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Mar. Drugs, Volume 16, Issue 10 (October 2018)

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Open AccessArticle Structure and Anti-Inflammatory Activity of a New Unusual Fucosylated Chondroitin Sulfate from Cucumaria djakonovi
Mar. Drugs 2018, 16(10), 389; https://doi.org/10.3390/md16100389 (registering DOI)
Received: 12 September 2018 / Revised: 12 October 2018 / Accepted: 12 October 2018 / Published: 17 October 2018
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Abstract
Fucosylated chondroitin sulfate CD was isolated from the sea cucumber Cucumaria djakonovi collected from the Avachinsky Gulf of the eastern coast of Kamchatka. Structural characterization of CD was performed using a series of non-destructive NMR spectroscopic procedures. The polysaccharide was shown to contain
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Fucosylated chondroitin sulfate CD was isolated from the sea cucumber Cucumaria djakonovi collected from the Avachinsky Gulf of the eastern coast of Kamchatka. Structural characterization of CD was performed using a series of non-destructive NMR spectroscopic procedures. The polysaccharide was shown to contain a chondroitin core [→3)-β-d-GalNAc-(1→4)-β-d-GlcA-(1→]n where about 60% of GlcA residues were 3-O-fucosylated, while another part of GlcA units did not contain any substituents. The presence of unsubstituted both at O-2 and O-3 glucuronic acid residues in a structure of holothurian chondroitin sulfate is unusual and has not been reported previously. Three different fucosyl branches Fucp2S4S, Fucp3S4S and Fucp4S were found in the ratio of 2:1:1. The GalNAc units were mono- or disulfated at positions 4 and 6. Anti-inflammatory activity of CD was assessed on a model of acute peritoneal inflammation in rats. About 45% inhibition was found for CD, while a structurally related linear chondroitin sulfate SS from cartilage of the fish Salmo salar demonstrated only 31% inhibition, indicating that the presence of sulfated fucosyl branches is essential for anti-inflammatory effect of chondroitin sulfates of marine origin. Full article
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Open AccessArticle For a Correct Application of the CD Exciton Chirality Method: The Case of Laucysteinamide A
Mar. Drugs 2018, 16(10), 388; https://doi.org/10.3390/md16100388 (registering DOI)
Received: 21 September 2018 / Revised: 10 October 2018 / Accepted: 15 October 2018 / Published: 16 October 2018
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Abstract
The circular dichroism (CD) exciton chirality method (ECM) is a very popular approach for assigning the absolute configuration (AC) of natural products, thanks to its immediacy and ease of application. The sign of an exciton couplet (two electronic CD bands with opposite sign
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The circular dichroism (CD) exciton chirality method (ECM) is a very popular approach for assigning the absolute configuration (AC) of natural products, thanks to its immediacy and ease of application. The sign of an exciton couplet (two electronic CD bands with opposite sign and similar intensity) can be directly correlated with the molecular stereochemistry, including the AC. However, a correct application of the ECM necessitates several prerequisites: knowledge of the molecular conformation; knowledge of transition moment direction; and preeminence of the exciton coupling mechanism with respect to other sources of CD signals. In recent years, by using quantum-chemical CD calculations, we have demonstrated that some previous applications of ECM were wrong or based on incorrect assumptions. In a recent publication of this journal (Mar. Drugs, 2017, 15(4), 121), the ECM was employed to assign the AC of a marine metabolite, laucysteinamide A. This is a further case of incorrect application of the method, where none of the aforementioned prerequisites is fully met. Using this example, we will discuss the criteria required for a correct application of the ECM. Full article
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Open AccessArticle Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model
Mar. Drugs 2018, 16(10), 387; https://doi.org/10.3390/md16100387 (registering DOI)
Received: 16 September 2018 / Revised: 15 October 2018 / Accepted: 15 October 2018 / Published: 16 October 2018
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Abstract
Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit
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Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics. Full article
(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)
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Open AccessArticle Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study
Mar. Drugs 2018, 16(10), 386; https://doi.org/10.3390/md16100386
Received: 30 August 2018 / Revised: 10 October 2018 / Accepted: 11 October 2018 / Published: 16 October 2018
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Abstract
Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration
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Alzheimer’s disease (AD) is becoming one of the most disturbing health and socioeconomic problems nowadays, as it is a neurodegenerative pathology with no treatment, which is expected to grow further due to population ageing. Actual treatments for AD produce only a modest amelioration of symptoms, although there is a constant ongoing research of new therapeutic strategies oriented to improve the amelioration of the symptoms, and even to completely cure the disease. A principal feature of AD is the presence of neurofibrillary tangles (NFT) induced by the aberrant phosphorylation of the microtubule-associated protein tau in the brains of affected individuals. Glycogen synthetase kinase-3 beta (GSK3β), casein kinase 1 delta (CK1δ), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and dual-specificity kinase cdc2-like kinase 1 (CLK1) have been identified as the principal proteins involved in this process. Due to this, the inhibition of these kinases has been proposed as a plausible therapeutic strategy to fight AD. In this study, we tested in silico the inhibitory activity of different marine natural compounds, as well as newly-designed molecules from some of them, over the mentioned protein kinases, finding some new possible inhibitors with potential therapeutic application. Full article
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Open AccessArticle New Mammalian Target of Rapamycin (mTOR) Modulators Derived from Natural Product Databases and Marine Extracts by Using Molecular Docking Techniques
Mar. Drugs 2018, 16(10), 385; https://doi.org/10.3390/md16100385
Received: 24 September 2018 / Revised: 11 October 2018 / Accepted: 12 October 2018 / Published: 15 October 2018
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Abstract
Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive
[...] Read more.
Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects. Full article
(This article belongs to the Special Issue Marine Small-Molecule Bioactive Agents and Therapeutic Targets)
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Open AccessArticle A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands
Mar. Drugs 2018, 16(10), 384; https://doi.org/10.3390/md16100384
Received: 1 October 2018 / Revised: 10 October 2018 / Accepted: 11 October 2018 / Published: 14 October 2018
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Abstract
Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2
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Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor. Full article
(This article belongs to the Special Issue Marine Small-Molecule Bioactive Agents and Therapeutic Targets)
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Open AccessArticle Anticancer Activity of Fascaplysin against Lung Cancer Cell and Small Cell Lung Cancer Circulating Tumor Cell Lines
Mar. Drugs 2018, 16(10), 383; https://doi.org/10.3390/md16100383
Received: 15 September 2018 / Revised: 4 October 2018 / Accepted: 10 October 2018 / Published: 14 October 2018
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Abstract
Lung cancer is a leading cause of tumor-associated mortality. Fascaplysin, a bis-indole of a marine sponge, exhibit broad anticancer activity as specific CDK4 inhibitor among several other mechanisms, and is investigated as a drug to overcome chemoresistance after the failure of targeted agents
[...] Read more.
Lung cancer is a leading cause of tumor-associated mortality. Fascaplysin, a bis-indole of a marine sponge, exhibit broad anticancer activity as specific CDK4 inhibitor among several other mechanisms, and is investigated as a drug to overcome chemoresistance after the failure of targeted agents or immunotherapy. The cytotoxic activity of fascaplysin was studied using lung cancer cell lines, primary Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) cells, as well as SCLC circulating tumor cell lines (CTCs). This compound exhibited high activity against SCLC cell lines (mean IC50 0.89 µM), as well as SCLC CTCs as single cells and in the form of tumorospheres (mean IC50 0.57 µM). NSCLC lines showed a mean IC50 of 1.15 µM for fascaplysin. Analysis of signal transduction mediators point to an ATM-triggered signaling cascade provoked by drug-induced DNA damage. Fascaplysin reveals at least an additive cytotoxic effect with cisplatin, which is the mainstay of lung cancer chemotherapy. In conclusion, fascaplysin shows high activity against lung cancer cell lines and spheroids of SCLC CTCs which are linked to the dismal prognosis of this tumor type. Derivatives of fascaplysin may constitute valuable new agents for the treatment of lung cancer. Full article
(This article belongs to the collection Marine Compounds and Cancer) Printed Edition available
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Open AccessArticle New Sulfur-Containing Polyarsenicals from the New Caledonian Sponge Echinochalina bargibanti
Mar. Drugs 2018, 16(10), 382; https://doi.org/10.3390/md16100382
Received: 14 September 2018 / Revised: 3 October 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
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Abstract
Arsenicin A (C3H6As4O3) was isolated from the New Caledonian poecilosclerid sponge Echinochalina bargibanti, and described as the first natural organic polyarsenic compound. Further bioguided fractionation of the extracts of this sponge led us to
[...] Read more.
Arsenicin A (C3H6As4O3) was isolated from the New Caledonian poecilosclerid sponge Echinochalina bargibanti, and described as the first natural organic polyarsenic compound. Further bioguided fractionation of the extracts of this sponge led us to isolate the first sulfur-containing organic polyarsenicals ever found in Nature. These metabolites, called arsenicin B and arsenicin C, are built on a noradamantane-type framework that is characterized by an unusual As–As bonding. Extensive NMR measurements, in combination with mass spectra, enabled the assignment of the structure for arsenicin B (C3H6As4S2) as 2. The scarcity of arsenicin C and its intrinsic chemical instability only allowed the collection of partial spectral data, which prevented the full structural definition. After the extensive computational testing of several putative structures, structure 3 was inferred for arsenicin C (C3H6As4OS) by comparing the experimental and density functional theory (DFT)-calculated 1H and 13C NMR spectra. Finally, the absolute configurations of 2 and 3 were determined with a combined use of experimental and time-dependent (TD)-DFT calculated electronic circular dichroism (ECD) spectra and observed specific rotations. These findings pose great challenges for the investigation of the biosynthesis of these metabolites and the cycle of arsenic in Nature. Arsenicins B and C showed strong antimicrobial activities, especially against S. aureus, which is comparable to the reference compound gentamycin. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)
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Open AccessArticle Massive Gene Expansion and Sequence Diversification Is Associated with Diverse Tissue Distribution, Regulation and Antimicrobial Properties of Anti-Lipopolysaccharide Factors in Shrimp
Mar. Drugs 2018, 16(10), 381; https://doi.org/10.3390/md16100381
Received: 15 September 2018 / Revised: 3 October 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
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Abstract
Anti-lipopolysaccharide factors (ALFs) are antimicrobial peptides with a central β-hairpin structure able to bind to microbial components. Mining sequence databases for ALFs allowed us to show the remarkable diversity of ALF sequences in shrimp. We found at least seven members of the ALF
[...] Read more.
Anti-lipopolysaccharide factors (ALFs) are antimicrobial peptides with a central β-hairpin structure able to bind to microbial components. Mining sequence databases for ALFs allowed us to show the remarkable diversity of ALF sequences in shrimp. We found at least seven members of the ALF family (Groups A to G), including two novel Groups (F and G), all of which are encoded by different loci with conserved gene organization. Phylogenetic analyses revealed that gene expansion and subsequent diversification of the ALF family occurred in crustaceans before shrimp speciation occurred. The transcriptional profile of ALFs was compared in terms of tissue distribution, response to two pathogens and during shrimp development in Litopenaeus vannamei, the most cultivated species. ALFs were found to be constitutively expressed in hemocytes and to respond differently to tissue damage. While synthetic β-hairpins of Groups E and G displayed both antibacterial and antifungal activities, no activity was recorded for Group F β-hairpins. Altogether, our results showed that ALFs form a family of shrimp AMPs that has been the subject of intense diversification. The different genes differ in terms of tissue expression, regulation and function. These data strongly suggest that multiple selection pressures have led to functional diversification of ALFs in shrimp. Full article
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Open AccessArticle Synthesis of Novel Chitin Derivatives Bearing Amino Groups and Evaluation of Their Antifungal Activity
Mar. Drugs 2018, 16(10), 380; https://doi.org/10.3390/md16100380
Received: 13 September 2018 / Revised: 28 September 2018 / Accepted: 3 October 2018 / Published: 11 October 2018
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Abstract
Chemical modification is one of the most effective methods to improve the biological activity of chitin. In the current study, we modified C3-OH and C6-OH of chitin (CT) and successfully synthesized 6-amino-chitin (NCT) and 3,6-diamino-chitin (DNCT) through a series of chemical reactions. The
[...] Read more.
