spectroscopic data. The absolute configurations were confirmed by chemical transformations, extensively experimental electron capture detection (ECD) calculations, or X-ray crystallography. Among them, compound 2 represented the first example for a new family of chromone derivative possessing an unprecedented recombined five-member γ-lactone ring. Moreover, the new compounds (15) were evaluated for in vitro cytotoxic activities against a panel of human cancer cell lines. Full article
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Open AccessArticle Comparative Transcriptome Analyses Provide Potential Insights into the Molecular Mechanisms of Astaxanthin in the Protection against Alcoholic Liver Disease in Mice
Mar. Drugs 2019, 17(3), 181; https://doi.org/10.3390/md17030181
Received: 14 February 2019 / Revised: 11 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. It is a complex process, including a broad spectrum of hepatic lesions from fibrosis to cirrhosis. Our previous study suggested that astaxanthin (AST) could alleviate the hepatic inflammation and lipid [...] Read more.
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. It is a complex process, including a broad spectrum of hepatic lesions from fibrosis to cirrhosis. Our previous study suggested that astaxanthin (AST) could alleviate the hepatic inflammation and lipid dysmetabolism induced by ethanol administration. In this study, a total of 48 male C57BL/6J mice were divided into 4 groups: a Con group (fed with a Lieber–DeCarli liquid diet), an AST group (fed with a Lieber–DeCarli liquid diet and AST), an Et group (fed with an ethanol-containing Lieber–DeCarli liquid diet), and a EtAST group (fed with an ethanol-containing Lieber–DeCarli liquid diet and AST). Then, comparative hepatic transcriptome analysis among the groups was performed by Illumina RNA sequencing. Gene enrichment analysis was conducted to identify pathways affected by the differentially expressed genes. Changes of the top genes were verified by quantitative real-time PCR (qRT-PCR) and Western blot. A total of 514.95 ± 6.89, 546.02 ± 15.93, 576.06 ± 21.01, and 690.85 ± 54.14 million clean reads were obtained for the Con, AST, Et, and EtAST groups, respectively. Compared with the Et group, 1892 differentially expressed genes (DEGs) (including 351 upregulated and 1541 downregulated genes) were identified in the AST group, 1724 differentially expressed genes (including 233 upregulated and 1491 downregulated genes) were identified in the Con group, and 1718 DEGs (including 1380 upregulated and 338 downregulated genes) were identified in the EtAST group. The enrichment analyses revealed that the chemokine signaling, the antigen processing and presentation, the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, and the Toll-like receptor signaling pathways enriched the most differentially expressed genes. The findings of this study provide insights for the development of nutrition-related therapeutics for ALD. Full article
(This article belongs to the collection Marine Carotenoids)
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Open AccessArticle In Silico Analysis of the Subtype Selective Blockage of KCNA Ion Channels through the µ-Conotoxins PIIIA, SIIIA, and GIIIA
Mar. Drugs 2019, 17(3), 180; https://doi.org/10.3390/md17030180
Received: 21 February 2019 / Revised: 12 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Understanding subtype specific ion channel pore blockage by natural peptide-based toxins is crucial for developing such compounds into promising drug candidates. Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, [...] Read more.
Understanding subtype specific ion channel pore blockage by natural peptide-based toxins is crucial for developing such compounds into promising drug candidates. Herein, docking and molecular dynamics simulations were employed in order to understand the dynamics and binding states of the µ-conotoxins, PIIIA, SIIIA, and GIIIA, at the voltage-gated potassium channels of the KV1 family, and they were correlated with their experimental activities recently reported by Leipold et al. Their different activities can only adequately be understood when dynamic information about the toxin-channel systems is available. For all of the channel-bound toxins investigated herein, a certain conformational flexibility was observed during the molecular dynamic simulations, which corresponds to their bioactivity. Our data suggest a similar binding mode of µ-PIIIA at KV1.6 and KV1.1, in which a plethora of hydrogen bonds are formed by the Arg and Lys residues within the α-helical core region of µ-PIIIA, with the central pore residues of the channel. Furthermore, the contribution of the K+ channel’s outer and inner pore loops with respect to the toxin binding. and how the subtype specificity is induced, were proposed. Full article
(This article belongs to the Special Issue Bioinformatics of Marine Natural Products)
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Open AccessArticle Preparation and Identification of ACE Inhibitory Peptides from the Marine Macroalga Ulva intestinalis
Mar. Drugs 2019, 17(3), 179; https://doi.org/10.3390/md17030179
Received: 4 February 2019 / Revised: 7 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Angiotensin I-converting enzyme (ACE) inhibitory peptides derived from seaweed represent a potential source of new antihypertensive. The aim of this study was to isolate and purify ACE inhibitory peptides (ACEIPs) from the protein hydrolysate of the marine macroalga Ulva intestinalis. U. intestinalis [...] Read more.
