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Mar. Drugs, Volume 8, Issue 3 (March 2010), Pages 381-834

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Research

Jump to: Review

Open AccessArticle Isolation, Phylogenetic Analysis and Anti-infective Activity Screening of Marine Sponge-Associated Actinomycetes
Mar. Drugs 2010, 8(3), 399-412; doi:10.3390/md8030399
Received: 29 December 2009 / Revised: 3 February 2010 / Accepted: 5 February 2010 / Published: 26 February 2010
Cited by 63 | PDF Full-text (273 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Terrestrial actinomycetes are noteworthy producers of a multitude of antibiotics, however the marine representatives are much less studied in this regard. In this study, 90 actinomycetes were isolated from 11 different species of marine sponges that had been collected from offshore Ras [...] Read more.
Terrestrial actinomycetes are noteworthy producers of a multitude of antibiotics, however the marine representatives are much less studied in this regard. In this study, 90 actinomycetes were isolated from 11 different species of marine sponges that had been collected from offshore Ras Mohamed (Egypt) and from Rovinj (Croatia). Phylogenetic characterization of the isolates based on 16S rRNA gene sequencing supported their assignment to 18 different actinomycete genera representing seven different suborders. Fourteen putatively novel species were identified based on sequence similarity values below 98.2% to other strains in the NCBI database. A putative new genus related to Rubrobacter was isolated on M1 agar that had been amended with sponge extract, thus highlighting the need for innovative cultivation protocols. Testing for anti-infective activities was performed against clinically relevant, Gram-positive (Enterococcus faecalis, Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, fungi (Candida albicans) and human parasites (Leishmania major, Trypanosoma brucei). Bioactivities against these pathogens were documented for 10 actinomycete isolates. These results show a high diversity of actinomycetes associated with marine sponges as well as highlight their potential to produce anti-infective agents. Full article
(This article belongs to the Special Issue Marine Actinomycetes: A New Source of Natural Products)
Open AccessArticle Seasonal Variations of the Activity of Antioxidant Defense Enzymes in the Red Mullet (Mullus barbatus l.) from the Adriatic Sea
Mar. Drugs 2010, 8(3), 413-428; doi:10.3390/md8030413
Received: 28 December 2009 / Revised: 1 February 2010 / Accepted: 5 February 2010 / Published: 26 February 2010
Cited by 16 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated seasonal variations of antioxidant defense enzyme activities: total, manganese, copper zinc containing superoxide dismutase (Tot SOD, Mn SOD, CuZn SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and biotransformation phase II enzyme glutathione-S-transferase (GST) activity in the liver [...] Read more.
This study investigated seasonal variations of antioxidant defense enzyme activities: total, manganese, copper zinc containing superoxide dismutase (Tot SOD, Mn SOD, CuZn SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and biotransformation phase II enzyme glutathione-S-transferase (GST) activity in the liver and white muscle of red mullet (Mullus barbatus). The investigations were performed in winter and spring at two localities: Near Bar (NB) and Estuary of the River Bojana (EB) in the Southern Adriatic Sea. At both sites, Mn SOD, GSH-Px, GR and GST activities decreased in the liver in spring. In the white muscle, activities of Mn SOD, GSH-Px, GR and GST in NB decreased in spring. GR decreased in spring in EB, while CAT activity was higher in spring at both sites. The results of Principal Component Analysis (PCA) based on correlations indicated a clear separation of various sampling periods for both investigated tissues and a marked difference between two seasons. Our study is the first report on antioxidant defense enzyme activities in the red mullet in the Southern Adriatic Sea. It indicates that seasonal variations of antioxidant defense enzyme activities should be used in further biomonitoring studies in fish species. Full article
(This article belongs to the Special Issue Enzymes from the Sea: Sources, Molecular Biology and Bioprocesses)
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Open AccessArticle Inhibition of Nitric Oxide (NO) Production in Lipopolysaccharide (LPS)-Activated Murine Macrophage RAW 264.7 Cells by the Norsesterterpene Peroxide, Epimuqubilin A
Mar. Drugs 2010, 8(3), 429-437; doi:10.3390/md8030429
Received: 14 January 2010 / Revised: 20 January 2010 / Accepted: 22 February 2010 / Published: 1 March 2010
Cited by 9 | PDF Full-text (255 KB) | HTML Full-text | XML Full-text
Abstract
Seven norsesterterpene peroxides: epimuqubilin A (1), muqubilone B (2), unnamed cyclic peroxide ester (3), epimuqubilin B (4), sigmosceptrellin A methyl ester (5), sigmosceptrellin A (6), and sigmosceptrellin B methyl ester [...] Read more.