Chemical modification is one of the most effective methods to improve the biological activity of chitin. In the current study, we modified C3-OH and C6-OH of chitin (CT) and successfully synthesized 6-amino-chitin (NCT) and 3,6-diamino-chitin (DNCT) through a series of chemical reactions. The structure of NCT and DNCT were characterized by elemental analyses, FT-IR, 13C NMR, XRD, and SEM. The inhibitory effects of CT, NCT, and DNCT against six kinds of phytopathogen (F. oxysporum f. sp. cucumerium, B. cinerea, C. lagenarium, P. asparagi, F. oxysporum f. niveum, and G. zeae) were evaluated using disk diffusion method in vitro. Meanwhile, carbendazim and amphotericin B were used as positive controls. Results revealed that 6-amino-chitin (NCT) and 3,6-diamino-chitin (DNCT) showed improved antifungal properties compared with pristine chitin. Moreover, DNCT exhibited the better antifungal property than NCT. Especially, while the inhibition zone diameters of NCT are ranged from 11.2 to 16.3 mm, DNCT are about 11.4–20.4 mm. These data demonstrated that the introduction of amino group into chitin derivatives could be key to increasing the antifungal activity of such compounds, and the greater the number of amino groups in the chitin derivatives, the better their antifungal activity was. Full article
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Open AccessArticle Fatty Acid Composition and Fatty Acid Associated Gene-Expression in Gilthead Sea Bream (Sparus aurata) are Affected by Low-Fish Oil Diets, Dietary Resveratrol, and Holding Temperature
Mar. Drugs 2018, 16(10), 379; https://doi.org/10.3390/md16100379
Received: 30 August 2018 / Revised: 3 October 2018 / Accepted: 5 October 2018 / Published: 10 October 2018
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Abstract
To sustainably produce marine fish with a high lipid quality rich in omega-3 fatty acids, alternative sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are being identified. Moreover, the use of bioactive compounds that would stimulate the in vivo fatty acid synthesis,
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To sustainably produce marine fish with a high lipid quality rich in omega-3 fatty acids, alternative sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are being identified. Moreover, the use of bioactive compounds that would stimulate the in vivo fatty acid synthesis, such as resveratrol (RV), would reduce the dependence on fish oil in aquafeeds. Gilthead sea bream (Sparus aurata) were fed four experimental diets combining two fish oil levels (6% dry matter (DM); 2% DM) with or without 0.15% DM resveratrol supplementation (F6, F2, F6 + RV, F2 + RV) for two months. Additionally, the fish were challenged either at 19 °C or 23 °C. A higher water temperature promoted their feed intake and growth, resulting in an increased crude lipid content irrespective of dietary treatment. The fatty acid composition of different tissues was significantly affected by the holding temperature and dietary fish oil level. The dietary RV significantly affected the hepatic EPA and DHA content of fish held at 19 °C. The observed effect of RV may be partly explained by alterations of the mRNA steady-state levels of ∆6-desaturase and β-oxidation-related genes. Besides the relevant results concerning RV-mediated regulation of fatty acid synthesis in marine fish, further studies need to be conducted to clarify the potential value of RV to enhance fillet lipid quality. Full article
(This article belongs to the Special Issue The Sources and Production of Polyunsaturated Fatty Acids)
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Open AccessArticle Fucoxanthin-Containing Cream Prevents Epidermal Hyperplasia and UVB-Induced Skin Erythema in Mice
Mar. Drugs 2018, 16(10), 378; https://doi.org/10.3390/md16100378
Received: 20 September 2018 / Revised: 3 October 2018 / Accepted: 8 October 2018 / Published: 10 October 2018
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Abstract
Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1
[...] Read more.
Microalgae represent a source of bio-active compounds such as carotenoids with potent anti-inflammatory and antioxidant properties. We aimed to investigate the effects of fucoxanthin (FX) in both in vitro and in vivo skin models. Firstly, its anti-inflammatory activity was evaluated in LPS-stimulated THP-1 macrophages and TNF-α-stimulated HaCaT keratinocytes, and its antioxidant activity in UVB-irradiated HaCaT cells. Next, in vitro and ex vivo permeation studies were developed to determine the most suitable formulation for in vivo FX topical application. Then, we evaluated the effects of a FX-containing cream on TPA-induced epidermal hyperplasia in mice, as well as on UVB-induced acute erythema in hairless mice. Our results confirmed the in vitro reduction of TNF-α, IL-6, ROS and LDH production. Since the permeation results showed that cream was the most favourable vehicle, FX-cream was elaborated. This formulation effectively ameliorated TPA-induced hyperplasia, by reducing skin edema, epidermal thickness, MPO activity and COX-2 expression. Moreover, FX-cream reduced UVB-induced erythema through down-regulation of COX-2 and iNOS as well as up-regulation of HO-1 protein via Nrf-2 pathway. In conclusion, FX, administered in a topical formulation, could be a novel natural adjuvant for preventing exacerbations associated with skin inflammatory pathologies as well as protecting skin against UV radiation. Full article
(This article belongs to the Special Issue Marine Anti-inflammatory Agents)
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Open AccessArticle A Novel Natural Influenza A H1N1 Virus Neuraminidase Inhibitory Peptide Derived from Cod Skin Hydrolysates and Its Antiviral Mechanism
Mar. Drugs 2018, 16(10), 377; https://doi.org/10.3390/md16100377
Received: 13 September 2018 / Revised: 27 September 2018 / Accepted: 6 October 2018 / Published: 10 October 2018
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Abstract
In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA-inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration
[...] Read more.