Angiotensin I-converting enzyme (ACE) inhibitory peptides derived from seaweed represent a potential source of new antihypertensive. The aim of this study was to isolate and purify ACE inhibitory peptides (ACEIPs) from the protein hydrolysate of the marine macroalga Ulva intestinalis. U. intestinalis protein was hydrolyzed by five different proteases (trypsin, pepsin, papain, α-chymotrypsin, alcalase) to prepare peptides; compared with other hydrolysates, the trypsin hydrolysates exhibited the highest ACE inhibitory activity. The hydrolysis conditions were further optimized by response surface methodology (RSM), and the optimum conditions were as follows: pH 8.4, temperature 28.5 °C, enzyme/protein ratio (E/S) 4.0%, substrate concentration 15 mg/mL, and enzymolysis time 5.0 h. After fractionation and purification by ultrafiltration, gel exclusion chromatography and reverse-phase high-performance liquid chromatography, two novel purified ACE inhibitors with IC50 values of 219.35 μM (0.183 mg/mL) and 236.85 μM (0.179 mg/mL) were obtained. The molecular mass and amino acid sequence of the ACE inhibitory peptides were identified as Phe-Gly-Met-Pro-Leu-Asp-Arg (FGMPLDR; MW 834.41 Da) and Met-Glu-Leu-Val-Leu-Arg (MELVLR; MW 759.43 Da) by ultra-performance liquid chromatography-tandem mass spectrometry. A molecular docking study revealed that the ACE inhibitory activities of the peptides were mainly attributable to the hydrogen bond and Zn(II) interactions between the peptides and ACE. The results of this study provide a theoretical basis for the high-valued application of U. intestinalis and the development of food-derived ACE inhibitory peptides. Full article
(This article belongs to the Special Issue Enzyme Inhibitor from Marine Organisms)
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Open AccessArticle Steroids from the Deep-Sea-Derived Fungus Penicillium granulatum MCCC 3A00475 Induced Apoptosis via Retinoid X Receptor (RXR)-α Pathway
Mar. Drugs 2019, 17(3), 178; https://doi.org/10.3390/md17030178
Received: 24 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 19 March 2019
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Abstract
Five new ergostanes, penicisteroids D−H (15), were isolated from the liquid culture of the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475, along with 27 known compounds. The structures of the new steroids were established mainly on the basis of extensive [...] Read more.
Five new ergostanes, penicisteroids D−H (15), were isolated from the liquid culture of the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475, along with 27 known compounds. The structures of the new steroids were established mainly on the basis of extensive analysis of 1D and 2D NMR as well as HRESIMS data. Moreover, the absolute configurations of 1 were confirmed unambiguously by the single-crystal X-ray crystallography. Compounds 2 and 47 showed moderate antiproliferative effects selectively against 12 different cancer cell lines with IC50 values of around 5 μM. Compounds 2 and 6, potent RXRα binders with Kd values of 13.8 and 12.9 μM, respectively, could induce apoptosis by a Retinoid X Receptor (RXR)-α-dependent mechanism by regulating RXRα transcriptional expression and promoting the poly-ADP-ribose polymerase (PARP) cleavage. Moreover, they could inhibit proliferation by cell cycle arrest at the G0/G1 phase. Full article
(This article belongs to the Special Issue Steroids from Marine Sources)
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Open AccessFeature PaperArticle Transcriptomic-Proteomic Correlation in the Predation-Evoked Venom of the Cone Snail, Conus imperialis
Mar. Drugs 2019, 17(3), 177; https://doi.org/10.3390/md17030177
Received: 5 February 2019 / Revised: 12 March 2019 / Accepted: 14 March 2019 / Published: 19 March 2019
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Abstract
Individual variation in animal venom has been linked to geographical location, feeding habit, season, size, and gender. Uniquely, cone snails possess the remarkable ability to change venom composition in response to predatory or defensive stimuli. To date, correlations between the venom gland transcriptome [...] Read more.
