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Mar. Drugs, Volume 11, Issue 3 (March 2013), Pages 581-974

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Editorial

Jump to: Research, Review

Open AccessEditorial Marine Drugs Best Paper Award 2013
Mar. Drugs 2013, 11(3), 581-583; doi:10.3390/md11030581
Received: 18 February 2013 / Accepted: 22 February 2013 / Published: 26 February 2013
Cited by 2 | PDF Full-text (200 KB) | HTML Full-text | XML Full-text
Abstract To recognize the most outstanding papers in the area of research, development and production of drugs from the sea, including marine natural product chemistry, that have been published in Marine Drugs, we would like to start an annual “Best Paper Award”. [...] Full article
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Research

Jump to: Editorial, Review

Open AccessArticle Characterization of Palytoxin Binding to HaCaT Cells Using a Monoclonal Anti-Palytoxin Antibody
Mar. Drugs 2013, 11(3), 584-598; doi:10.3390/md11030584
Received: 18 December 2012 / Revised: 12 January 2013 / Accepted: 15 February 2013 / Published: 26 February 2013
Cited by 12 | PDF Full-text (735 KB) | HTML Full-text | XML Full-text
Abstract
Palytoxin (PLTX) is the reference compound for a group of potent marine biotoxins, for which the molecular target is Na+/K+-ATPase. Indeed, ouabain (OUA), a potent blocker of the pump, is used to inhibit some PLTX effects in vitro.
[...] Read more.
Palytoxin (PLTX) is the reference compound for a group of potent marine biotoxins, for which the molecular target is Na+/K+-ATPase. Indeed, ouabain (OUA), a potent blocker of the pump, is used to inhibit some PLTX effects in vitro. However, in an effort to explain incomplete inhibition of PLTX cytotoxicity, some studies suggest the possibility of two different binding sites on Na+/K+-ATPase. Hence, this study was performed to characterize PLTX binding to intact HaCaT keratinocytes and to investigate the ability of OUA to compete for this binding. PLTX binding to HaCaT cells was demonstrated by immunocytochemical analysis after 10 min exposure. An anti-PLTX monoclonal antibody-based ELISA showed that the binding was saturable and reversible, with a Kd of 3 × 10−10 M. However, kinetic experiments revealed that PLTX binding dissociation was incomplete, suggesting an additional, OUA-insensitive, PLTX binding site. Competitive experiments suggested that OUA acts as a negative allosteric modulator against high PLTX concentrations (0.3–1.0 × 10−7 M) and possibly as a non-competitive antagonist against low PLTX concentrations (0.1–3.0 × 10−9 M). Antagonism was supported by PLTX cytotoxicity inhibition at OUA concentrations that displaced PLTX binding (1 × 10−5 M). However, this inhibition was incomplete, supporting the existence of both OUA-sensitive and -insensitive PLTX binding sites. Full article
(This article belongs to the Special Issue Algal Toxins)
Open AccessArticle Eleganolone, a Diterpene from the French Marine Alga Bifurcaria bifurcata Inhibits Growth of the Human Pathogens Trypanosoma brucei and Plasmodium falciparum
Mar. Drugs 2013, 11(3), 599-610; doi:10.3390/md11030599
Received: 12 December 2012 / Revised: 18 January 2013 / Accepted: 7 February 2013 / Published: 26 February 2013
Cited by 7 | PDF Full-text (419 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Organic extracts of 20 species of French seaweed have been screened against Trypanosoma brucei rhodesiense trypomastigotes, the parasite responsible for sleeping sickness. These extracts have previously shown potent antiprotozoal activities in vitro against Plasmodium falciparum and Leishmania donovani. The selectivity of the
[...] Read more.
Organic extracts of 20 species of French seaweed have been screened against Trypanosoma brucei rhodesiense trypomastigotes, the parasite responsible for sleeping sickness. These extracts have previously shown potent antiprotozoal activities in vitro against Plasmodium falciparum and Leishmania donovani. The selectivity of the extracts was also evaluated by testing cytotoxicity on a mammalian L6 cell line. The ethyl acetate extract of the brown seaweed, Bifurcaria bifurcata, showed strong trypanocidal activity with a mild selectivity index (IC50 = 0.53 µg/mL; selectivity index (SI) = 11.6). Bio-guided fractionation led to the isolation of eleganolone, the main diterpenoid isolated from this species. Eleganolone contributes only mildly to the trypanocidal activity of the ethyl acetate extract (IC50 = 45.0 µM, SI = 4.0). However, a selective activity against P. falciparum erythrocytic stages in vitro has been highlighted (IC50 = 7.9 µM, SI = 21.6). Full article
(This article belongs to the Special Issue Marine Algae)
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Open AccessArticle Thalassospiramide G, a New γ-Amino-Acid-Bearing Peptide from the Marine Bacterium Thalassospira sp.