In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA-inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration membrane (5000 Da), sephadex G-15 gel column and reverse-phase high-performance liquid chromatography (RP-HPLC). The amino acid sequence of the pure peptide was determined by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) was PGEKGPSGEAGTAGPPGTPGPQGL, with a molecular weight of 2163 Da. The analysis of the Lineweacer–Burk model indicated that the peptide was a competitive NA inhibitor with Ki of 0.29 mM and could directly bind free enzymes. In addition, docking studies suggested that hydrogen binding might be the driving force for the binding affinity of PGEKGPSGEAGTAGPPGTPGPQGL to NA. The cytopathic effect reduction assay showed that the peptide PGEKGPSGEAGTAGPPGTPGPQGL protected Madin–Darby canine kidney (MDCK) cells from viral infection and reduced the viral production in a dose-dependent manner. The EC50 value was 471 ± 12 μg/mL against H1N1. Time-course analysis showed that PGEKGPSGEAGTAGPPGTPGPQGL inhibited influenza virus in the early stage of the infectious cycle. The virus titers assay indicated that the NA-inhibitory peptide PGEKGPSGEAGTAGPPGTPGPQGL could directly affect the virus toxicity and adsorption by host cells, further proving that the peptide had an anti-viral effect with multiple target sites. The activity of NA-inhibitory peptide was almost inactivated during the simulated in vitro gastrointestinal digestion, suggesting that oral administration is not recommended. The peptide PGEKGPSGEAGTAGPPGTPGPQGL acts as a neuraminidase blocker to inhibit influenza A virus in MDCK cells. Thus, the peptide PGEKGPSGEAGTAGPPGTPGPQGL has potential utility in the treatment of the influenza virus infection. Full article
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Open AccessArticle Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery
Mar. Drugs 2018, 16(10), 376; https://doi.org/10.3390/md16100376
Received: 17 September 2018 / Revised: 3 October 2018 / Accepted: 5 October 2018 / Published: 10 October 2018
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Abstract
There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule
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There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment. Full article
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Open AccessArticle Diphlorethohydroxycarmalol Isolated from Ishige okamurae Represses High Glucose-Induced Angiogenesis In Vitro and In Vivo
Mar. Drugs 2018, 16(10), 375; https://doi.org/10.3390/md16100375
Received: 18 August 2018 / Revised: 4 October 2018 / Accepted: 5 October 2018 / Published: 10 October 2018
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Abstract
Diabetes mellitus causes abnormalities of angiogenesis leading to vascular dysfunction and serious pathologies. Diphlorethohydroxycarmalol (DPHC), which is isolated from Ishige okamurae, is well known for its bioactivities, including antihyperglycemic and protective functions against diabetes-related pathologies. In the present study, the inhibitory effect
[...] Read more.
Diabetes mellitus causes abnormalities of angiogenesis leading to vascular dysfunction and serious pathologies. Diphlorethohydroxycarmalol (DPHC), which is isolated from Ishige okamurae, is well known for its bioactivities, including antihyperglycemic and protective functions against diabetes-related pathologies. In the present study, the inhibitory effect of DPHC on high glucose-induced angiogenesis was investigated on the human vascular endothelial cell line EA.hy926. DPHC inhibited the cell proliferation, cell migration, and tube formation in cells exposed to 30 mM of glucose to induce angiogenesis. Furthermore, the effect of DPHC against high glucose-induced angiogenesis was evaluated in zebrafish embryos. The treatment of embryos with DPHC suppressed high glucose-induced dilation in the retinal vessel diameter and vessel formation. Moreover, DPHC could inhibit high glucose-induced vascular endothelial growth factor receptor 2 (VEGFR-2) expression and its downstream signaling cascade. Overall, these findings suggest that DPHC is actively involved in the suppression of high glucose-induced angiogenesis. Hence, DPHC is a potential agent for the development of therapeutics against angiogenesis induced by diabetes. Full article
(This article belongs to the Special Issue Seaweeds and Their Biological Actions)
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Open AccessArticle Meroterpenoid-Rich Fraction of the Ethanolic Extract from Sargassum serratifolium Suppressed Oxidative Stress Induced by Tert-Butyl Hydroperoxide in HepG2 Cells
Mar. Drugs 2018, 16(10), 374; https://doi.org/10.3390/md16100374
Received: 6 August 2018 / Revised: 6 October 2018 / Accepted: 7 October 2018 / Published: 9 October 2018
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Abstract
Sargassum species have been reported to be a source of phytochemicals, with a wide range of biological activities. In this study, we evaluated the hepatoprotective effect of a meroterpenoid-rich fraction of the ethanolic extract from Sargassum serratifolium (MES) against tert-butyl hydroperoxide (
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Sargassum species have been reported to be a source of phytochemicals, with a wide range of biological activities. In this study, we evaluated the hepatoprotective effect of a meroterpenoid-rich fraction of the ethanolic extract from Sargassum serratifolium (MES) against tert-butyl hydroperoxide (t-BHP)-treated HepG2 cells. Treatment with MES recovered the cell viability from the t-BHP-induced oxidative damage in a dose-dependent manner. It suppressed the reactive oxygen species production, lipid peroxidation, and glutathione depletion in the t-BHP-treated HepG2 cells. The activity of the antioxidants induced by t-BHP, including superoxide dismutase (SOD) and catalase, was reduced by the MES treatment. Moreover, it increased the nuclear translocation of nuclear factor erythroid 2-related factor 2, leading to the enhanced activity of glutathione S transferase, and the increased production of heme oxygenase-1 and NAD(P)H:quinine oxidoreductase 1 in t-BHP-treated HepG2 cells. These results demonstrate that the antioxidant activity of MES substituted the activity of the SOD and catalase, and induced the production of detoxifying enzymes, indicating that MES might be used as a hepatoprotectant against t-BHP-induced oxidative stress. Full article
(This article belongs to the Special Issue Marine Antioxidant)
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Open AccessReview Chitosan-Based In Situ Gels for Ocular Delivery of Therapeutics: A State-of-the-Art Review