Individual variation in animal venom has been linked to geographical location, feeding habit, season, size, and gender. Uniquely, cone snails possess the remarkable ability to change venom composition in response to predatory or defensive stimuli. To date, correlations between the venom gland transcriptome and proteome within and between individual cone snails have not been reported. In this study, we use 454 pyrosequencing and mass spectrometry to decipher the transcriptomes and proteomes of the venom gland and corresponding predation-evoked venom of two specimens of Conus imperialis. Transcriptomic analyses revealed 17 conotoxin gene superfamilies common to both animals, including 5 novel superfamilies and two novel cysteine frameworks. While highly expressed transcripts were common to both specimens, variation of moderately and weakly expressed precursor sequences was surprisingly diverse, with one specimen expressing two unique gene superfamilies and consistently producing more paralogs within each conotoxin gene superfamily. Using a quantitative labelling method, conotoxin variability was compared quantitatively, with highly expressed peptides showing a strong correlation between transcription and translation, whereas peptides expressed at lower levels showed a poor correlation. These results suggest that major transcripts are subject to stabilizing selection, while minor transcripts are subject to diversifying selection. Full article
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Open AccessArticle Phenalenones from a Marine-Derived Fungus Penicillium sp.
Mar. Drugs 2019, 17(3), 176; https://doi.org/10.3390/md17030176
Received: 26 February 2019 / Revised: 14 March 2019 / Accepted: 14 March 2019 / Published: 18 March 2019
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Abstract
Six new phenalenone derivatives (16), along with five known compounds (711) of the herqueinone class, were isolated from a marine-derived fungus Penicillium sp. The absolute configurations of these compounds were assigned based on chemical modifications [...] Read more.
Six new phenalenone derivatives (16), along with five known compounds (711) of the herqueinone class, were isolated from a marine-derived fungus Penicillium sp. The absolute configurations of these compounds were assigned based on chemical modifications and their specific rotations. 4-Hydroxysclerodin (6) and an acetone adduct of a triketone (7) exhibited moderate anti-angiogenetic and anti-inflammatory activities, respectively, while ent-peniciherqueinone (1) and isoherqueinone (9) exhibited moderate abilities to induce adipogenesis without cytotoxicity. Full article
(This article belongs to the Special Issue Natural Products from Marine Fungi)
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Open AccessArticle Dietary Supplementation with Low-Molecular-Weight Fucoidan Enhances Innate and Adaptive Immune Responses and Protects against Mycoplasma pneumoniae Antigen Stimulation
Mar. Drugs 2019, 17(3), 175; https://doi.org/10.3390/md17030175
Received: 15 February 2019 / Revised: 14 March 2019 / Accepted: 14 March 2019 / Published: 18 March 2019
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Abstract
In this study, the low-molecular-weight (LMW) fucoidan, rich in fucose and sulfate, was extracted and purified from the edible brown seaweed, Laminaria japonica. In this study, we orally administered LMW fucoidan to mice for 6 weeks. We then examined fucoidan’s effects on [...] Read more.
