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Mar. Drugs, Volume 12, Issue 7 (July 2014), Pages 3792-4273

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Open AccessArticle Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats
Mar. Drugs 2014, 12(7), 3792-3817; doi:10.3390/md12073792
Received: 8 April 2014 / Revised: 28 May 2014 / Accepted: 29 May 2014 / Published: 27 June 2014
Cited by 13 | PDF Full-text (628 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we [...] Read more.
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Lamellarin O, a Pyrrole Alkaloid from an Australian Marine Sponge, Ianthella sp., Reverses BCRP Mediated Drug Resistance in Cancer Cells
Mar. Drugs 2014, 12(7), 3818-3837; doi:10.3390/md12073818
Received: 29 May 2014 / Revised: 13 June 2014 / Accepted: 16 June 2014 / Published: 27 June 2014
Cited by 14 | PDF Full-text (1262 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this [...] Read more.
ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 112 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure–activity relationship analysis inclusive of the natural products 112 and the synthetic analogues 1319, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore. Full article
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Open AccessArticle Bis(2,3-dibromo-4,5-dihydroxybenzyl) Ether, a Marine Algae Derived Bromophenol, Inhibits the Growth of Botrytis cinerea and Interacts with DNA Molecules
Mar. Drugs 2014, 12(7), 3838-3851; doi:10.3390/md12073838
Received: 23 January 2014 / Revised: 12 May 2014 / Accepted: 13 May 2014 / Published: 27 June 2014
Cited by 4 | PDF Full-text (513 KB) | HTML Full-text | XML Full-text
Abstract
Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a bromophenol isolated from marine algae. Previous reports have shown that BDDE possesses cytotoxic and antibacterial activity. In the present study, we demonstrate that BDDE displays broad-spectrum antifungal activities, especially on Botrytis cinerea. BDDE inhibits the growth [...] Read more.
Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a bromophenol isolated from marine algae. Previous reports have shown that BDDE possesses cytotoxic and antibacterial activity. In the present study, we demonstrate that BDDE displays broad-spectrum antifungal activities, especially on Botrytis cinerea. BDDE inhibits the growth of B. cinerea cultured on a solid medium of potato dextrose agar (PDA) as well as on the potato dextrose broth (PDB) medium. Moreover, BDDE decreases the incidence of fruit decay and severity of strawberries infected with B. cinerea. Further studies have revealed that BDDE decreases the germination rate and inhibits the mycelial growth of B. cinerea. The inhibition mechanisms are related to the disruption of the cell membrane integrity in B. cinerea spores and newly formed germ tubes. This study also suggests that BDDE possibly interacts with DNA via intercalation and minor groove binding. The studies provide evidence that BDDE has potential application in the control of gray mold after fruit harvest and the compound could serve as a candidate or lead template for rational drug design and for the development of antifungal agents. Full article
Open AccessArticle Type II Collagen and Gelatin from Silvertip Shark (Carcharhinus albimarginatus) Cartilage: Isolation, Purification, Physicochemical and Antioxidant Properties
Mar. Drugs 2014, 12(7), 3852-3873; doi:10.3390/md12073852
Received: 21 January 2014 / Revised: 1 June 2014 / Accepted: 3 June 2014 / Published: 27 June 2014
Cited by 8 | PDF Full-text (1377 KB) | HTML Full-text | XML Full-text
Abstract
Type II acid soluble collagen (CIIA), pepsin soluble collagen (CIIP) and type II gelatin (GII) were isolated from silvertip shark (Carcharhinus albimarginatus) cartilage and examined for their physicochemical and antioxidant properties. GII had a higher hydroxyproline content (173 mg/g) than [...] Read more.
Type II acid soluble collagen (CIIA), pepsin soluble collagen (CIIP) and type II gelatin (GII) were isolated from silvertip shark (Carcharhinus albimarginatus) cartilage and examined for their physicochemical and antioxidant properties. GII had a higher hydroxyproline content (173 mg/g) than the collagens and cartilage. CIIA, CIIP and GII were composed of two identical α1 and β chains and were characterized as type II. Amino acid analysis of CIIA, CIIP and GII indicated imino acid contents of 150, 156 and 153 amino acid residues per 1000 residues, respectively. Differing Fourier transform infrared (FTIR) spectra of CIIA, CIIP and GII were observed, which suggested that the isolation process affected the secondary structure and molecular order of collagen, particularly the triple-helical structure. The denaturation temperature of GII (32.5 °C) was higher than that of CIIA and CIIP. The antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl radicals and the reducing power of CIIP was greater than that of CIIA and GII. SEM microstructure of the collagens depicted a porous, fibrillary and multi-layered structure. Accordingly, the physicochemical and antioxidant properties of type II collagens (CIIA, CIIP) and GII isolated from shark cartilage were found to be suitable for biomedical applications. Full article
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Open AccessArticle Pigment Cell Differentiation in Sea Urchin Blastula-Derived Primary Cell Cultures
Mar. Drugs 2014, 12(7), 3874-3891; doi:10.3390/md12073874
Received: 27 January 2014 / Revised: 27 May 2014 / Accepted: 30 May 2014 / Published: 27 June 2014
Cited by 4 | PDF Full-text (1495 KB) | HTML Full-text | XML Full-text
Abstract
The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by [...] Read more.