Mar. Drugs 2018, 16(10), 373; https://doi.org/10.3390/md16100373
Received: 14 September 2018 / Revised: 1 October 2018 / Accepted: 6 October 2018 / Published: 9 October 2018
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Abstract
Ocular in situ gels are a promising alternative to overcome drawbacks of conventional eye drops because they associate the advantages of solutions such as accuracy and reproducibility of dosing, or ease of administration with prolonged contact time of ointments. Chitosan is a natural
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Ocular in situ gels are a promising alternative to overcome drawbacks of conventional eye drops because they associate the advantages of solutions such as accuracy and reproducibility of dosing, or ease of administration with prolonged contact time of ointments. Chitosan is a natural polymer suitable for use in ophthalmic formulations due to its biocompatibility, biodegradability, mucoadhesive character, antibacterial and antifungal properties, permeation enhancement and corneal wound healing effects. The combination of chitosan, pH-sensitive polymer, with other stimuli-responsive polymers leads to increased mechanical strength of formulations and an improved therapeutic effect due to prolonged ocular contact time. This review describes in situ gelling systems resulting from the association of chitosan with various stimuli-responsive polymers with emphasis on the mechanism of gel formation and application in ophthalmology. It also comprises the main techniques for evaluation of chitosan in situ gels, along with requirements of safety and ocular tolerability. Full article
(This article belongs to the Special Issue Marine Biopolymers and Drug Delivery)
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Open AccessFeature PaperArticle Optimization of Growth and Carotenoid Production by Haloferax mediterranei Using Response Surface Methodology
Mar. Drugs 2018, 16(10), 372; https://doi.org/10.3390/md16100372
Received: 11 September 2018 / Revised: 26 September 2018 / Accepted: 3 October 2018 / Published: 9 October 2018
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Abstract
Haloferax mediterranei produces C50 carotenoids that have strong antioxidant properties. The response surface methodology (RSM) tool helps to accurately analyze the most suitable conditions to maximize C50 carotenoids production by haloarchaea. The effects of temperature (15–50 °C), pH (4−10), and salinity (5–28% NaCl
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Haloferax mediterranei produces C50 carotenoids that have strong antioxidant properties. The response surface methodology (RSM) tool helps to accurately analyze the most suitable conditions to maximize C50 carotenoids production by haloarchaea. The effects of temperature (15–50 °C), pH (4−10), and salinity (5–28% NaCl (w/v)) on the growth and carotenoid content of H. mediterranei were analyzed using the RSM approach. Growth was determined by measuring the turbidity at 600 nm. To determine the carotenoid content, harvested cells were lysed by freeze/thawing, then re-suspended in acetone and the total carotenoid content determined by measuring the absorbance at 494 nm. The analysis of carotenoids was performed by an HPLC system coupled with mass spectrometry. The results indicated the theoretical optimal conditions of 36.51 or 36.81 °C, pH of 8.20 or 8.96, and 15.01% or 12.03% (w/v) salinity for the growth of haloarchaea (OD600 = 12.5 ± 0.64) and production of total carotenoids (3.34 ± 0.29 mg/L), respectively. These conditions were validated experimentally for growth (OD600 = 13.72 ± 0.98) and carotenoid production (3.74 ± 0.20 mg/L). The carotenoid profile showed four isomers of bacterioruberin (89.13%). Our findings suggest that the RSM approach is highly useful for determining optimal conditions for large-scale production of bacterioruberin by haloarchaea. Full article
(This article belongs to the Special Issue Marine Bacteria as Sources of Bioactive Compounds)
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Open AccessArticle New 3-Hydroxyquinaldic Acid Derivatives from Cultures of the Marine Derived Actinomycete Streptomyces cyaneofuscatus M-157
Mar. Drugs 2018, 16(10), 371; https://doi.org/10.3390/md16100371
Received: 13 September 2018 / Revised: 4 October 2018 / Accepted: 4 October 2018 / Published: 8 October 2018
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Abstract
Fractionation of the bioactive extract of a culture of the marine derived actinomycete Streptomyces cyaneofuscatus M-157 led to the isolation of the known 3-hydroxyquinaldic acid (4), its amide (5) and three new derivatives (13) containing
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Fractionation of the bioactive extract of a culture of the marine derived actinomycete Streptomyces cyaneofuscatus M-157 led to the isolation of the known 3-hydroxyquinaldic acid (4), its amide (5) and three new derivatives (13) containing different amino acid residues. The structures of the new molecules (13), including their absolute configuration, were determined by the analysis of their ESI-TOF MS and one-dimensional (1D) and two-dimensional (2D) NMR spectra and advanced Marfey’s analysis of their hydrolyzation products. Compound 3 spontaneously dimerized in solution to give the disulfide derivative 6. Unfortunately, none of the new compounds isolated confirmed the antimicrobial activity found in the bacterial extract, perhaps indicating that such antibacterial activity might be due to presence in the extract at the trace level of larger bioactive 3-hydroxyquinaldic acid derivatives from which compounds 13 are biosynthetic precursors. Cytotoxicity tests confirmed the moderate and weak IC50 values of 15.6 and 51.5 µM for compounds 5 and 1, respectively. Full article
(This article belongs to the Special Issue Isolation and Structure Elucidation of Marine Secondary Metabolites)
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Open AccessArticle Characterization of a Novel N-Acylhomoserine Lactonase RmmL from Ruegeria mobilis YJ3
Mar. Drugs 2018, 16(10), 370; https://doi.org/10.3390/md16100370
Received: 19 August 2018 / Revised: 27 September 2018 / Accepted: 1 October 2018 / Published: 8 October 2018
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Abstract
Gram-negative bacteria utilize N-acylhomoserine lactones (AHLs) as quorum sensing (QS) signaling molecules for intercellular communication. Cell-to-cell communication depends on cell population density, and AHL-dependent QS is related to the production of multiple genes including virulence factors. Quorum quenching (QQ), signal inactivation by