In this study, the low-molecular-weight (LMW) fucoidan, rich in fucose and sulfate, was extracted and purified from the edible brown seaweed, Laminaria japonica. In this study, we orally administered LMW fucoidan to mice for 6 weeks. We then examined fucoidan’s effects on innate immunity, adaptive immunity, and Mycoplasma pneumoniae (MP)-antigen-stimulated immune responses. Our data showed that LMW fucoidan stimulated the innate immune system by increasing splenocyte proliferation, natural killer (NK) cell activity, and phagocytic activity. LMW fucoidan also increased interleukin (IL)-2, IL-4, and interferon (IFN)-γ secretion by splenocytes and immunoglobulin (Ig)-G and IgA content in serum, which help regulate adaptive immune cell functions, and decreased allergen-specific IgE. In MP-antigen-stimulated immune responses, the IgM and IgG content in the serum were significantly higher in the LMW fucoidan group after MP-antigen stimulation. Our study provides further information about the immunomodulatory effects of LMW fucoidan and highlights a potential role in preventing M. pneumoniae infection. Full article
(This article belongs to the Special Issue Characterization of Bioactive Components in Edible Algae)
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Open AccessReview Mexican Microalgae Biodiversity and State-Of-The-Art Extraction Strategies to Meet Sustainable Circular Economy Challenges: High-Value Compounds and Their Applied Perspectives
Mar. Drugs 2019, 17(3), 174; https://doi.org/10.3390/md17030174
Received: 13 February 2019 / Revised: 5 March 2019 / Accepted: 9 March 2019 / Published: 18 March 2019
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Abstract
In recent years, the demand for naturally derived products has hiked with enormous pressure to propose or develop state-of-the-art strategies to meet sustainable circular economy challenges. Microalgae possess the flexibility to produce a variety of high-value products of industrial interests. From pigments such [...] Read more.
In recent years, the demand for naturally derived products has hiked with enormous pressure to propose or develop state-of-the-art strategies to meet sustainable circular economy challenges. Microalgae possess the flexibility to produce a variety of high-value products of industrial interests. From pigments such as phycobilins or lutein to phycotoxins and several polyunsaturated fatty acids (PUFAs), microalgae have the potential to become the primary producers for the pharmaceutical, food, and agronomical industries. Also, microalgae require minimal resources to grow due to their autotrophic nature or by consuming waste matter, while allowing for the extraction of several valuable side products such as hydrogen gas and biodiesel in a single process, following a biorefinery agenda. From a Mexican microalgae biodiversity perspective, more than 70 different local species have been characterized and isolated, whereas, only a minimal amount has been explored to produce commercially valuable products, thus ignoring their potential as a locally available resource. In this paper, we discuss the microalgae diversity present in Mexico with their current applications and potential, while expanding on their future applications in bioengineering along with other industrial sectors. In conclusion, the use of available microalgae to produce biochemically revenuable products currently represents an untapped potential that could lead to the solution of several problems through green technologies. As such, if the social, industrial and research communities collaborate to strive towards a greener economy by preserving the existing biodiversity and optimizing the use of the currently available resources, the enrichment of our society and the solution to several environmental problems could be attained. Full article
(This article belongs to the Special Issue Marine-Derived Products for Biomedicine)
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Open AccessArticle Evaluation of Prebiotic Potential of Three Marine Algae Oligosaccharides from Enzymatic Hydrolysis
Mar. Drugs 2019, 17(3), 173; https://doi.org/10.3390/md17030173
Received: 25 February 2019 / Revised: 9 March 2019 / Accepted: 11 March 2019 / Published: 18 March 2019
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Abstract
Alginate oligosaccharides (AlgO), agarose oligosaccharides (AO), and κ-carrageenan oligosaccharides (KCO) were obtained by specific enzymatic hydrolysis method. The molecular weight distributions of the three oligosaccharides were 1.0–5.0 kDa, 0.4–1.4 kDa, and 1.0–7.0 kDa, respectively. The culture medium was supplemented with the three oligosaccharides [...] Read more.