The quinone pigments of sea urchins, specifically echinochrome and spinochromes, are known for their effective antioxidant, antibacterial, antifungal, and antitumor activities. We developed in vitro technology for inducing pigment differentiation in cell culture. The intensification of the pigment differentiation was accompanied by a simultaneous decrease in cell proliferation. The number of pigment cells was two-fold higher in the cells cultivated in the coelomic fluids of injured sea urchins than in those intact. The possible roles of the specific components of the coelomic fluids in the pigment differentiation process and the quantitative measurement of the production of naphthoquinone pigments during cultivation were examined by MALDI and electrospray ionization mass spectrometry. Echinochrome A and spinochrome E were produced by the cultivated cells of the sand dollar Scaphechinus mirabilis in all tested media, while only spinochromes were found in the cultivated cells of another sea urchin, Strongylocentrotus intermedius. The expression of genes associated with the induction of pigment differentiation was increased in cells cultivated in the presence of shikimic acid, a precursor of naphthoquinone pigments. Our results should contribute to the development of new techniques in marine biotechnology, including the generation of cell cultures producing complex bioactive compounds with therapeutic potential. Full article
Open AccessArticle Oleosome-Associated Protein of the Oleaginous Diatom Fistulifera solaris Contains an Endoplasmic Reticulum-Targeting Signal Sequence
Mar. Drugs 2014, 12(7), 3892-3903; doi:10.3390/md12073892
Received: 30 January 2014 / Revised: 1 May 2014 / Accepted: 13 June 2014 / Published: 30 June 2014
Cited by 4 | PDF Full-text (774 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Microalgae tend to accumulate lipids as an energy storage material in the specific organelle, oleosomes. Current studies have demonstrated that lipids derived from microalgal oleosomes are a promising source of biofuels, while the oleosome formation mechanism has not been fully elucidated. Oleosome-associated [...] Read more.
Microalgae tend to accumulate lipids as an energy storage material in the specific organelle, oleosomes. Current studies have demonstrated that lipids derived from microalgal oleosomes are a promising source of biofuels, while the oleosome formation mechanism has not been fully elucidated. Oleosome-associated proteins have been identified from several microalgae to elucidate the fundamental mechanisms of oleosome formation, although understanding their functions is still in infancy. Recently, we discovered a diatom-oleosome-associated-protein 1 (DOAP1) from the oleaginous diatom, Fistulifera solaris JPCC DA0580. The DOAP1 sequence implied that this protein might be transported into the endoplasmic reticulum (ER) due to the signal sequence. To ensure this, we fused the signal sequence to green fluorescence protein. The fusion protein distributed around the chloroplast as like a meshwork membrane structure, indicating the ER localization. This result suggests that DOAP1 could firstly localize at the ER, then move to the oleosomes. This study also demonstrated that the DOAP1 signal sequence allowed recombinant proteins to be specifically expressed in the ER of the oleaginous diatom. It would be a useful technique for engineering the lipid synthesis pathways existing in the ER, and finally controlling the biofuel quality. Full article
Open AccessArticle Punctaporonins H–M: Caryophyllene-Type Sesquiterpenoids from the Sponge-Associated Fungus Hansfordia sinuosae
Mar. Drugs 2014, 12(7), 3904-3916; doi:10.3390/md12073904
Received: 11 April 2014 / Revised: 20 May 2014 / Accepted: 5 June 2014 / Published: 30 June 2014
Cited by 6 | PDF Full-text (570 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Six new caryophyllene-based sesquiterpenoids named punctaporonins H–M (16), together with punctaporonin B (7) and humulane (8) were isolated from the fermentation broth of the sponge-derived fungus Hansfordia sinuosae. Their structures were determined by [...] Read more.
Six new caryophyllene-based sesquiterpenoids named punctaporonins H–M (16), together with punctaporonin B (7) and humulane (8) were isolated from the fermentation broth of the sponge-derived fungus Hansfordia sinuosae. Their structures were determined by the extensive HRESIMS and NMR spectroscopic analysis, including the X-ray crystallographic data for the assignment of the absolute configurations of punctaporonins H–I (12). The isolated compounds were evaluated for antihyperlipidemic, cytotoxic and antimicrobial activities, and punctaporonin K (4) exhibited potent effects to reduce the triglycerides and total cholesterol in the intracellular levels. Full article
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Open AccessArticle Characterization of ACE Inhibitory Peptides from Mactra veneriformis Hydrolysate by Nano-Liquid Chromatography Electrospray Ionization Mass Spectrometry (Nano-LC-ESI-MS) and Molecular Docking
Mar. Drugs 2014, 12(7), 3917-3928; doi:10.3390/md12073917
Received: 27 February 2014 / Revised: 12 May 2014 / Accepted: 15 May 2014 / Published: 30 June 2014
PDF Full-text (1075 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Food-derived bioactive compounds are gaining increasing significance in life sciences. In the present study, we identified angiotensin I-converting enzyme (ACE)-inhibitory peptides from Mactra veneriformis hydrolysate using a nano-LC-MS/MS method. Mactra veneriformis hydrolysate was first separated into four fractions (F1–F4) based on molecular [...] Read more.
Food-derived bioactive compounds are gaining increasing significance in life sciences. In the present study, we identified angiotensin I-converting enzyme (ACE)-inhibitory peptides from Mactra veneriformis hydrolysate using a nano-LC-MS/MS method. Mactra veneriformis hydrolysate was first separated into four fractions (F1–F4) based on molecular weight by ultrafiltration. The fraction with molecular weight lower than 1 kDa (F1) showed the highest ACE inhibitory activity. F1 was then analyzed by a high throughput nano-LC-MS/MS method and sequences of peptides in F1 were calculated accordingly. The 27 peptides identified as above were chemically synthesized and tested for ACE-inhibitory activity. The hexapeptide VVCVPW showed the highest potency with an IC50 value of 4.07 μM. We then investigated the interaction mechanism between the six most potent peptides and ACE by molecular docking. Our docking results suggested that the ACE inhibitory peptides bind to ACE via interactions with His383, His387, and Glu411 residues. Particularly, similar to the thiol group of captopril, the cysteine thiol group of the most potent peptide VVCVPW may play a key role in the binding of this peptide to the ACE active site. Full article
Open AccessArticle Inactivation of Heparin by Cationically Modified Chitosan
Mar. Drugs 2014, 12(7), 3953-3969; doi:10.3390/md12073953
Received: 21 February 2014 / Revised: 13 May 2014 / Accepted: 16 May 2014 / Published: 30 June 2014
Cited by 4 | PDF Full-text (795 KB) | HTML Full-text | XML Full-text
Abstract
This study was performed to evaluate the ability of N-(2-hydroxypropyl)-3-tri methylammonium chitosan chloride (HTCC), the cationically modified chitosan, to form biologically inactive complexes with unfractionated heparin and thereby blocking its anticoagulant activity. Experiments were carried out in rats in vivo and [...] Read more.