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Gram-negative bacteria utilize N-acylhomoserine lactones (AHLs) as quorum sensing (QS) signaling molecules for intercellular communication. Cell-to-cell communication depends on cell population density, and AHL-dependent QS is related to the production of multiple genes including virulence factors. Quorum quenching (QQ), signal inactivation by enzymatic degradation, is a potential strategy for attenuating QS regulated bacterial infections. Both Gram-positive and -negative bacteria have QQ enzymes that can degrade AHLs. In our previous study, strain Ruegeria mobilis YJ3, isolated from healthy shrimp, showed strong AHLs degradative activity. In the current study, an AHL lactonase (designated RmmL) was cloned and characterized from Ruegeria mobilis YJ3. Amino acid sequence analysis showed that RmmL has a conserved “HXHXDH” motif and clusters together with lactonase AidC that belongs to the metallo-β-lactamase superfamily. Recombinant RmmL could degrade either short- or long-chain AHLs in vitro. High-performance liquid chromatography analysis indicated that RmmL works as an AHL lactonase catalyzing AHL ring-opening by hydrolyzing lactones. Furthermore, RmmL can reduce the production of pyocyanin by Pseudomonas aeruginosa PAO1, while for the violacein and the extracellular protease activities by Chromobacterium violaceum CV026 and Vibrio anguillarum VIB72, no significant reduction was observed. This study suggests that RmmL might be used as a therapeutic agent in aquaculture. Full article
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Open AccessArticle Cyclopropane-Containing Fatty Acids from the Marine Bacterium Labrenzia sp. 011 with Antimicrobial and GPR84 Activity
Mar. Drugs 2018, 16(10), 369; https://doi.org/10.3390/md16100369
Received: 17 July 2018 / Revised: 1 October 2018 / Accepted: 3 October 2018 / Published: 8 October 2018
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Abstract
Bacteria of the family Rhodobacteraceae are widespread in marine environments and known to colonize surfaces, such as those of e.g., oysters and shells. The marine bacterium Labrenzia sp. 011 is here investigated and it was found to produce two cyclopropane-containing medium-chain fatty acids
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Bacteria of the family Rhodobacteraceae are widespread in marine environments and known to colonize surfaces, such as those of e.g., oysters and shells. The marine bacterium Labrenzia sp. 011 is here investigated and it was found to produce two cyclopropane-containing medium-chain fatty acids (1, 2), which inhibit the growth of a range of bacteria and fungi, most effectively that of a causative agent of Roseovarius oyster disease (ROD), Pseudoroseovarius crassostreae DSM 16950. Additionally, compound 2 acts as a potent partial, β-arrestin-biased agonist at the medium-chain fatty acid-activated orphan G-protein coupled receptor GPR84, which is highly expressed on immune cells. The genome of Labrenzia sp. 011 was sequenced and bioinformatically compared with those of other Labrenzia spp. This analysis revealed several cyclopropane fatty acid synthases (CFAS) conserved in all Labrenzia strains analyzed and a putative gene cluster encoding for two distinct CFASs is proposed as the biosynthetic origin of 1 and 2. Full article
(This article belongs to the Special Issue Marine-Derived Polyketides with Antibiotic Activity)
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Open AccessArticle Fucosterol from an Edible Brown Alga Ecklonia stolonifera Prevents Soluble Amyloid Beta-Induced Cognitive Dysfunction in Aging Rats
Mar. Drugs 2018, 16(10), 368; https://doi.org/10.3390/md16100368
Received: 3 September 2018 / Revised: 26 September 2018 / Accepted: 3 October 2018 / Published: 5 October 2018
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Abstract
Fucosterol from edible brown seaweeds has various biological activities, including anti-inflammatory, anti-adipogenic, antiphotoaging, anti-acetylcholinesterase, and anti-beta-secretase 1 activities. However, little is known about its effects on soluble amyloid beta peptide (sAβ)-induced endoplasmic reticulum (ER) stress and cognitive impairment. Fucosterol was isolated from the
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Fucosterol from edible brown seaweeds has various biological activities, including anti-inflammatory, anti-adipogenic, antiphotoaging, anti-acetylcholinesterase, and anti-beta-secretase 1 activities. However, little is known about its effects on soluble amyloid beta peptide (sAβ)-induced endoplasmic reticulum (ER) stress and cognitive impairment. Fucosterol was isolated from the edible brown seaweed Ecklonia stolonifera, and its neuroprotective effects were analyzed in primary hippocampal neurons and in aging rats. Fucosterol attenuated sAβ1-42-induced decrease in the viability of hippocampal neurons and downregulated sAβ1-42-induced increase in glucose-regulated protein 78 (GRP78) expression in hippocampal neurons via activation of tyrosine receptor kinase B-mediated ERK1/2 signaling. Fucosterol co-infusion attenuated sAβ1-42-induced cognitive impairment in aging rats via downregulation of GRP78 expression and upregulation of mature brain-derived neurotrophic factor expression in the dentate gyrus. Fucosterol might be beneficial for the management of cognitive dysfunction via suppression of aging-induced ER stress. Full article
(This article belongs to the Special Issue Marine Compounds in Neurodegenerative Diseases)
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Open AccessArticle APS8 Delays Tumor Growth in Mice by Inducing Apoptosis of Lung Adenocarcinoma Cells Expressing High Number of α7 Nicotinic Receptors
Mar. Drugs 2018, 16(10), 367; https://doi.org/10.3390/md16100367
Received: 7 September 2018 / Revised: 21 September 2018 / Accepted: 29 September 2018 / Published: 3 October 2018
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Abstract
The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung
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The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the in-vitro mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca2+ influx into cells, and evaluated the effects of APS8 on Ca2+ uptake while siRNA silencing of the gene for α7 nAChRs, CHRNA7. APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca2+ uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs. Full article
(This article belongs to the Special Issue Marine Toxins Affecting Cholinergic System)
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Open AccessArticle Antimicrobial and Antibiofilm Activity of a Recombinant Fragment of β-Thymosin of Sea Urchin Paracentrotus lividus
Mar. Drugs 2018, 16(10), 366; https://doi.org/10.3390/md16100366