Alginate oligosaccharides (AlgO), agarose oligosaccharides (AO), and κ-carrageenan oligosaccharides (KCO) were obtained by specific enzymatic hydrolysis method. The molecular weight distributions of the three oligosaccharides were 1.0–5.0 kDa, 0.4–1.4 kDa, and 1.0–7.0 kDa, respectively. The culture medium was supplemented with the three oligosaccharides and fermented by pig fecal microbiota in vitro, for 24 h. Each oligosaccharide was capable of increasing the concentration of short-chain fatty acids (SCFAs), especially butyric acid, and altering the microbiota composition. Linear discriminant analysis effect size (LEfSe) analysis results showed that the opportunistic pathogenic bacteria Escherichia, Shigella, and Peptoniphilus, were significantly decreased in AlgO supplemented medium. AO could improve the gut microbiota composition by enriching the abundance of Ruminococcaceae, Coprococcus, Roseburia, and Faecalibacterium. Besides, KCO could increase the abundance of SCFA microbial producers and opportunistic pathogenic flora. Therefore, these results indicate that AlgO and AO can be used as gut microbial regulators and can potentially improve animal/human gastrointestinal health and prevent gut disease, whereas the physiological function of KCO needs further evaluation. Full article
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Open AccessArticle A Multi-screening Evaluation of the Nutritional and Nutraceutical Potential of the Mediterranean Jellyfish Pelagia noctiluca
Mar. Drugs 2019, 17(3), 172; https://doi.org/10.3390/md17030172
Received: 30 January 2019 / Revised: 8 March 2019 / Accepted: 13 March 2019 / Published: 17 March 2019
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Abstract
The phylum Cnidaria is one of the most important contributors in providing abundance of bio- and chemodiversity. In this study, a comprehensive chemical investigation on the nutritional and nutraceutical properties of Mediterranean jellyfish Pelagia noctiluca was carried out. Also, compositional differences between male [...] Read more.
The phylum Cnidaria is one of the most important contributors in providing abundance of bio- and chemodiversity. In this study, a comprehensive chemical investigation on the nutritional and nutraceutical properties of Mediterranean jellyfish Pelagia noctiluca was carried out. Also, compositional differences between male and female organisms, as well as between their main anatomical parts, namely bell and oral arms, were explored in an attempt to select the best potential sources of nutrients and/or nutraceuticals from jellyfish. With the exception of higher energy densities and total phenolic contents observed in females than males, no statistically significant differences related to the specimen’s sex were highlighted for the other compound classes. Rather, the distribution of the investigated chemical classes varied depending on the jellyfish’s body parts. In fact, crude proteins were more abundant in oral arms than bells; saturated fatty acids were more concentrated in bells than oral arms, whereas polyunsaturated fatty acids were distributed in the exact opposite way. On the other hand, major elements and trace elements demonstrated an opposite behavior, being the latter most accumulated in oral arms than bells. Additionally, important nutraceuticals, such as eicosapentaenoic and docosahexaenoic acids, and antioxidant minerals, were determined. Overall, obtained data suggest the potential employment of the Mediterranean P. noctiluca for the development of natural aquafeed and food supplements. Full article
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Open AccessArticle Stereo-Selective Pharmacokinetics of Ilimaquinone Epimers Extracted from a Marine Sponge in Rats
Mar. Drugs 2019, 17(3), 171; https://doi.org/10.3390/md17030171
Received: 20 February 2019 / Revised: 12 March 2019 / Accepted: 13 March 2019 / Published: 17 March 2019
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Abstract
An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. [...] Read more.
An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h−1 for IQ and 1.7 h−1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability. Full article
(This article belongs to the Special Issue Pharmacokinetic Research of Marine Drugs)
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Open AccessReview Antithrombotics from the Sea: Polysaccharides and Beyond
Mar. Drugs 2019, 17(3), 170; https://doi.org/10.3390/md17030170
Received: 31 January 2019 / Revised: 1 March 2019 / Accepted: 13 March 2019 / Published: 16 March 2019
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Abstract
Marine organisms exhibit some advantages as a renewable source of potential drugs, far beyond chemotherapics. Particularly, the number of marine natural products with antithrombotic activity has increased in the last few years, and reports show a wide diversity in scaffolds, beyond the polysaccharide [...] Read more.