Mar. Drugs 2013, 11(3), 611-622; doi:10.3390/md11030611
Received: 13 December 2012 / Revised: 29 January 2013 / Accepted: 6 February 2013 / Published: 26 February 2013
Cited by 8 | PDF Full-text (627 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In the chemical investigation of marine unicellular bacteria, a new peptide, thalassospiramide G (1), along with thalassospiramides A and D (23), was discovered from a large culture of Thalassospira sp. The structure of thalassospiramide G, bearing γ-amino
[...] Read more.
In the chemical investigation of marine unicellular bacteria, a new peptide, thalassospiramide G (1), along with thalassospiramides A and D (23), was discovered from a large culture of Thalassospira sp. The structure of thalassospiramide G, bearing γ-amino acids, such as 4-amino-5-hydroxy-penta-2-enoic acid (AHPEA), 4-amino-3,5-dihydroxy-pentanoic acid (ADPA), and unique 2-amino-1-(1H-indol-3-yl) ethanone (AIEN), was determined via extensive spectroscopic analysis. The absolute configuration of thalassospiramide D (3), including 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), was rigorously determined by 1H–1H coupling constant analysis and chemical derivatization. Thalassospiramides A and D (23) inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells, with IC50 values of 16.4 and 4.8 μM, respectively. Full article
(This article belongs to the Special Issue Marine Secondary Metabolites)
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Open AccessArticle Synthesis and Antiproliferative Activity of 2,5-bis(3′-Indolyl)pyrroles, Analogues of the Marine Alkaloid Nortopsentin
Mar. Drugs 2013, 11(3), 643-654; doi:10.3390/md11030643
Received: 21 December 2012 / Revised: 22 January 2013 / Accepted: 6 February 2013 / Published: 1 March 2013
Cited by 32 | PDF Full-text (544 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
2,5-bis(3′-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54
[...] Read more.
2,5-bis(3′-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 μM and 0.67 μM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes. Full article
Open AccessArticle Biochemical and Electrophysiological Characterization of Two Sea Anemone Type 1 Potassium Toxins from a Geographically Distant Population of Bunodosoma caissarum
Mar. Drugs 2013, 11(3), 655-679; doi:10.3390/md11030655
Received: 17 December 2012 / Revised: 23 January 2013 / Accepted: 15 February 2013 / Published: 6 March 2013
Cited by 8 | PDF Full-text (1363 KB) | HTML Full-text | XML Full-text
Abstract
Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K+ channels (KV). These neurotoxins can be divided into four different types, according to their structure and
[...] Read more.
Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K+ channels (KV). These neurotoxins can be divided into four different types, according to their structure and mode of action. In this work, for the first time, two toxins were purified from the venom of Bunodosoma caissarum population from Saint Peter and Saint Paul Archipelago, Brazil. Sequence alignment and phylogenetic analysis reveals that BcsTx1 and BcsTx2 are the newest members of the sea anemone type 1 potassium channel toxins. Their functional characterization was performed by means of a wide electrophysiological screening on 12 different subtypes of KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; hERG and Shaker IR). BcsTx1 shows a high affinity for rKv1.2 over rKv1.6, hKv1.3, Shaker IR and rKv1.1, while Bcstx2 potently blocked rKv1.6 over hKv1.3, rKv1.1, Shaker IR and rKv1.2. Furthermore, we also report for the first time a venom composition and biological activity comparison between two geographically distant populations of sea anemones. Full article
(This article belongs to the Special Issue Marine Neurotoxins)
Open AccessArticle Bioactive Polyoxygenated Steroids from the South China Sea Soft Coral, Sarcophyton sp.
Mar. Drugs 2013, 11(3), 775-787; doi:10.3390/md11030775
Received: 26 November 2012 / Revised: 23 January 2013 / Accepted: 26 February 2013 / Published: 11 March 2013
Cited by 14 | PDF Full-text (557 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Seven new polyoxygenated steroids (17) were isolated together with seven known analogues (814) from the South China Sea soft coral, Sarcophyton sp. The structures of the new compounds were identified on the basis of
[...] Read more.