This study was performed to evaluate the ability of N-(2-hydroxypropyl)-3-tri methylammonium chitosan chloride (HTCC), the cationically modified chitosan, to form biologically inactive complexes with unfractionated heparin and thereby blocking its anticoagulant activity. Experiments were carried out in rats in vivo and in vitro using the activated partial thromboplastin time (APTT) and prothrombin time (PT) tests for evaluation of heparin anticoagulant activity. For the first time we have found that HTCC effectively neutralizes anticoagulant action of heparin in rat blood in vitro as well as in rats in vivo. The effect of HTCC on suppression of heparin activity is dose-dependent and its efficacy can be comparable to that of protamine-the only agent used in clinic for heparin neutralization. HTCC administered i.v. alone had no direct effect on any of the coagulation tests used. The potential adverse effects of HTCC were further explored using rat experimental model of acute toxicity. When administered i.p. at high doses (250 and 500 mg/kg body weight), HTCC induced some significant dose-dependent structural abnormalities in the liver. However, when HTCC was administered at low doses, comparable to those used for neutralization of anticoagulant effect of heparin, no histopathological abnormalities in liver were observed. Full article
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Open AccessCommunication Indole Diterpenoids and Isocoumarin from the Fungus, Aspergillus flavus, Isolated from the Prawn, Penaeus vannamei
Mar. Drugs 2014, 12(7), 3970-3981; doi:10.3390/md12073970
Received: 24 April 2014 / Revised: 3 June 2014 / Accepted: 13 June 2014 / Published: 30 June 2014
Cited by 9 | PDF Full-text (473 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Two new indole-diterpenoids (1 and 2) and a new isocoumarin (3), along with the known β-aflatrem (4), paspalinine (5), leporin B (6), α-cyclopiazonic acid (7), iso-α-cyclopiazonic acid (8), [...] Read more.
Two new indole-diterpenoids (1 and 2) and a new isocoumarin (3), along with the known β-aflatrem (4), paspalinine (5), leporin B (6), α-cyclopiazonic acid (7), iso-α-cyclopiazonic acid (8), ditryptophenaline (9), aflatoxin B1 (10), 7-O-acetylkojic acid (11) and kojic acid (12), were isolated from the fermentation broth of the marine-derived fungus, Aspergillus flavus OUCMDZ-2205. The structures of Compounds 112 were elucidated by spectroscopic analyses, quantum ECD calculations and the chemical method. New Compound 1 exhibited antibacterial activity against Staphylococcus aureus with a MIC value of 20.5 μM. Both new Compounds 1 and 2 could arrest the A549 cell cycle in the S phase at a concentration of 10 μM. Compound 1 showed PKC-beta inhibition with an IC50 value of 15.6 μM. In addition, the absolute configurations of the known compounds, 46 and leporin A (6a), were also determined for the first time. Full article
Open AccessArticle Hainanerectamines A–C, Alkaloids from the Hainan Sponge Hyrtios erecta
Mar. Drugs 2014, 12(7), 3982-3993; doi:10.3390/md12073982
Received: 28 March 2014 / Revised: 28 May 2014 / Accepted: 3 June 2014 / Published: 30 June 2014
Cited by 6 | PDF Full-text (864 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Two new indole alkaloids, hainanerectamines A (1) and B (2), and one new β-carboline alkaloids, hainanerectamines C (4), along with five known related alkaloids (3, 58), have been isolated from the [...] Read more.
Two new indole alkaloids, hainanerectamines A (1) and B (2), and one new β-carboline alkaloids, hainanerectamines C (4), along with five known related alkaloids (3, 58), have been isolated from the Hainan marine sponge Hyrtios erecta. The structures of new compounds 1, 2 and 4 were determined by detailed analysis of their 1D and 2D NMR spectra and by comparison of their spectroscopic data with those of related model compounds. Compounds 24 exhibited moderate inhibitory activity against Aurora A, a member of serine/threonine kinase family involving in the regulation of cell division and a new target in cancer treatment, with IC50 values of 24.5, 13.6, and 18.6 μg/mL, respectively. Full article
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Open AccessArticle Adenovirus Carrying Gene Encoding Haliotis discus discus Sialic Acid Binding Lectin Induces Cancer Cell Apoptosis
Mar. Drugs 2014, 12(7), 3994-4004; doi:10.3390/md12073994
Received: 31 December 2013 / Revised: 14 May 2014 / Accepted: 26 May 2014 / Published: 30 June 2014
Cited by 3 | PDF Full-text (1271 KB) | HTML Full-text | XML Full-text
Abstract
Lectins exist widely in marine bioresources such as bacteria, algae, invertebrate animals and fishes. Some purified marine lectins have been found to elicit cytotoxicity to cancer cells. However, there are few reports describing the cytotoxic effect of marine lectins on cancer cells [...] Read more.