Marine organisms exhibit some advantages as a renewable source of potential drugs, far beyond chemotherapics. Particularly, the number of marine natural products with antithrombotic activity has increased in the last few years, and reports show a wide diversity in scaffolds, beyond the polysaccharide framework. While there are several reviews highlighting the anticoagulant and antithrombotic activities of marine-derived sulfated polysaccharides, reports including other molecules are sparse. Therefore, the present paper provides an update of the recent progress in marine-derived sulfated polysaccharides and quotes other scaffolds that are being considered for investigation due to their antithrombotic effect. Full article
(This article belongs to the Special Issue Marine Polysaccharides in Pharmaceutical Applications)
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Open AccessArticle Preparation and Evaluation of Peptides with Potential Antioxidant Activity by Microwave Assisted Enzymatic Hydrolysis of Collagen from Sea Cucumber Acaudina Molpadioides Obtained from Zhejiang Province in China
Mar. Drugs 2019, 17(3), 169; https://doi.org/10.3390/md17030169
Received: 16 February 2019 / Revised: 2 March 2019 / Accepted: 11 March 2019 / Published: 15 March 2019
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Abstract
The present study was focused on the preparation and characterization of the antioxidant peptides by microwave-assisted enzymatic hydrolysis of collagen from sea cucumber Acaudina molpadioides (ASC-Am) obtained from Zhejiang Province in China. The results exhibited the effects of microwave irradiation on hydrolysis of [...] Read more.
The present study was focused on the preparation and characterization of the antioxidant peptides by microwave-assisted enzymatic hydrolysis of collagen from sea cucumber Acaudina molpadioides (ASC-Am) obtained from Zhejiang Province in China. The results exhibited the effects of microwave irradiation on hydrolysis of ASC-Am with different protease. Neutrase was selected from the four common proteases (papain, pepsin, trypsin, and neutrase) based on the highest content and DPPH scavenging activity of hydrolysate Fa (Molecular weight < 1 kDa). The content and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of Fa obtained by hydrolysis of neutrase increased by 100% and 109% respectively at a microwave power of 300 W compared with no microwave irradiation. Five subfractions were obtained after performing the gel filtration chromatography, and the Fa.2 exhibited the highest DPPH scavenging activity. The amino acid analysis showed that the contents of Glutamic acid, Alanine, Tyrosine, and Phenylalanine in fraction Fa.2 increased significantly, but an obvious decrease in the content of Glycine was observed compared to Fa. Four peptides (Fa.2-A, Fa.2-B, Fa.2-C, and Fa.2-D) were purified from Fa.2 by high performance liquid chromatography, and Fa.2-C showed the highest DPPH scavenging activity. The sequence of Fa.2-C was identified as Phenylalanine-Leucine- Alanine-Proline with a half elimination ratio (EC50) of 0.385 mg/mL. The antioxidant activity of Fa.2-C was probably attributed to the small molecular sizes and the presence of hydrophobic amino acid residues in its sequence. This report provided a promising method for the preparation of antioxidant peptides from collagen for food and medicinal purposes. Full article
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Open AccessArticle Hydrophilic Glycoproteins of an Edible Green Alga Capsosiphon fulvescens Prevent Aging-Induced Spatial Memory Impairment by Suppressing GSK-3β-Mediated ER Stress in Dorsal Hippocampus
Mar. Drugs 2019, 17(3), 168; https://doi.org/10.3390/md17030168
Received: 9 February 2019 / Revised: 27 February 2019 / Accepted: 12 March 2019 / Published: 15 March 2019
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Abstract
Endoplasmic reticulum (ER) stress is involved in various neurodegenerative disorders. We previously found that Capsosiphon fulvescens (C. fulvescens) crude proteins enhance spatial memory by increasing the expression of brain-derived neurotrophic factor (BDNF) in rat dorsal hippocampus. The present study investigated whether [...] Read more.