Seven norsesterterpene peroxides: epimuqubilin A (1), muqubilone B (2), unnamed cyclic peroxide ester (3), epimuqubilin B (4), sigmosceptrellin A methyl ester (5), sigmosceptrellin A (6), and sigmosceptrellin B methyl ester (7), isolated from the marine sponge Latrunculia sp., were examined with regard to their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. The results indicated epimuqubilin A (1) possessed potent NO inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide release with an IC50 value of 7.4 µM, a level three times greater than the positive control, L-NG-monomethyl arginine citrate, followed by 6 (sigmosceptrellin A, IC50 = 9.9 µM), whereas other compounds exhibited only modest activity (Table 1). These compounds did not show appreciable cytotoxicity at their IC50 values for NO–inhibitory activity. The structure–activity upon NO inhibition could be summarized as follows: (1) a monocyclic carbon skeleton framework was essential for activity,(2) free acids gave higher activity, (3) the orientation of H3-22 with an equatorial position increased activity, and (4) a bicyclic structure reduced activity. This is the first report of a norsesterterpene peroxide with NO–inhibitory activity. In addition, compounds 17 were also evaluated for their inhibitory activities in the yeast glycogen synthase kinase-3βassay. In summary, several norsesterterpene peroxides showed novel biological activities of inhibition in NO production, suggesting that these might provide leads for anti-inflammatory or cancer chemopreventive agents. Full article
Open AccessArticle Is Yessotoxin the Main Phycotoxin in Croatian Waters?
Mar. Drugs 2010, 8(3), 460-470; doi:10.3390/md8030460
Received: 21 January 2010 / Revised: 8 February 2010 / Accepted: 20 February 2010 / Published: 5 March 2010
Cited by 6 | PDF Full-text (247 KB) | HTML Full-text | XML Full-text
Abstract
With the aim of investigating whether yessotoxin (YTX) is responsible for diarrhetic shellfish poisoning (DSP) events in Croatian waters, three different methods were combined: a modified mouse bioassay (MBA) that discriminates YTX from other DSP toxins, the enzyme-linked immunosorbent assay method (ELISA) [...] Read more.
With the aim of investigating whether yessotoxin (YTX) is responsible for diarrhetic shellfish poisoning (DSP) events in Croatian waters, three different methods were combined: a modified mouse bioassay (MBA) that discriminates YTX from other DSP toxins, the enzyme-linked immunosorbent assay method (ELISA) and liquid chromatography-mass spectrometry (LC-MS/MS). Among 453 samples of mussels and seawater analyzed in 2007, 10 samples were DSP positive. Results obtained by the modified MBA method revealed that most of the samples were positive for YTX, with the exception of samples from Lim Bay (LB 1) The ELISA method also identified the presence of YTX in these samples. DSP toxin profiles showed the presence of okadaic acid (OA) in three, and YTX in four out of nine samples that were analyzed by LC-MS/MS. The phytoplankton community structure pattern revealed Lingulodinium polyedrum (Stein) Dodge, which was present in the water prior to and/or during toxicity events at low concentrations (80 to 1440 cells L-1), as a potential YTX producing species. It is proposed that L. polyedrum cells accumulated in mussels and the subsequently observed toxicity may be related to metabolism after ingestion, resulting in carboxy YTX as the major analog in the mussel. Full article
(This article belongs to the Special Issue Algal Toxins)
Open AccessArticle Primary Screening of the Bioactivity of Brackishwater Cyanobacteria: Toxicity of Crude Extracts to Artemia salina Larvae and Paracentrotus lividus Embryos
Mar. Drugs 2010, 8(3), 471-482; doi:10.3390/md8030471
Received: 30 December 2009 / Revised: 18 February 2010 / Accepted: 3 March 2010 / Published: 5 March 2010
Cited by 22 | PDF Full-text (343 KB) | HTML Full-text | XML Full-text
Abstract
Cyanobacteria are a diverse group of Gram-negative bacteria that produce an array of secondary compounds with selective bioactivity against vertebrates, invertebrates, plants, microalgae, fungi, bacteria, viruses and cell lines. The aim of this study was to assess the toxic effects of aqueous, [...] Read more.