Lectins exist widely in marine bioresources such as bacteria, algae, invertebrate animals and fishes. Some purified marine lectins have been found to elicit cytotoxicity to cancer cells. However, there are few reports describing the cytotoxic effect of marine lectins on cancer cells through virus-mediated gene delivery. We show here that a replication-deficient adenovirus-carrying gene encoding Haliotis discus discus sialic acid binding lectin (Ad.FLAG-HddSBL) suppressed cancer cell proliferation by inducing apoptosis, as compared to the control virus Ad.FLAG. A down-regulated level of anti-apoptosis factor Bcl-2 was suggested to be responsible for the apoptosis induced by Ad.FLAG-HddSBL infection. Further subcellular localization studies revealed that HddSBL distributed in cell membrane, ER, and the nucleus, but not in mitochondria and Golgi apparatus. In contrast, a previously reported mannose-binding lectin Pinellia pedatisecta agglutinin entered the nucleus as well, but did not distribute in inner membrane systems, suggesting differed intracellular sialylation and mannosylation, which may provide different targets for lectin binding. Further cancer-specific controlling of HddSBL expression and animal studies may help to provide insights into a novel way of anti-cancer marine lectin gene therapy. Lectins may provide a reservoir of anti-cancer genes. Full article
Open AccessArticle Stereochemical Determination of Five-Membered Cyclic Ether Acetogenins Using a Spin-Spin Coupling Constant Approach and DFT Calculations
Mar. Drugs 2014, 12(7), 4031-4044; doi:10.3390/md12074031
Received: 25 February 2014 / Revised: 28 March 2014 / Accepted: 10 April 2014 / Published: 1 July 2014
Cited by 4 | PDF Full-text (584 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Five-membered rings are of particular interest, due to their presence in some of the most common molecules in chemistry and biology. Despite their apparent simplicity, the structural resolution of these rings is complex, due to their inherent conformational flexibility. Here, we describe [...] Read more.
Five-membered rings are of particular interest, due to their presence in some of the most common molecules in chemistry and biology. Despite their apparent simplicity, the structural resolution of these rings is complex, due to their inherent conformational flexibility. Here, we describe an application of a recently reported simple and efficient NMR protocol based on the measurement of spin-spin coupling constants to achieve the challenging relative configurations of five new halogenated C15 tetrahydrofuranyl-acetogenins, marilzafurollenes A–D (14) and 12-acetoxy-marilzafurenyne (5), isolated from the red alga, Laurencia marilzae. Although DFT chemical shift calculations were used to connect remote stereocenters, the NMR-based approach seems advantageous over computational techniques in this context, as the presence of halogens may interfere with reliable calculations. Full article
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Open AccessArticle Bioactive Cembrane Derivatives from the Indian Ocean Soft Coral, Sinularia kavarattiensis
Mar. Drugs 2014, 12(7), 4045-4068; doi:10.3390/md12074045
Received: 1 April 2014 / Revised: 5 June 2014 / Accepted: 17 June 2014 / Published: 3 July 2014
Cited by 5 | PDF Full-text (1559 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Marine organisms and their metabolites represent a unique source of potential pharmaceutical substances. In this study, we examined marine-derived substances for their bioactive properties in a cell-based Chikungunya virus (CHIKV) replicon model and for in vitro anti-inflammatory activity. In the screening of [...] Read more.
Marine organisms and their metabolites represent a unique source of potential pharmaceutical substances. In this study, we examined marine-derived substances for their bioactive properties in a cell-based Chikungunya virus (CHIKV) replicon model and for in vitro anti-inflammatory activity. In the screening of a marine sample library, crude extracts from the Indian soft coral, Sinularia kavarattiensis, showed promising activity against the CHIKV replicon. Bioassay-guided chemical fractionation of S. kavarattiensis resulted in the isolation of six known norcembranoids (16) and one new compound, named kavaranolide (7). The structures were elucidated on the basis of NMR and MS spectroscopic data. Compounds 13 and 57 were evaluated for their replicon-inhibiting potential in the CHIKV model by using a luminescence-based detection technique and live cell imaging. Compounds 1 and 2 showed moderate inhibition of the CHIKV replicon, but imaging studies also revealed cytotoxic properties. Moreover, the effects of the isolated compounds on primary microglial cells, an experimental model for neuroinflammation, were evaluated. Compound 2 was shown to modulate the immune response in microglial cells and to possess potential anti-inflammatory properties by dose-dependently reducing the release of pro- and anti-inflammatory cytokines. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
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Open AccessArticle Ovothiol Isolated from Sea Urchin Oocytes Induces Autophagy in the Hep-G2 Cell Line
Mar. Drugs 2014, 12(7), 4069-4085; doi:10.3390/md12074069
Received: 1 April 2014 / Revised: 11 June 2014 / Accepted: 23 June 2014 / Published: 7 July 2014
Cited by 6 | PDF Full-text (584 KB) | HTML Full-text | XML Full-text
Abstract
Ovothiols are histidine-derived thiols isolated from sea urchin eggs, where they play a key role in the protection of cells toward the oxidative burst associated with fertilization by controlling the cellular redox balance and recycling oxidized glutathione. In this study, we show [...] Read more.