Endoplasmic reticulum (ER) stress is involved in various neurodegenerative disorders. We previously found that Capsosiphon fulvescens (C. fulvescens) crude proteins enhance spatial memory by increasing the expression of brain-derived neurotrophic factor (BDNF) in rat dorsal hippocampus. The present study investigated whether the chronic oral administration of hydrophilic C. fulvescens glycoproteins (Cf-hGP) reduces aging-induced cognitive dysfunction by regulating ER stress in the dorsal hippocampus. The oral administration of Cf-hGP (15 mg/kg/day) for four weeks attenuated the aging-induced increase in ER stress response protein glucose-regulated protein 78 (GRP78) in the synaptosome of the dorsal hippocampus; this was attenuated by the function-blocking anti-BDNF antibody (1 μg/μL) and a matrix metallopeptidase 9 inhibitor 1 (5 μM). Aging-induced GRP78 expression was associated with glycogen synthase kinase-3 beta (GSK-3β) (Tyr216)-mediated c-Jun N-terminal kinase phosphorylation, which was downregulated upon Cf-hGP administration. The Cf-hGP-induced increase in GSK-3β (Ser9) phosphorylation was downregulated by inhibiting tyrosine receptor kinase B and extracellular signal-regulated kinase (ERK)1/2 with cyclotraxin-B (200 nM) and SL327 (10 μM), respectively. Cf-hGP administration or the inhibition of ER stress with salubrinal (1 mg/kg, i.p.) significantly decreased aging-induced spatial memory impairment. These findings suggest that the activation of the synaptosomal BDNF-ERK1/2 signaling in the dorsal hippocampus by Cf-hGP attenuates age-dependent ER stress-induced cognitive dysfunction. Full article
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Open AccessArticle New Antimalarial and Antimicrobial Tryptamine Derivatives from the Marine Sponge Fascaplysinopsis reticulata
Mar. Drugs 2019, 17(3), 167; https://doi.org/10.3390/md17030167
Received: 22 February 2019 / Revised: 6 March 2019 / Accepted: 12 March 2019 / Published: 15 March 2019
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Abstract
Chemical study of the CH2Cl2-MeOH (1:1) extract of the sponge Fascaplysinopsis reticulata collected in Mayotte highlighted three new tryptophan derived alkaloids, 6,6′-bis-(debromo)-gelliusine F (1), 6-bromo-8,1′-dihydro-isoplysin A (2) and 5,6-dibromo-8,1′-dihydro-isoplysin A (3), along with [...] Read more.
Chemical study of the CH2Cl2-MeOH (1:1) extract of the sponge Fascaplysinopsis reticulata collected in Mayotte highlighted three new tryptophan derived alkaloids, 6,6′-bis-(debromo)-gelliusine F (1), 6-bromo-8,1′-dihydro-isoplysin A (2) and 5,6-dibromo-8,1′-dihydro-isoplysin A (3), along with the synthetically known 8-oxo-tryptamine (4) and the three known molecules from the same family, tryptamine (5), (E)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin (6) and (Z)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin (7). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their antimicrobial and their antiplasmodial activities. Regarding antimicrobial activities, the best compounds are (2) and (3), with minimum inhibitory concentration (MIC) of 0.01 and 1 µg/mL, respectively, towards Vibrio natrigens, and (5), with MIC values of 1 µg/mL towards Vibrio carchariae. In addition the known 8-oxo-tryptamine (4) and the mixture of the (E)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin (6) and (Z)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin (7) showed moderate antiplasmodial activity against Plasmodium falciparum with IC50 values of 8.8 and 8.0 µg/mL, respectively. Full article
(This article belongs to the collection TASCMAR)
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Open AccessArticle Anti-Diabetic Activity of 2,3,6-Tribromo-4,5-Dihydroxybenzyl Derivatives from Symphyocladia latiuscula through PTP1B Downregulation and α-Glucosidase Inhibition
Mar. Drugs 2019, 17(3), 166; https://doi.org/10.3390/md17030166
Received: 18 January 2019 / Revised: 27 February 2019 / Accepted: 11 March 2019 / Published: 14 March 2019
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Abstract
The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, [...] Read more.