Seven new polyoxygenated steroids (17) were isolated together with seven known analogues (814) from the South China Sea soft coral, Sarcophyton sp. The structures of the new compounds were identified on the basis of extensive spectroscopic analysis and comparison with reported data. All the steroids are characterized with 3β,5α,6β-hydroxy moiety, displaying carbon skeletons of cholestane, ergostane, gorgostane and 23,24-dimethyl cholestane. In the in vitro bioassay, metabolites exhibited different levels of antimicrobial activity against bacterial species Escherichia coli and Bacillus megaterium, and fungal species Microbotryum violaceum and Septoria tritici. No inhibition was detected towards microalga Chlorella fusca. Preliminary structure-activity analysis suggests that the 11α-acetoxy group may increase both antibacterial and antifungal activities. The terminal-double bond and the cyclopropane moiety at the side chain may also contribute to the bioactivity. Full article
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Open AccessArticle Cytotoxic and Anti-Inflammatory Eunicellin-Based Diterpenoids from the Soft Coral Cladiella krempfi
Mar. Drugs 2013, 11(3), 788-799; doi:10.3390/md11030788
Received: 9 January 2013 / Revised: 6 February 2013 / Accepted: 19 February 2013 / Published: 12 March 2013
Cited by 16 | PDF Full-text (911 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Five new eunicellin-based diterpenoids, krempfielins E–I (15) and seven known compounds (612) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on
[...] Read more.
Five new eunicellin-based diterpenoids, krempfielins E–I (15) and seven known compounds (612) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analysis. Metabolites 5, 6, 10 and 12 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 6 and 10 could potently inhibit the accumulation of the pro-inflammatory iNOS protein, and 6 and 12 could significantly reduce the expression of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells. Full article
Open AccessArticle Helicusin E, Isochromophilone X and Isochromophilone XI: New Chloroazaphilones Produced by the Fungus Bartalinia robillardoides Strain LF550
Mar. Drugs 2013, 11(3), 800-816; doi:10.3390/md11030800
Received: 18 December 2012 / Revised: 17 January 2013 / Accepted: 6 February 2013 / Published: 12 March 2013
Cited by 12 | PDF Full-text (615 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Microbial studies of the Mediterranean sponge Tethya aurantium led to the isolation of the fungus Bartalinia robillardoides strain LF550. The strain produced a number of secondary metabolites belonging to the chloroazaphilones. This is the first report on the isolation of chloroazaphilones of a
[...] Read more.
Microbial studies of the Mediterranean sponge Tethya aurantium led to the isolation of the fungus Bartalinia robillardoides strain LF550. The strain produced a number of secondary metabolites belonging to the chloroazaphilones. This is the first report on the isolation of chloroazaphilones of a fungal strain belonging to the genus Bartalinia. Besides some known compounds (helicusin A (1) and deacetylsclerotiorin (2)), three new chloroazaphilones (helicusin E (3); isochromophilone X (4) and isochromophilone XI (5)) and one new pentaketide (bartanolide (6)) were isolated. The structure elucidations were based on spectroscopic analyses. All isolated compounds revealed different biological activity spectra against a test panel of four bacteria: three fungi; two tumor cell lines and two enzymes. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Fungi)
Open AccessArticle New Azalomycin F Analogs from Mangrove Streptomyces sp. 211726 with Activity against Microbes and Cancer Cells
Mar. Drugs 2013, 11(3), 817-829; doi:10.3390/md11030817
Received: 7 November 2012 / Revised: 30 January 2013 / Accepted: 26 February 2013 / Published: 12 March 2013
Cited by 10 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Seven new azalomycin F analogs (17) were isolated from the broth of mangrove Streptomyces sp. 211726, and respectively identified as 25-malonyl demalonylazalomycin F5a monoester (1), 23-valine demalonylazalomycin F5a ester (2), 23-(6-methyl)heptanoic acid demalonylazalomycins
[...] Read more.