Cyanobacteria are a diverse group of Gram-negative bacteria that produce an array of secondary compounds with selective bioactivity against vertebrates, invertebrates, plants, microalgae, fungi, bacteria, viruses and cell lines. The aim of this study was to assess the toxic effects of aqueous, methanolic and hexane crude extracts of benthic and picoplanktonic cyanobacteria isolated from estuarine environments, towards the nauplii of the brine shrimp Artemia salina and embryos of the sea urchin Paracentrotus lividus. The A. salina lethality test was used as a frontline screen and then complemented by the more specific sea urchin embryo-larval assay. Eighteen cyanobacterial isolates, belonging to the genera Cyanobium, Leptolyngbya, Microcoleus, Phormidium, Nodularia, Nostoc and Synechocystis, were tested. Aqueous extracts of cyanobacteria strains showed potent toxicity against A. salina, whereas in P. lividus, methanolic and aqueous extracts showed embryo toxicity, with clear effects on development during early stages. The results suggest that the brackishwater cyanobacteria are producers of bioactive compounds with toxicological effects that may interfere with the dynamics of invertebrate populations. Full article
(This article belongs to the Special Issue Marine Bioactive Compounds Acting on Animal Reproduction)
Open AccessArticle Fluidic Force Discrimination Assays: A New Technology for Tetrodotoxin Detection
Mar. Drugs 2010, 8(3), 565-576; doi:10.3390/md8030565
Received: 3 February 2010 / Revised: 3 March 2010 / Accepted: 5 March 2010 / Published: 10 March 2010
Cited by 8 | PDF Full-text (514 KB) | HTML Full-text | XML Full-text
Abstract
Tetrodotoxin (TTX) is a low molecular weight (~319 Da) neurotoxin found in a number of animal species, including pufferfish. Protection from toxin tainted food stuffs requires rapid, sensitive, and specific diagnostic tests. An emerging technique for the detection of both proteins and [...] Read more.
Tetrodotoxin (TTX) is a low molecular weight (~319 Da) neurotoxin found in a number of animal species, including pufferfish. Protection from toxin tainted food stuffs requires rapid, sensitive, and specific diagnostic tests. An emerging technique for the detection of both proteins and nucleic acids is Fluidic Force Discrimination (FFD) assays. This simple and rapid method typically uses a sandwich immunoassay format labeled with micrometer-diameter beads and has the novel capability of removing nonspecifically attached beads under controlled, fluidic conditions. This technique allows for near real-time, multiplexed analysis at levels of detection that exceed many of the conventional transduction methods (e.g., ELISAs). In addition, the large linear dynamic range afforded by FFD should decrease the need to perform multiple sample dilutions, a common challenge for food testing. By applying FFD assays to an inhibition immunoassay platform specific for TTX and transduction via low magnification microscopy, levels of detection of ~15 ng/mL and linear dynamic ranges of 4 to 5 orders of magnitude were achieved. The results from these studies on the first small molecule FFD assay, along with the impact to detection of seafood toxins, will be discussed in this manuscript. Full article
(This article belongs to the Special Issue Tetrodotoxin)
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Open AccessArticle Regulation of the Spontaneous Augmentation of NaV1.9 in Mouse Dorsal Root Ganglion Neurons: Effect of PKA and PKC Pathways
Mar. Drugs 2010, 8(3), 728-740; doi:10.3390/md8030728
Received: 15 January 2010 / Revised: 8 February 2010 / Accepted: 18 March 2010 / Published: 19 March 2010
Cited by 2 | PDF Full-text (231 KB) | HTML Full-text | XML Full-text
Abstract
Sensory neurons in the dorsal root ganglion express two kinds of tetrodotoxin resistant (TTX-R) isoforms of voltage-gated sodium channels, NaV1.8 and NaV1.9. These isoforms play key roles in the pathophysiology of chronic pain. Of special interest is Na [...] Read more.