Received: 13 September 2018 / Revised: 25 September 2018 / Accepted: 29 September 2018 / Published: 2 October 2018
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Abstract
With the aim to obtain new antimicrobials against important pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, we focused on antimicrobial peptides (AMPs) from Echinoderms. An example of such peptides is Paracentrin 1 (SP1), a chemically synthesised peptide fragment of a sea
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With the aim to obtain new antimicrobials against important pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, we focused on antimicrobial peptides (AMPs) from Echinoderms. An example of such peptides is Paracentrin 1 (SP1), a chemically synthesised peptide fragment of a sea urchin thymosin. In the present paper, we report on the biological activity of a Paracentrin 1 derivative obtained by recombination. The recombinant paracentrin RP1, in comparison to the synthetic SP1, is 22 amino acids longer and it was considerably more active against the planktonic forms of S. aureus ATCC 25923 and P. aeruginosa ATCC 15442 at concentrations of 50 µg/mL. Moreover, it was able to inhibit biofilm formation of staphylococcal and P. aeruginosa strains at concentrations equal to 5.0 and 10.7 µg/mL, respectively. Molecular dynamics (MD) simulations allowed to rationalise the results of the experimental investigations, providing atomistic insights on the binding of RP1 toward models of mammalian and bacterial cell membranes. Overall, the results obtained point out that RP1 shows a remarkable preference for bacterial membranes, in excellent agreement with the antibacterial activity, highlighting the promising potential of using the tested peptide as a template for the development of novel antimicrobial agents. Full article
(This article belongs to the Special Issue New Strategies to Counteract Antibiotic Resistance Mechanisms)
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Open AccessArticle High Throughput Identification of Antihypertensive Peptides from Fish Proteome Datasets
Mar. Drugs 2018, 16(10), 365; https://doi.org/10.3390/md16100365
Received: 30 August 2018 / Revised: 21 September 2018 / Accepted: 24 September 2018 / Published: 2 October 2018
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Abstract
Antihypertensive peptides (AHTPs) are a group of small peptides with the main role to block key enzymes or receptors in the angiotensin genesis pathway. A great number of AHTPs have been isolated or digested from natural food resources; however, comprehensive studies on comparisons
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Antihypertensive peptides (AHTPs) are a group of small peptides with the main role to block key enzymes or receptors in the angiotensin genesis pathway. A great number of AHTPs have been isolated or digested from natural food resources; however, comprehensive studies on comparisons of AHTPs in various species from the perspective of big data are rare. Here, we established a simplified local AHTP database, and performed in situ mapping for high throughput identification of AHTPs with high antihypertensive activity from high-quality whole proteome datasets of 18 fish species. In the 35 identified AHTPs with reported high activity, we observed that Gly-Leu-Pro, Leu-Pro-Gly, and Val-Ser-Val are the major components of fish proteins, and AHTP hit numbers in various species demonstrated a similar distributing pattern. Interestingly, Atlantic salmon (Salmo salar) is in possession of far more abundant AHTPs compared with other fish species. In addition, collagen subunit protein is the largest group with more matching AHTPs. Further exploration of two collagen subunits (col4a5 and col8a1) in more fish species suggested that the hit pattern of these conserved proteins among teleost is almost the same, and their phylogeny is consistent with the evolution of these fish species. In summary, our present study provides basic information for the relationship of AHTPs with fish proteins, which sheds light on rapid discovery of marine drugs or food additives from fish protein hydrolysates to alleviate hypertension. Full article
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Open AccessArticle Effect of Arthrospira (Spirulina) maxima Supplementation and a Systematic Physical Exercise Program on the Body Composition and Cardiorespiratory Fitness of Overweight or Obese Subjects: A Double-Blind, Randomized, and Crossover Controlled Trial
Mar. Drugs 2018, 16(10), 364; https://doi.org/10.3390/md16100364
Received: 24 August 2018 / Revised: 11 September 2018 / Accepted: 25 September 2018 / Published: 1 October 2018
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Abstract
Excess weight and obesity are major risk factors for many chronic diseases, and weight-loss interventions often include systematic exercise and nutritional supplements. The purpose of this study was to determine the independent/synergistic effects of Arthrospira (Spirulina) maxima supplementation (six weeks, 4.5 g·day−1
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Excess weight and obesity are major risk factors for many chronic diseases, and weight-loss interventions often include systematic exercise and nutritional supplements. The purpose of this study was to determine the independent/synergistic effects of Arthrospira (Spirulina) maxima supplementation (six weeks, 4.5 g·day−1) and a systematic physical exercise program (six weeks, twice weekly) on the body composition and cardiorespiratory fitness of overweight and obese subjects. To achieve this, 27 overweight and 25 obese sedentary male subjects were assigned to four interventions through a randomized double-blind, crossover controlled trial: A physical exercise program, with (SE) or without (Ex) Spirulina maxima; or no-exercise program, with (Sm) and without (C) Spirulina maxima. The body composition and cardiorespiratory fitness parameters were taken during a maximum intensity test. As compared to the C group, the body fat percentage of the SE, Sm and Ex groups was reduced (p < 0.05), while their maximal oxygen uptake improved (r = −0.40), and obese subjects benefited more significantly. Weight loss, the time to reach fatigue and the onset of blood lactate accumulation were improved in both of the Spirulina maxima supplemented groups, regardless of the subjects’ body weight. Spirulina maxima supplementation synergistically improves the effects of systematic exercise on body composition and cardiorespiratory fitness parameters in overweight, but mostly in individuals with obesity. Trial registration: Clinical Trials, NCT02837666. Registered 19 July 2016. Full article