Ovothiols are histidine-derived thiols isolated from sea urchin eggs, where they play a key role in the protection of cells toward the oxidative burst associated with fertilization by controlling the cellular redox balance and recycling oxidized glutathione. In this study, we show that treatment of a human liver carcinoma cell line, Hep-G2, with ovothiol A, isolated from Paracentrotus lividus oocytes, results in a decrease of cell proliferation in a dose-dependent manner. The activation of an autophagic process is revealed by phase contrast and fluorescence microscopy, together with the expression of the specific autophagic molecular markers, LC3 II and Beclin-1. The effect of ovothiol is not due to its antioxidant capacity or to hydrogen peroxide generation. The concentration of ovothiol A in the culture media, as monitored by HPLC analysis, decreased by about 24% within 30 min from treatment. The proliferation of normal human embryonic lung cells is not affected by ovothiol A. These results hint at ovothiol as a promising bioactive molecule from marine organisms able to inhibit cell proliferation in cancer cells. Full article
(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)
Open AccessArticle Deferoxamine Compensates for Decreases in B Cell Counts and Reduces Mortality in Enterovirus 71-Infected Mice
Mar. Drugs 2014, 12(7), 4086-4095; doi:10.3390/md12074086
Received: 27 March 2014 / Revised: 11 June 2014 / Accepted: 25 June 2014 / Published: 7 July 2014
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Abstract
Enterovirus 71 is one of the major causative agents of hand, foot and mouth disease in children under six years of age. No vaccine or antiviral therapy is currently available. In this work, we found that the number of B cells was [...] Read more.
Enterovirus 71 is one of the major causative agents of hand, foot and mouth disease in children under six years of age. No vaccine or antiviral therapy is currently available. In this work, we found that the number of B cells was reduced in enterovirus 71-infected mice. Deferoxamine, a marine microbial natural product, compensated for the decreased levels of B cells caused by enterovirus 71 infection. The neutralizing antibody titer was also improved after deferoxamine treatment. Furthermore, deferoxamine relieved symptoms and reduced mortality and muscle damage caused by enterovirus 71 infection. This work suggested that deferoxamine has the potential for further development as a B cell-immunomodulator against enterovirus 71. Full article
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Open AccessArticle New Hippolide Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activity from the Marine Sponge Hippospongia lachne
Mar. Drugs 2014, 12(7), 4096-4109; doi:10.3390/md12074096
Received: 23 May 2014 / Revised: 15 June 2014 / Accepted: 19 June 2014 / Published: 8 July 2014
Cited by 4 | PDF Full-text (612 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Five new sesterterpenoids, compounds 15, have been isolated from the sponge Hippospongia lachne off Yongxing Island in the South China Sea. The structures of compounds 15 were elucidated through extensive spectroscopic analysis, including HRMS, 1D, and 2D [...] Read more.
Five new sesterterpenoids, compounds 15, have been isolated from the sponge Hippospongia lachne off Yongxing Island in the South China Sea. The structures of compounds 15 were elucidated through extensive spectroscopic analysis, including HRMS, 1D, and 2D NMR experiments. The stereochemistry, including absolute configurations of these compounds, was determined by spectroscopic, chemical, and computational methods. Compounds 1 and 5 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibitory activities with IC50 values of 5.2 μM and 8.7 μM, respectively, more potent than previously reported hippolides. Full article
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Open AccessArticle Nocapyrones: α- and γ-Pyrones from a Marine-Derived Nocardiopsis sp.
Mar. Drugs 2014, 12(7), 4110-4125; doi:10.3390/md12074110
Received: 5 May 2014 / Revised: 4 June 2014 / Accepted: 20 June 2014 / Published: 8 July 2014
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Abstract
One new α-pyrone (nocapyrone R (1)), and three known γ-pyrones (nocapyrones B, H and L (24)) were isolated from the culture extract of a Nocardiopsis strain collected from marine sediment. Structures of these compounds were determined [...] Read more.
One new α-pyrone (nocapyrone R (1)), and three known γ-pyrones (nocapyrones B, H and L (24)) were isolated from the culture extract of a Nocardiopsis strain collected from marine sediment. Structures of these compounds were determined on the basis of spectroscopic data including NMR and MS. γ-Pyrones 24 were found to induce adiponectin production in murine ST-13 preadipocyte cells but the α-pyrone 1 had no activity. The absolute configuration of the anteiso-methyl branching in 4 was determined by HPLC comparison of a degraded product of 4 with standard samples as a 2:3 enantiomeric mixture of (R)- and (S)-isomers. Full article
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Open AccessArticle Endotoxin Structures in the Psychrophiles Psychromonas marina and Psychrobacter cryohalolentis Contain Distinctive Acyl Features
Mar. Drugs 2014, 12(7), 4126-4147; doi:10.3390/md12074126
Received: 4 May 2014 / Revised: 23 June 2014 / Accepted: 27 June 2014 / Published: 9 July 2014
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Abstract
Lipid A is the essential component of endotoxin (Gram-negative lipopolysaccharide), a potent immunostimulatory compound. As the outer surface of the outer membrane, the details of lipid A structure are crucial not only to bacterial pathogenesis but also to membrane integrity. This work [...] Read more.
Lipid A is the essential component of endotoxin (Gram-negative lipopolysaccharide), a potent immunostimulatory compound. As the outer surface of the outer membrane, the details of lipid A structure are crucial not only to bacterial pathogenesis but also to membrane integrity. This work characterizes the structure of lipid A in two psychrophiles, Psychromonas marina and Psychrobacter cryohalolentis, and also two mesophiles to which they are related using MALDI-TOF MS and fatty acid methyl ester (FAME) GC-MS. P. marina lipid A is strikingly similar to that of Escherichia coli in organization and total acyl size, but incorporates an unusual doubly unsaturated tetradecadienoyl acyl residue. P. cryohalolentis also shows structural organization similar to a closely related mesophile, Acinetobacter baumannii, however it has generally shorter acyl constituents and shows many acyl variants differing by single methylene (-CH2-) units, a characteristic it shares with the one previously reported psychrotolerant lipid A structure. This work is the first detailed structural characterization of lipid A from an obligate psychrophile and the second from a psychrotolerant species. It reveals distinctive structural features of psychrophilic lipid A in comparison to that of related mesophiles which suggest constitutive adaptations to maintain outer membrane fluidity in cold environments. Full article
(This article belongs to the Special Issue Emerging Marine Toxins)
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Open AccessArticle Ascophyllan Purified from Ascophyllum nodosum Induces Th1 and Tc1 Immune Responses by Promoting Dendritic Cell Maturation
Mar. Drugs 2014, 12(7), 4148-4164; doi:10.3390/md12074148
Received: 3 April 2014 / Revised: 6 June 2014 / Accepted: 25 June 2014 / Published: 14 July 2014
Cited by 8 | PDF Full-text (2641 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Marine-derived sulfated polysaccharides have been shown to possess certain anti-virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide [...] Read more.