Seven new azalomycin F analogs (17) were isolated from the broth of mangrove Streptomyces sp. 211726, and respectively identified as 25-malonyl demalonylazalomycin F5a monoester (1), 23-valine demalonylazalomycin F5a ester (2), 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester (3), F4a ester (4) and F5a ester (5), 23-(9-methyl)decanoic acid demalonylazalomycin F4a ester (6) and 23-(10-methyl)undecanoic acid demalony lazalomycin F4a ester (7). Their structures were established by their spectroscopic data and by comparing with those of azalomycins F3a, F4a and F5a. Biological assays exhibited that 17 showed broad-spectrum antimicrobial and anti HCT-116 activities. Full article
Open AccessArticle The CHROMEVALOA Database: A Resource for the Evaluation of Okadaic Acid Contamination in the Marine Environment Based on the Chromatin-Associated Transcriptome of the Mussel Mytilus galloprovincialis
Mar. Drugs 2013, 11(3), 830-841; doi:10.3390/md11030830
Received: 4 January 2013 / Revised: 28 January 2013 / Accepted: 21 February 2013 / Published: 12 March 2013
Cited by 12 | PDF Full-text (1041 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Okadaic Acid (OA) constitutes the main active principle in Diarrhetic Shellfish Poisoning (DSP) toxins produced during Harmful Algal Blooms (HABs), representing a serious threat for human consumers of edible shellfish. Furthermore, OA conveys critical deleterious effects for marine organisms due to its genotoxic
[...] Read more.
Okadaic Acid (OA) constitutes the main active principle in Diarrhetic Shellfish Poisoning (DSP) toxins produced during Harmful Algal Blooms (HABs), representing a serious threat for human consumers of edible shellfish. Furthermore, OA conveys critical deleterious effects for marine organisms due to its genotoxic potential. Many efforts have been dedicated to OA biomonitoring during the last three decades. However, it is only now with the current availability of detailed molecular information on DNA organization and the mechanisms involved in the maintenance of genome integrity, that a new arena starts opening up for the study of OA contamination. In the present work we address the links between OA genotoxicity and chromatin by combining Next Generation Sequencing (NGS) technologies and bioinformatics. To this end, we introduce CHROMEVALOAdb, a public database containing the chromatin-associated transcriptome of the mussel Mytilus galloprovincialis (a sentinel model organism) in response to OA exposure. This resource constitutes a leap forward for the development of chromatin-based biomarkers, paving the road towards the generation of powerful and sensitive tests for the detection and evaluation of the genotoxic effects of OA in coastal areas. Full article
(This article belongs to the Special Issue Okadaic Acid and Dinophysis Toxins)
Open AccessArticle Two New Bromophenols with Radical Scavenging Activity from Marine Red Alga Symphyocladia latiuscula
Mar. Drugs 2013, 11(3), 842-847; doi:10.3390/md11030842
Received: 7 December 2012 / Revised: 29 January 2013 / Accepted: 6 February 2013 / Published: 13 March 2013
Cited by 5 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Chemical investigation of a Chinese collection of marine red alga Symphyocladia latiuscula yielded two new highly brominated phenols. The structures of the new compounds were elucidated by detailed spectroscopic analysis, including HRMS, 1D and 2D NMR and MS methods. Compounds 1 and 2
[...] Read more.
Chemical investigation of a Chinese collection of marine red alga Symphyocladia latiuscula yielded two new highly brominated phenols. The structures of the new compounds were elucidated by detailed spectroscopic analysis, including HRMS, 1D and 2D NMR and MS methods. Compounds 1 and 2 were evaluated for radical scavenging capability by 1,1-diphenyl-2-picrylhydrazuyl (DPPH) radical with the IC50 value of 14.5 and 20.5 μg/mL, respectively. Full article
(This article belongs to the Special Issue Marine Algae)
Open AccessArticle The Protection of Polysaccharide from the Brown Seaweed Sargassum graminifolium against Ethylene Glycol-Induced Mitochondrial Damage
Mar. Drugs 2013, 11(3), 870-880; doi:10.3390/md11030870
Received: 20 December 2012 / Revised: 1 February 2013 / Accepted: 6 February 2013 / Published: 13 March 2013
Cited by 4 | PDF Full-text (345 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The aim of the present study is to evaluate the protective effect of polysaccharide from the Brown Seaweed Sargassum graminifolium (SGP) on ethylene glycol-induced kidney damage and the mechanism of SGP-mediated protection. Mitochondrial lipid peroxidation, mitochondrial swelling, the activity of succinate dehydrogenase (SDH),
[...] Read more.