(This article belongs to the collection Marine Drugs in the Management of Metabolic Diseases)
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Open AccessArticle Meroterpenoids and Isocoumarinoids from a Myrothecium Fungus Associated with Apocynum venetum
Mar. Drugs 2018, 16(10), 363; https://doi.org/10.3390/md16100363
Received: 31 August 2018 / Revised: 25 September 2018 / Accepted: 27 September 2018 / Published: 1 October 2018
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Four new meroterpenoids 14 and four new isocoumarinoids 58, along with five known isocoumarinoids (913), were isolated from the fungus Myrothecium sp. OUCMDZ-2784 associated with the salt-resistant medicinal plant, Apocynum venetum (Apocynaceae). Their structures
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Four new meroterpenoids 14 and four new isocoumarinoids 58, along with five known isocoumarinoids (913), were isolated from the fungus Myrothecium sp. OUCMDZ-2784 associated with the salt-resistant medicinal plant, Apocynum venetum (Apocynaceae). Their structures were elucidated by means of spectroscopic analysis, X-ray crystallography, ECD spectra and quantum chemical calculations. Compounds 15, 7, 9 and 10 showed weak α-glucosidase inhibition with the IC50 values of 0.50, 0.66, 0.058, 0.20, 0.32, 0.036, 0.026 and 0.37 mM, respectively. Full article
(This article belongs to the Special Issue Natural Products from Marine Fungi)
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Open AccessReview Biological and Chemical Diversity of Ascidian-Associated Microorganisms
Mar. Drugs 2018, 16(10), 362; https://doi.org/10.3390/md16100362
Received: 14 September 2018 / Revised: 23 September 2018 / Accepted: 27 September 2018 / Published: 1 October 2018
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Ascidians are a class of sessile filter-feeding invertebrates, that provide unique and fertile niches harboring various microorganisms, such as bacteria, actinobacteria, cyanobacteria and fungi. Over 1000 natural products, including alkaloids, cyclic peptides, and polyketides, have been isolated from them, which display diverse properties,
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Ascidians are a class of sessile filter-feeding invertebrates, that provide unique and fertile niches harboring various microorganisms, such as bacteria, actinobacteria, cyanobacteria and fungi. Over 1000 natural products, including alkaloids, cyclic peptides, and polyketides, have been isolated from them, which display diverse properties, such as antibacterial, antifungal, antitumor, and anti-inflammatory activities. Strikingly, direct evidence has confirmed that ~8% of natural products from ascidians are actually produced by symbiotic microorganisms. In this review, we present 150 natural products from microorganisms associated with ascidians that have been reported up to 2017. Full article
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Open AccessArticle Aurantoside C Targets and Induces Apoptosis in Triple Negative Breast Cancer Cells
Mar. Drugs 2018, 16(10), 361; https://doi.org/10.3390/md16100361
Received: 11 September 2018 / Revised: 24 September 2018 / Accepted: 29 September 2018 / Published: 1 October 2018
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Triple negative breast cancer (TNBC) is a subtype of breast cancers that currently lacks effective targeted therapy. In this study, we found that aurantoside C (C828), isolated from the marine sponge Manihinea lynbeazleyae collected from Western Australia, exhibited higher cytotoxic activities in TNBC
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Triple negative breast cancer (TNBC) is a subtype of breast cancers that currently lacks effective targeted therapy. In this study, we found that aurantoside C (C828), isolated from the marine sponge Manihinea lynbeazleyae collected from Western Australia, exhibited higher cytotoxic activities in TNBC cells compared with non-TNBC (luminal and normal-like) cells. The cytotoxic effect of C828 was associated to the accumulation of cell at S-phase, resulting in the decline of cyclin D1, cyclin E1, CDK4, and CDK6, and an increase in p21. We also found that C828 inhibited the phosphorylation of Akt/mTOR and NF-kB pathways and increased the phosphorylation of p38 MAPK and SAPK/JNK pathways, leading to apoptosis in TNBC cells. These effects of C828 were not observed in non-TNBC cells at the concentrations that were cytotoxic to TNBC cells. When compared to the cytotoxic effect with the chemotherapeutic drugs doxorubicin and cisplatin, C828 was found to be 20 times and 35 times more potent than doxorubicin and cisplatin, respectively. These results indicate that C828 could be a promising lead for developing new anticancer agents that target TNBC cells. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)
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Open AccessArticle AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation
Mar. Drugs 2018, 16(10), 360; https://doi.org/10.3390/md16100360
Received: 31 August 2018 / Revised: 25 September 2018 / Accepted: 29 September 2018 / Published: 1 October 2018
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Abstract
Voltage-gated potassium (KV) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on KV channels. From
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Voltage-gated potassium (KV) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on KV channels. From the nematocysts of the sea anemone Actinia bermudensis, a peptide that we named AbeTx1 was purified and functionally characterized on 12 different subtypes of KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; KV11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (NaV1.2, NaV1.4, and BgNaV). AbeTx1 was selective for Shaker-related K+ channels and is capable of inhibiting K+ currents, not only by blocking the K+ current of KV1.2 subtype, but by altering the energetics of activation of KV1.1 and KV1.6. Moreover, experiments using six synthetic alanine point-mutated analogs further showed that a ring of basic amino acids acts as a multipoint interaction for the binding of the toxin to the channel. The AbeTx1 primary sequence is composed of 17 amino acids with a high proportion of lysines and arginines, including two disulfide bridges (Cys1–Cys4 and Cys2–Cys3), and it is devoid of aromatic or aliphatic amino acids. Secondary structure analysis reveals that AbeTx1 has a highly flexible, random-coil-like conformation, but with a tendency of structuring in the beta sheet. Its overall structure is similar to open-ended cyclic peptides found on the scorpion κ-KTx toxins family, cone snail venoms, and antimicrobial peptides. Full article
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