The marine alga, Symphyocladia latiuscula (Harvey) Yamada, is a good source of bromophenols with numerous biological activities. This study aims to characterize the anti-diabetic potential of 2,3,6-tribromo-4,5-dihydroxybenzyl derivatives isolated from S. latiuscula via their inhibition of tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Additionally, this study uses in silico modeling and glucose uptake potential analysis in insulin-resistant (IR) HepG2 cells to reveal the mechanism of anti-diabetic activity. This bioassay-guided isolation led to the discovery of three potent bromophenols that act against PTP1B and α-glucosidase: 2,3,6-tribromo-4,5-dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether) (3). All compounds inhibited the target enzymes by 50% at concentrations below 10 μM. The activity of 1 and 2 was comparable to ursolic acid (IC50; 8.66 ± 0.82 μM); however, 3 was more potent (IC50; 5.29 ± 0.08 μM) against PTP1B. Interestingly, the activity of 13 against α-glucosidase was 30–110 times higher than acarbose (IC50; 212.66 ± 0.35 μM). Again, 3 was the most potent α-glucosidase inhibitor (IC50; 1.92 ± 0.02 μM). Similarly, 13 showed concentration-dependent glucose uptake in insulin-resistant HepG2 cells and downregulated PTP1B expression. Enzyme kinetics revealed different modes of inhibition. In silico molecular docking simulations demonstrated the importance of the 7–OH group for H-bond formation and bromine/phenyl ring number for halogen-bond interactions. These results suggest that bromophenols from S. latiuscula, especially highly brominated 3, are inhibitors of PTP1B and α-glucosidase, enhance insulin sensitivity and glucose uptake, and may represent a novel class of anti-diabetic drugs. Full article
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Open AccessArticle ‘Messy’ Processing of χ-conotoxin MrIA Generates Homologues with Reduced hNET Potency
Mar. Drugs 2019, 17(3), 165; https://doi.org/10.3390/md17030165
Received: 1 February 2019 / Revised: 26 February 2019 / Accepted: 12 March 2019 / Published: 14 March 2019
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Abstract
Integrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and [...] Read more.
Integrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and therefore a drug candidate for attenuating chronic neuropathic pain. It has been found that “messy” processing of the MrIA transcripts results in the expression of MrIA analogs with different truncations of the pro-peptide that contains portions of the MrIA molecule. The aim of this study was to investigate if variable processing of the expressed peptides results in modulation of the existing hNET pharmacology or creates new pharmacologies. To this end, a number of MrIA analogs found in C. marmoreus venom were synthesized and evaluated for their activity at hNET receptors. While several of the analogs exhibited norepinephrine transporter inhibitory activity comparable to that of MrIA, none significantly improved on the potency of conotoxin MrIA, and those analogs with disrupted pharmacophores produced greatly reduced NET inhibition, confirming previous structure-activity relationships seen on χ-class conopeptides. Additionally, analogs were screened for new activities on ion channels using calcium influx assays, although no major new pharmacology was revealed. Full article
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Open AccessArticle Novel Fibrinolytic Protease Producing Streptomyces radiopugnans VITSD8 from Marine Sponges
Mar. Drugs 2019, 17(3), 164; https://doi.org/10.3390/md17030164
Received: 1 February 2019 / Revised: 3 March 2019 / Accepted: 5 March 2019 / Published: 13 March 2019
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Abstract
Fibrinolytic enzymes have received more attention due to their medicinal potential for thrombolytic diseases. The aim of this study is to characterize the in vitro fibrinolytic nature of purified protease producing Streptomyces radiopugnans VITSD8 from marine brown tube sponges Agelas conifera. Three [...] Read more.
Fibrinolytic enzymes have received more attention due to their medicinal potential for thrombolytic diseases. The aim of this study is to characterize the in vitro fibrinolytic nature of purified protease producing Streptomyces radiopugnans VITSD8 from marine brown tube sponges Agelas conifera. Three varieties of sponge were collected from the Rameshwaram Sea coast, Tamil Nadu, India. The fibrinolytic activity of Streptomyces sp. was screened and determined by casein plasminogen plate and fibrin plate methods respectively. The crude caseinolytic protease was purified using ammonium sulfate fractionation, affinity and ion-exchange chromatography. Based on the morphological, biochemical, and molecular characterization, the isolate VITSD8 was confirmed as Streptomyces radiopugnans. Maltose and peptone were found to be the best carbon and nitrogen sources for the production of fibrinolytic protease. The carbon and nitrogen source peptone showed (781 U/mL) enzyme activity. The optimum pH and temperature for fibrinolytic protease production was found to be 7.0 and 33 °C respectively. The purified enzyme showed a maximum specific activity of 3891 U. The blood clot lysis activity was compared with the standard, and it was concluded that a minimum of 0.18 U (10 µL) of purified protease was required to dissolve the blood clot. This is the first report which exploits the fibrinolytic protease activity of Streptomyces radiopugnans VITSD8 extracted from a marine sponge. Hence the investigation suggests a potential benefit of purified fibrinolytic protease which will serve as an excellent clot buster alternative. Full article
(This article belongs to the Special Issue Marine Molecules for the Treatment of Thrombosis)
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