The aim of the present study is to evaluate the protective effect of polysaccharide from the Brown Seaweed Sargassum graminifolium (SGP) on ethylene glycol-induced kidney damage and the mechanism of SGP-mediated protection. Mitochondrial lipid peroxidation, mitochondrial swelling, the activity of succinate dehydrogenase (SDH), ATPases and mitochondrial antioxidant enzymes was observed in hyperoxaluric rats. Administration of SGP (25, 100 and 400 mg·kg−1, intragastrically) increased the activities of antioxidant enzymes, SDH and Na+/K+-ATPases, Ca2+-ATPases, Mg2+-ATPases, also decreased mitochondrial lipid peroxidation and mitochondrial swelling. SGP exhibited a protective effect by improving antioxidant enzymes and restoring mitochondrial dysfunction in the kidney of hyperoxaluric rats. It may be used as a promising therapeutic agent to provide superior renal protection. Full article
Open AccessArticle Improved Detection of Domoic Acid Using Covalently Immobilised Antibody Fragments
Mar. Drugs 2013, 11(3), 881-895; doi:10.3390/md11030881
Received: 26 December 2012 / Revised: 13 January 2013 / Accepted: 21 February 2013 / Published: 14 March 2013
Cited by 9 | PDF Full-text (312 KB) | HTML Full-text | XML Full-text
Abstract
Antibody molecules, and antibody fragments in particular, have enormous potential in the development of biosensors for marine monitoring. Conventional immobilisation approaches used in immunoassays typically yield unstable and mostly incorrectly oriented antibodies, however, resulting in reduced detection sensitivities for already low concentration analytes.
[...] Read more.
Antibody molecules, and antibody fragments in particular, have enormous potential in the development of biosensors for marine monitoring. Conventional immobilisation approaches used in immunoassays typically yield unstable and mostly incorrectly oriented antibodies, however, resulting in reduced detection sensitivities for already low concentration analytes. The 2H12 anti-domoic acid scFv antibody fragment was engineered with cysteine-containing linkers of two different lengths, distal to the antigen binding pocket, for covalent and correctly oriented immobilisation of the scFvs on functionalised solid supports. The Escherichia coli-produced, cysteine-engineered scFvs dimerised in solution and demonstrated similar efficiencies of covalent immobilisation on maleimide-activated plates and minimal non-covalent attachment. The covalently attached scFvs exhibited negligible leaching from the support under acidic conditions that removed almost 50% of the adsorbed wildtype fragment, and IC50s for domoic acid of 270 and 297 ng/mL compared with 1126 and 1482 ng/mL, respectively, for their non-covalently adsorbed counterparts. The expression and immobilisation approach will facilitate the development of stable, reusable biosensors with increased stability and detection sensitivity for marine neurotoxins. Full article
(This article belongs to the Special Issue Marine Neurotoxins)
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Open AccessArticle Evaluation of Macroalgae Sulfated Polysaccharides on the Leishmania (L.) amazonensis Promastigote
Mar. Drugs 2013, 11(3), 934-943; doi:10.3390/md11030934
Received: 17 January 2013 / Revised: 28 January 2013 / Accepted: 25 February 2013 / Published: 20 March 2013
Cited by 5 | PDF Full-text (356 KB) | HTML Full-text | XML Full-text
Abstract
The sulfated polysaccharides from Solieria filiformis (Sf), Botryocladia occidentalis (Bo), Caulerpa racemosa (Cr) and Gracilaria caudata (Gc) were extracted and extensively purified. These compounds were then subjected to in vitro assays to evaluate the inhibition of these polysaccharides on the growth of Leishmania
[...] Read more.
The sulfated polysaccharides from Solieria filiformis (Sf), Botryocladia occidentalis (Bo), Caulerpa racemosa (Cr) and Gracilaria caudata (Gc) were extracted and extensively purified. These compounds were then subjected to in vitro assays to evaluate the inhibition of these polysaccharides on the growth of Leishmania (L.) amazonensis promastigotes. Under the same assay conditions, only three of the four sulfated polysaccharides were active against L. amazonensis, and the polysaccharide purified from Cr was the most potent (EC50 value: 34.5 μg/mL). The polysaccharides derived from Bo and Sf demonstrated moderate anti-leishmanial activity (EC50 values of 63.7 μg/mL and 137.4 μg/mL). In addition, we also performed in vitro cytotoxic assays toward peritoneal macrophages and J774 macrophages. For the in vitro cytotoxicity assay employing J774 cells, all of the sulfated polysaccharides decreased cell survival, with CC50 values of 27.3 μg/mL, 49.3 μg/mL, 73.2 μg/mL, and 99.8 μg/mL for Bo, Cr, Gc, and Sf, respectively. However, none of the sulfated polysaccharides reduced the cell growth rate of the peritoneal macrophages. These results suggest that macroalgae contain compounds with various chemical properties that can control specific pathogens. According to our results, the assayed sulfated polysaccharides were able to modulate the growth rate and cell survival of Leishmania (L.) amazonensis promastigotes in in vitro assays, and these effects involved the interaction of the sulfated polysaccharides on the cell membrane of the parasites. Full article
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Open AccessArticle Predictive Factors of Sensitivity to Elisidepsin, a Novel Kahalalide F-Derived Marine Compound
Mar. Drugs 2013, 11(3), 944-959; doi:10.3390/md11030944
Received: 28 December 2012 / Revised: 21 January 2013 / Accepted: 22 February 2013 / Published: 20 March 2013
Cited by 9 | PDF Full-text (903 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of
[...] Read more.
Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)
Open AccessArticle Astaxanthin Attenuates the Apoptosis of Retinal Ganglion Cells in db/db Mice by Inhibition of Oxidative Stress
Mar. Drugs 2013, 11(3), 960-974; doi:10.3390/md11030960
Received: 7 December 2012 / Revised: 17 February 2013 / Accepted: 1 March 2013 / Published: 21 March 2013
Cited by 20 | PDF Full-text (1031 KB) | HTML Full-text | XML Full-text
Abstract
Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). It is an ocular manifestation of systemic disease, which affects up to 80% of all patients who have had diabetes for 10 years or more. The genetically
[...] Read more.
Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). It is an ocular manifestation of systemic disease, which affects up to 80% of all patients who have had diabetes for 10 years or more. The genetically diabetic db/db mouse, as a model of type-2 diabetes, shows diabetic retinopathy induced by apoptosis of RGCs. Astaxanthin is a carotenoid with powerful antioxidant properties that exists naturally in various plants, algae and seafood. Here, astaxanthin was shown to reduce the apoptosis of RGCs and improve the levels of oxidative stress markers, including superoxide anion, malondialdehyde (MDA, a marker of lipid peroxidation), 8-hydroxy-2-deoxyguanosine (8-OHdG, indicator of oxidative DNA damage) and MnSOD (manganese superoxide dismutase) activity in the retinal tissue of db/db mouse. In addition, astaxanthin attenuated hydrogen peroxide(H2O2)-induced apoptosis in the transformed rat retinal ganglion cell line RGC-5. Therefore, astaxanthin may be developed as an antioxidant drug to treat diabetic retinopathy. Full article

Review

Jump to: Editorial, Research

Open AccessReview Glycosylation of Conotoxins
Mar. Drugs 2013, 11(3), 623-642; doi:10.3390/md11030623
Received: 14 December 2012 / Revised: 25 January 2013 / Accepted: 6 February 2013 / Published: 1 March 2013
Cited by 9 | PDF Full-text (1028 KB) | HTML Full-text | XML Full-text
Abstract
Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological
[...] Read more.
Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological studies and for drug development, because they target with exquisite specificity membrane receptors, transporters, and various ion channels in the nervous system. However, these peptides are known to contain a high frequency and variability of post-translational modifications—including sometimes O-glycosylation—which are of importance for biological activity. The potential application of specific conotoxins as neuropharmalogical agents and chemical probes requires a full characterization of the relevant peptides, including the structure of the carbohydrate part. In this review, the currently existing knowledge of O-glycosylation of conotoxins is described. Full article
(This article belongs to the Special Issue Marine Glycoconjugates)
Open AccessReview Omega-Conotoxins as Experimental Tools and Therapeutics in Pain Management
Mar. Drugs 2013, 11(3), 680-699; doi:10.3390/md11030680
Received: 21 December 2012 / Revised: 14 February 2013 / Accepted: 15 February 2013 / Published: 7 March 2013
Cited by 6 | PDF Full-text (904 KB) | HTML Full-text | XML Full-text
Abstract
Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including
[...] Read more.
Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies. Full article
(This article belongs to the Special Issue Marine Neurotoxins)
Open AccessReview Recent Advances in the Discovery and Development of Marine Microbial Natural Products
Mar. Drugs 2013, 11(3), 700-717; doi:10.3390/md11030700
Received: 28 December 2012 / Revised: 25 January 2013 / Accepted: 6 February 2013 / Published: 8 March 2013
Cited by 39 | PDF Full-text (652 KB) | HTML Full-text | XML Full-text
Abstract
Marine microbial natural products (MMNPs) have attracted increasing attention from microbiologists, taxonomists, ecologists, agronomists, chemists and evolutionary biologists during the last few decades. Numerous studies have indicated that diverse marine microbes appear to have the capacity to produce an impressive array of MMNPs
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Marine microbial natural products (MMNPs) have attracted increasing attention from microbiologists, taxonomists, ecologists, agronomists, chemists and evolutionary biologists during the last few decades. Numerous studies have indicated that diverse marine microbes appear to have the capacity to produce an impressive array of MMNPs exhibiting a wide variety of biological activities such as antimicrobial, anti-tumor, anti-inflammatory and anti-cardiovascular agents. Marine microorganisms represent an underexplored reservoir for the discovery of MMNPs with unique scaffolds and for exploitation in the pharmaceutical and agricultural industries. This review focuses on MMNPs discovery and development over the past decades, including innovative isolation and culture methods, strategies for discovering novel MMNPs via routine screenings, metagenomics, genomics, combinatorial biosynthesis, and synthetic biology. The potential problems and future directions for exploring MMNPs are also discussed. Full article
(This article belongs to the Special Issue Marine Secondary Metabolites)
Open AccessReview The Deep-Sea Natural Products, Biogenic Polyphosphate (Bio-PolyP) and Biogenic Silica (Bio-Silica), as Biomimetic Scaffolds for Bone Tissue Engineering: Fabrication of a Morphogenetically-Active Polymer
Mar. Drugs 2013, 11(3), 718-746; doi:10.3390/md11030718
Received: 10 January 2013 / Revised: 4 February 2013 / Accepted: 6 February 2013 / Published: 8 March 2013
Cited by 9 | PDF Full-text (1910 KB) | HTML Full-text | XML Full-text
Abstract
Bone defects in human, caused by fractures/nonunions or trauma, gain increasing impact and have become a medical challenge in the present-day aging population. Frequently, those fractures require surgical intervention which ideally relies on autografts or suboptimally on allografts. Therefore, it is pressing and
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Bone defects in human, caused by fractures/nonunions or trauma, gain increasing impact and have become a medical challenge in the present-day aging population. Frequently, those fractures require surgical intervention which ideally relies on autografts or suboptimally on allografts. Therefore, it is pressing and likewise challenging to develop bone substitution materials to heal bone defects. During the differentiation of osteoblasts from their mesenchymal progenitor/stem cells and of osteoclasts from their hemopoietic precursor cells, a lineage-specific release of growth factors and a trans-lineage homeostatic cross-talk via signaling molecules take place. Hence, the major hurdle is to fabricate a template that is functioning in a way mimicking the morphogenetic, inductive role(s) of the native extracellular matrix. In the last few years, two naturally occurring polymers that are produced by deep-sea sponges, the biogenic polyphosphate (bio-polyP) and biogenic silica (bio-silica) have also been identified as promoting morphogenetic on both osteoblasts and osteoclasts. These polymers elicit cytokines that affect bone mineralization (hydroxyapatite formation). In this manner, bio-silica and bio-polyP cause an increased release of BMP-2, the key mediator activating the anabolic arm of the hydroxyapatite forming cells, and of RANKL. In addition, bio-polyP inhibits the progression of the pre-osteoclasts to functionally active osteoclasts. Based on these findings, new bioinspired strategies for the fabrication of bone biomimetic templates have been developed applying 3D-printing techniques. Finally, a strategy is outlined by which these two morphogenetically active polymers might be used to develop a novel functionally active polymer. Full article
(This article belongs to the Special Issue Deep-Sea Natural Products)
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Open AccessReview Chondroitin Sulfate, Hyaluronic Acid and Chitin/Chitosan Production Using Marine Waste Sources: Characteristics, Applications and Eco-Friendly Processes: A Review
Mar. Drugs 2013, 11(3), 747-774; doi:10.3390/md11030747
Received: 17 December 2012 / Revised: 28 January 2013 / Accepted: 6 February 2013 / Published: 11 March 2013
Cited by 37 | PDF Full-text (768 KB) | HTML Full-text | XML Full-text
Abstract
In the last decade, an increasing number of glycosaminoglycans (GAGs), chitin and chitosan applications have been reported. Their commercial demands have been extended to different markets, such as cosmetics, medicine, biotechnology, food and textiles. Marine wastes from fisheries and aquaculture are susceptible sources