Marine-derived sulfated polysaccharides have been shown to possess certain anti-virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide purified from Ascophyllum nodosum, on the maturation of mouse dendritic cells (DCs) in vitro and in vivo. Ascophyllan induced up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs). Moreover, in vivo administration of ascophyllan promotes up-regulation of CD40, CD80, CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-α in spleen cDCs. Interestingly, ascophyllan induced a higher degree of co-stimulatory molecule up-regulation and pro-inflammatory cytokine production than fucoidan, a marine-derived polysaccharide with well-defined effect for promoting DC maturation. Ascophyllan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in the presence of DCs in an IL-12-dependent manner. Finally, myeloid differentiation primary response 88 (MyD88) signaling pathway was essential for DC maturation induced by ascophyllan. Taken together, these results demonstrate that ascophyllan induces DC maturation, and consequently enhances Th1 and Tc1 responses in vivo. This knowledge could facilitate the development of novel therapeutic strategies to combat infectious diseases and cancer. Full article
Open AccessArticle The Effect of Polyunsaturated Aldehydes on Skeletonema marinoi (Bacillariophyceae): The Involvement of Reactive Oxygen Species and Nitric Oxide
Mar. Drugs 2014, 12(7), 4165-4187; doi:10.3390/md12074165
Received: 18 January 2014 / Revised: 4 June 2014 / Accepted: 30 June 2014 / Published: 14 July 2014
Cited by 9 | PDF Full-text (854 KB) | HTML Full-text | XML Full-text
Abstract
Nitric oxide (NO) and reactive oxygen species (ROS) production was investigated in the marine diatom, Skeletonema marinoi (SM), exposed to 2E,4E/Z-decadienal (DECA), 2E,4E/Z-octadienal (OCTA), 2E,4E/Z [...] Read more.
Nitric oxide (NO) and reactive oxygen species (ROS) production was investigated in the marine diatom, Skeletonema marinoi (SM), exposed to 2E,4E/Z-decadienal (DECA), 2E,4E/Z-octadienal (OCTA), 2E,4E/Z-heptadienal (HEPTA) and a mix of these last two (MIX). When exposed to polyunsaturated aldehydes (PUA), a decrease of NO was observed, proportional to the PUA concentration (85% of the initial level after 180 min with 66 µM DECA). Only OCTA, HEPTA and MIX induced a parallel increase of ROS, the highest (2.9-times the control) with OCTA concentrations twice the EC50 for growth at 24 h (20 μM). The synthesis of carotenoids belonging to the xanthophyll cycle (XC) was enhanced during exposure, suggesting their antioxidant activity. Our data provide evidence that specific pathways exist as a reaction to PUA and that they depend upon the PUA used and/or the diatom species. In fact, Phaeodactylum tricornutum (PT) produces NO in response to DECA, but not to OCTA. We advance the hypothesis that SM perceives OCTA and HEPTA as intra-population infochemicals (as it produces PUA), while PT (non-PUA producing species) perceives them as allelochemicals. The ability to produce and to use PUA as infochemicals may underlie ecological traits of different diatom species and modulate ecological success in natural communities. Full article
(This article belongs to the Special Issue Metabolites in Diatoms)
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Open AccessArticle Pseudaboydins A and B: Novel Isobenzofuranone Derivatives from Marine Fungus Pseudallescheria boydii Associated with Starfish Acanthaster planci
Mar. Drugs 2014, 12(7), 4188-4199; doi:10.3390/md12074188
Received: 4 June 2014 / Revised: 3 July 2014 / Accepted: 3 July 2014 / Published: 14 July 2014
Cited by 10 | PDF Full-text (860 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Two novel isobenzofuranone derivatives, pseudaboydins A (1) and B (2), along with five known compounds, including (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-hydroxybenzofuran (3), (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-methoxybenzofuran (4), 3,3′-dihydroxy-5,5′-dimethyldiphenyl ether (5), 3-(3-methoxy-5-methylphenoxy)-5-methylphenol (6) and [...] Read more.
Two novel isobenzofuranone derivatives, pseudaboydins A (1) and B (2), along with five known compounds, including (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-hydroxybenzofuran (3), (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-methoxybenzofuran (4), 3,3′-dihydroxy-5,5′-dimethyldiphenyl ether (5), 3-(3-methoxy-5-methylphenoxy)-5-methylphenol (6) and (−)-regiolone (7), were isolated from the culture broth of the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Their structures were elucidated primarily based on NMR and MS data. The absolute configurations of 14 were determined by CD spectroscopy and single-crystal X-ray diffraction studies. The cytotoxic and antibacterial activities of 14 were evaluated. Pseudaboydin A (1) showed moderate cytotoxic activity against human nasopharyngeal carcinoma cell line HONE1, human nasopharyngeal carcinoma cell line SUNE1 and human glandular lung cancer cell line GLC82 with IC50 values of 37.1, 46.5 and 87.2 μM, respectively. Full article
Open AccessArticle In Vitro Antitumor Activity of Stellettin B, a Triterpene from Marine Sponge Jaspis stellifera, on Human Glioblastoma Cancer SF295 Cells
Mar. Drugs 2014, 12(7), 4200-4213; doi:10.3390/md12074200
Received: 21 May 2014 / Revised: 25 June 2014 / Accepted: 2 July 2014 / Published: 15 July 2014
Cited by 6 | PDF Full-text (1117 KB) | HTML Full-text | XML Full-text
Abstract
Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 [...] Read more.
Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 μM. In contrast, stellettin B showed very weak inhibitory activity on normal cell lines including HMEC, RPTEC, NHBE and PrEC, with GI50s higher than 10 μM, suggesting its relatively selective cytotoxicity against human cancer cells compared to normal human cell lines. We then focused on the antitumor activity of this compound on SF295 cells. Flow cytometric analysis indicated that stellettin B induced apoptosis in SF295 cells in a concentration-dependent manner. Further study indicated that stellettin B increased the production of ROS, the activity of caspase 3/7, as well as the cleavage of PARP, each of which is known to be involved in apoptosis. To investigate the molecular mechanism for cell proliferation inhibition and apoptosis induction, effect on the phosphorylation of several signal proteins of PI3K/Akt and RAS/MAPK pathways was examined. Stellettin B inhibited the phosphorylation of Akt potently, with no activity on p-ERK and p-p38, suggesting that inhibition of PI3K/Akt pathway might be involved in the antiproliferative and apoptosis-inducing effect. However, homogenous time-resolved fluorescence (HTRF) assay indicated that stellettin B did not inhibit PI3K activity, suggesting that the direct target might be signal protein upstream of Akt pathway other than PI3K. Full article
Open AccessArticle Fucoxanthin Enhances the Level of Reduced Glutathione via the Nrf2-Mediated Pathway in Human Keratinocytes
Mar. Drugs 2014, 12(7), 4214-4230; doi:10.3390/md12074214
Received: 4 June 2014 / Revised: 1 July 2014 / Accepted: 4 July 2014 / Published: 15 July 2014
Cited by 3 | PDF Full-text (1463 KB) | HTML Full-text | XML Full-text
Abstract
Fucoxanthin, a natural carotenoid, is abundant in seaweed with antioxidant properties. This study investigated the role of fucoxanthin in the induction of antioxidant enzymes involved in the synthesis of reduced glutathione (GSH), synthesized by glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase [...] Read more.
Fucoxanthin, a natural carotenoid, is abundant in seaweed with antioxidant properties. This study investigated the role of fucoxanthin in the induction of antioxidant enzymes involved in the synthesis of reduced glutathione (GSH), synthesized by glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS), via Akt/nuclear factor-erythroid 2-related (Nrf2) pathway in human keratinocytes (HaCaT) and elucidated the underlying mechanism. Fucoxanthin treatment increased the mRNA and protein levels of GCLC and GSS in HaCaT cells. In addition, fucoxanthin treatment promoted the nuclear translocation and phosphorylation of Nrf2, a transcription factor for the genes encoding GCLC and GSS. Chromatin immune-precipitation and luciferase reporter gene assays revealed that fucoxanthin treatment increased the binding of Nrf2 to the antioxidant response element (ARE) sequence and transcriptional activity of Nrf2. Fucoxanthin treatment increased phosphorylation of Akt (active form), an up-regulator of Nrf2 and exposure to LY294002, a phosphoinositide 3-kinase (PI3K)/Akt inhibitor, suppressed the fucoxanthin-induced activation of Akt, Nrf2, resulting in decreased GCLC and GSS expression. In accordance with the effects on GCLC and GSS expression, fucoxanthin induced the level of GSH. In addition, fucoxanthin treatment recovered the level of GSH reduced by ultraviolet B irradiation. Taken together, these findings suggest that fucoxanthin treatment augments cellular antioxidant defense by inducing Nrf2-driven expression of enzymes involved in GSH synthesis via PI3K/Akt signaling. Full article
(This article belongs to the Special Issue Marine Carotenoids (Special Issue))
Open AccessArticle Dolabelladienols A–C, New Diterpenes Isolated from Brazilian Brown Alga Dictyota pfaffii
Mar. Drugs 2014, 12(7), 4247-4259; doi:10.3390/md12074247
Received: 31 March 2014 / Revised: 27 June 2014 / Accepted: 30 June 2014 / Published: 23 July 2014
Cited by 6 | PDF Full-text (758 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The marine brown alga Dictyota pfaffii from Atol das Rocas, in Northeast Brazil is a rich source of dolabellane diterpene, which has the potential to be used in future antiviral drugs by inhibiting reverse transcriptase (RT) of HIV-1. Reexamination of the minor [...] Read more.
The marine brown alga Dictyota pfaffii from Atol das Rocas, in Northeast Brazil is a rich source of dolabellane diterpene, which has the potential to be used in future antiviral drugs by inhibiting reverse transcriptase (RT) of HIV-1. Reexamination of the minor diterpene constituents yielded three new dolabellane diterpenes, (1R*,2E,4R*,7S,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene (1), (1R*,2E,4R*,7R*,10S*,11S*,12R*)10,18-diacetoxy-7-hydroxy-2,8(17)-dolabelladiene (2), (1R*,2E,4R*,8E,10S*,11S,12R*)10,18-diacetoxy-7-hydroxy-2,8-dolabelladiene (3), termed dolabelladienols A–C (13) respectively, in addition to the known dolabellane diterpenes (46). The elucidation of the compounds 13 was assigned by 1D and 2D NMR, MS, optical rotation and molecular modeling, along with the relative configuration of compound 4 and the absolute configuration of 5 by X-ray diffraction. The potent anti-HIV-1 activities displayed by compounds 1 and 2 (IC50 = 2.9 and 4.1 μM), which were more active than even the known dolabelladienetriol 4, and the low cytotoxic activity against MT-2 lymphocyte tumor cells indicated that these compounds are promising anti-HIV-1 agents. Full article

Review

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Open AccessReview Marine Microorganism-Invertebrate Assemblages: Perspectives to Solve the “Supply Problem” in the Initial Steps of Drug Discovery
Mar. Drugs 2014, 12(7), 3929-3952; doi:10.3390/md12073929
Received: 29 January 2014 / Revised: 4 April 2014 / Accepted: 6 June 2014 / Published: 30 June 2014
Cited by 7 | PDF Full-text (970 KB) | HTML Full-text | XML Full-text
Abstract
The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the “blue gold” in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past [...] Read more.
The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the “blue gold” in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts. Full article
Open AccessReview Applications of Mass Spectrometry to Structural Analysis of Marine Oligosaccharides
Mar. Drugs 2014, 12(7), 4005-4030; doi:10.3390/md12074005
Received: 13 March 2014 / Revised: 28 April 2014 / Accepted: 6 May 2014 / Published: 30 June 2014
Cited by 2 | PDF Full-text (2359 KB) | HTML Full-text | XML Full-text
Abstract
Marine oligosaccharides have attracted increasing attention recently in developing potential drugs and biomaterials for their particular physical and chemical properties. However, the composition and sequence analysis of marine oligosaccharides are very challenging for their structural complexity and heterogeneity. Mass spectrometry (MS) has [...] Read more.
Marine oligosaccharides have attracted increasing attention recently in developing potential drugs and biomaterials for their particular physical and chemical properties. However, the composition and sequence analysis of marine oligosaccharides are very challenging for their structural complexity and heterogeneity. Mass spectrometry (MS) has become an important technique for carbohydrate analysis by providing more detailed structural information, including molecular mass, sugar constituent, sequence, inter-residue linkage position and substitution pattern. This paper provides an overview of the structural analysis based on MS approaches in marine oligosaccharides, which are derived from some biologically important marine polysaccharides, including agaran, carrageenan, alginate, sulfated fucan, chitosan, glycosaminoglycan (GAG) and GAG-like polysaccharides. Applications of electrospray ionization mass spectrometry (ESI-MS) are mainly presented and the general applications of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) are also outlined. Some technical challenges in the structural analysis of marine oligosaccharides by MS have also been pointed out. Full article
(This article belongs to the Special Issue Marine Biomaterials)
Open AccessReview Understanding Nanocalcification: A Role Suggested for Crystal Ghosts
Mar. Drugs 2014, 12(7), 4231-4246; doi:10.3390/md12074231
Received: 19 June 2014 / Revised: 7 July 2014 / Accepted: 8 July 2014 / Published: 23 July 2014
Cited by 1 | PDF Full-text (1846 KB) | HTML Full-text | XML Full-text
Abstract
The present survey deals with the initial stage of the calcification process in bone and other hard tissues, with special reference to the organic-inorganic relationship and the transformation that the early inorganic particles undergo as the process moves towards completion. Electron microscope [...] Read more.
The present survey deals with the initial stage of the calcification process in bone and other hard tissues, with special reference to the organic-inorganic relationship and the transformation that the early inorganic particles undergo as the process moves towards completion. Electron microscope studies clearly exclude the possibility that these particles might be crystalline structures, as often believed, by showing that they are, instead, organic-inorganic hybrids, each comprising a filamentous organic component (the crystal ghost) made up of acidic proteins. The hypothesis is suggested that the crystal ghosts bind and stabilize amorphous calcium phosphate and that their subsequent degradation allows the calcium phosphate, once released, to acquire a hydroxyapatite, crystal-like organization. A conclusive view of the mechanism of biological calcification cannot yet be proposed; even so, however, the role of crystal ghosts as a template of the structures usually called “crystallites” is a concept that has gathered increasing support and can no longer be disregarded. Full article
(This article belongs to the Special Issue Marine Biomaterials)
Open AccessReview Recognition of LPS by TLR4: Potential for Anti-Inflammatory Therapies
Mar. Drugs 2014, 12(7), 4260-4273; doi:10.3390/md12074260
Received: 8 April 2014 / Revised: 10 June 2014 / Accepted: 4 July 2014 / Published: 23 July 2014
Cited by 6 | PDF Full-text (1001 KB) | HTML Full-text | XML Full-text
Abstract
LPS molecules of marine bacteria show structures distinct from terrestrial bacteria, due to the different environment that marine bacteria live in. Because of these different structures, lipid A molecules from marine bacteria are most often poor stimulators of the Toll-like receptor 4 [...] Read more.
LPS molecules of marine bacteria show structures distinct from terrestrial bacteria, due to the different environment that marine bacteria live in. Because of these different structures, lipid A molecules from marine bacteria are most often poor stimulators of the Toll-like receptor 4 (TLR4) pathway. Due to their low stimulatory potential, these lipid A molecules are suggested to be applicable as antagonists of TLR4 signaling in sepsis patients, where this immune response is amplified and unregulated. Antagonizing lipid A molecules might be used for future therapies against sepsis, therapies that currently do not exist. In this review, we will discuss these differences in lipid A structures and their recognition by the immune system. The modifications present in marine lipid A structures are described, and their potential as LPS antagonists will be discussed. Finally, since clinical trials built on antagonizing lipid A molecules have proven unsuccessful, we propose to also focus on different aspects of the TLR4 signaling pathway when searching for new potential drugs. Furthermore, we put forward the notion that bacteria probably already produce inhibitors of TLR4 signaling, making these bacterial products interesting molecules to investigate for future sepsis therapies. Full article
(This article belongs to the Special Issue Marine Lipopolysaccharides)

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