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In the last decade, an increasing number of glycosaminoglycans (GAGs), chitin and chitosan applications have been reported. Their commercial demands have been extended to different markets, such as cosmetics, medicine, biotechnology, food and textiles. Marine wastes from fisheries and aquaculture are susceptible sources for polymers but optimized processes for their recovery and production must be developed to satisfy such necessities. In the present work, we have reviewed different alternatives reported in the literature to produce and purify chondroitin sulfate (CS), hyaluronic acid (HA) and chitin/chitosan (CH/CHs) with the aim of proposing environmentally friendly processes by combination of various microbial, chemical, enzymatic and membranes strategies and technologies. Full article
(This article belongs to the collection Marine Polysaccharides)
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Open AccessReview Computational Studies of Marine Toxins Targeting Ion Channels
Mar. Drugs 2013, 11(3), 848-869; doi:10.3390/md11030848
Received: 19 December 2012 / Revised: 30 January 2013 / Accepted: 7 February 2013 / Published: 13 March 2013
Cited by 11 | PDF Full-text (1632 KB) | HTML Full-text | XML Full-text
Abstract
Toxins from marine animals offer novel drug leads for treatment of diseases involving ion channels. Computational methods could be very helpful in this endeavour in several ways, e.g., (i) constructing accurate models of the channel-toxin complexes using docking and molecular dynamics (MD) simulations;
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Toxins from marine animals offer novel drug leads for treatment of diseases involving ion channels. Computational methods could be very helpful in this endeavour in several ways, e.g., (i) constructing accurate models of the channel-toxin complexes using docking and molecular dynamics (MD) simulations; (ii) determining the binding free energies of toxins from umbrella sampling MD simulations; (iii) predicting the effect of mutations from free energy MD simulations. Using these methods, one can design new analogs of toxins with improved affinity and selectivity properties. Here we present a review of the computational methods and discuss their applications to marine toxins targeting potassium and sodium channels. Detailed examples from the potassium channel toxins—ShK from sea anemone and κ-conotoxin PVIIA—are provided to demonstrate capabilities of the computational methods to give accurate descriptions of the channel-toxin complexes and the energetics of their binding. An example is also given from sodium channel toxins (μ-conotoxin GIIIA) to illustrate the differences between the toxin binding modes in potassium and sodium channels. Full article
Open AccessReview Okadaic Acid: A Tool to Study the Hippo Pathway
Mar. Drugs 2013, 11(3), 896-902; doi:10.3390/md11030896
Received: 8 January 2013 / Revised: 4 February 2013 / Accepted: 19 February 2013 / Published: 14 March 2013
Cited by 5 | PDF Full-text (389 KB) | HTML Full-text | XML Full-text
Abstract
Mammalian Ste20-like kinases 1 and 2 (MST1 and MST2) are activated in NIH3T3 cells exposed to okadaic acid. The Hippo pathway is a newly emerging signaling that functions as a tumor suppressor. MST1 and MST2 work as core kinases of the Hippo pathway
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Mammalian Ste20-like kinases 1 and 2 (MST1 and MST2) are activated in NIH3T3 cells exposed to okadaic acid. The Hippo pathway is a newly emerging signaling that functions as a tumor suppressor. MST1 and MST2 work as core kinases of the Hippo pathway and their activities depend on the autophosphorylation, which is negatively regulated by protein phosphatase 2A (PP2A). Okadaic acid has been frequently used to enhance the phosphorylation of MST1 and MST2 and to trigger the activation of the Hippo pathway. However other components of the Hippo pathway could also be targets of okadaic acid. In this review we first briefly summarize the molecular architecture of the Hippo pathway for the reference of researchers outside the field. We explain how MST kinases are regulated by PP2A and how okadaic acid activates MST2. Thereafter we discuss which components of the Hippo pathway are candidate substrates of protein phosphatases and which points we need to consider in the usage of okadaic acid to study the Hippo pathway. Full article
(This article belongs to the Special Issue Okadaic Acid and Dinophysis Toxins)
Open AccessReview Marine-Derived Angiogenesis Inhibitors for Cancer Therapy
Mar. Drugs 2013, 11(3), 903-933; doi:10.3390/md11030903
Received: 4 February 2013 / Revised: 25 February 2013 / Accepted: 1 March 2013 / Published: 15 March 2013
Cited by 21 | PDF Full-text (1747 KB) | HTML Full-text | XML Full-text
Abstract
Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical
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Angiogenesis inhibitors have been successfully used for cancer therapy in the clinic. Many marine-derived natural products and their analogues have been reported to show antiangiogenic activities. Compared with the drugs in the clinic, these agents display interesting characteristics, including diverse sources, unique chemical structures, special modes of action, and distinct activity and toxicity profiles. This review will first provide an overview of the current marine-derived angiogenesis inhibitors based on their primary targets and/or mechanisms of action. Then, the marine-derived antiangiogenic protein kinase inhibitors will be focused on. And finally, the clinical trials of the marine-derived antiangiogenic agents will be discussed, with special emphasis on their application potentials, problems and possible coping strategies in their future development as anticancer drugs. Full article
(This article belongs to the Special Issue Marine Compounds as Protein Kinase Inhibitors)

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