Sensory neurons in the dorsal root ganglion express two kinds of tetrodotoxin resistant (TTX-R) isoforms of voltage-gated sodium channels, NaV1.8 and NaV1.9. These isoforms play key roles in the pathophysiology of chronic pain. Of special interest is NaV1.9: our previous studies revealed a unique property of the NaV1.9 current, i.e., the NaV1.9 current shows a gradual and notable up-regulation of the peak amplitude during recording (“spontaneous augmentation of NaV1.9”). However, the mechanism underlying the spontaneous augmentation of NaV1.9 is still unclear. In this study, we examined the effects of protein kinases A and C (PKA and PKC), on the spontaneous augmentation of NaV1.9. The spontaneous augmentation of the NaV1.9 current was significantly suppressed by activation of PKA, whereas activation of PKA did not affect the voltage dependence of inactivation for the NaV1.9 current. On the contrary, the finding that activation of PKC can affect the voltage dependence of inactivation for NaV1.9 in the perforated patch recordings, where the augmentation does not occur, suggests that the effects of PMA are independent of the augmentation process. These results indicate that the spontaneous augmentation of NaV1.9 was regulated directly by PKA, and indirectly by PKC. Full article
(This article belongs to the Special Issue Tetrodotoxin)

Review

Jump to: Research

Open AccessReview Behavioral and Chemical Ecology of Marine Organisms with Respect to Tetrodotoxin
Mar. Drugs 2010, 8(3), 381-398; doi:10.3390/md8030381
Received: 4 February 2010 / Revised: 24 February 2010 / Accepted: 25 February 2010 / Published: 26 February 2010
Cited by 40 | PDF Full-text (151 KB) | HTML Full-text | XML Full-text
Abstract
The behavioral and chemical ecology of marine organisms that possess tetrodotoxin (TTX) has not been comprehensively reviewed in one work to date. The evidence for TTX as an antipredator defense, as venom, as a sex pheromone, and as an attractant for TTX-sequestering [...] Read more.
The behavioral and chemical ecology of marine organisms that possess tetrodotoxin (TTX) has not been comprehensively reviewed in one work to date. The evidence for TTX as an antipredator defense, as venom, as a sex pheromone, and as an attractant for TTX-sequestering organisms is discussed. Little is known about the adaptive value of TTX in microbial producers; thus, I focus on what is known about metazoans that are purported to accumulate TTX through diet or symbioses. Much of what has been proposed is inferred based on the anatomical distribution of TTX. Direct empirical tests of these hypotheses are absent in most cases. Full article
(This article belongs to the Special Issue Tetrodotoxin)
Open AccessReview Development of Novel Drugs from Marine Surface Associated Microorganisms
Mar. Drugs 2010, 8(3), 438-459; doi:10.3390/md8030438
Received: 18 January 2010 / Revised: 3 February 2010 / Accepted: 22 February 2010 / Published: 1 March 2010
Cited by 81 | PDF Full-text (172 KB) | HTML Full-text | XML Full-text
Abstract
While the oceans cover more than 70% of the Earth’s surface, marine derived microbial natural products have been largely unexplored. The marine environment is a habitat for many unique microorganisms, which produce biologically active compounds (“bioactives”) to adapt to particular environmental conditions. [...] Read more.
While the oceans cover more than 70% of the Earth’s surface, marine derived microbial natural products have been largely unexplored. The marine environment is a habitat for many unique microorganisms, which produce biologically active compounds (“bioactives”) to adapt to particular environmental conditions. For example, marine surface associated microorganisms have proven to be a rich source for novel bioactives because of the necessity to evolve allelochemicals capable of protecting the producer from the fierce competition that exists between microorganisms on the surfaces of marine eukaryotes. Chemically driven interactions are also important for the establishment of cross-relationships between microbes and their eukaryotic hosts, in which organisms producing antimicrobial compounds (“antimicrobials”), may protect the host surface against over colonisation in return for a nutrient rich environment. As is the case for bioactive discovery in general, progress in the detection and characterization of marine microbial bioactives has been limited by a number of obstacles, such as unsuitable culture conditions, laborious purification processes, and a lack of de-replication. However many of these limitations are now being overcome due to improved microbial cultivation techniques, microbial (meta-) genomic analysis and novel sensitive analytical tools for structural elucidation. Here we discuss how these technical advances, together with a better understanding of microbial and chemical ecology, will inevitably translate into an increase in the discovery and development of novel drugs from marine microbial sources in the future. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Microbes)
Open AccessReview Synthesis of 3-Alkyl Pyridinium Alkaloids from the Arctic Sponge Haliclona viscosa
Mar. Drugs 2010, 8(3), 483-497; doi:10.3390/md8030483
Received: 21 January 2010 / Revised: 2 March 2010 / Accepted: 2 March 2010 / Published: 5 March 2010
Cited by 10 | PDF Full-text (390 KB) | HTML Full-text | XML Full-text
Abstract
3-Alkyl pyridinium alkaloids (3-APAs) are common secondary metabolites in marine sponges of the order Haplosclerida. In recent years, our laboratory has isolated and synthesized several new members of this family such as haliclamines C–F, viscosamine, viscosaline and a cyclic monomer. All of [...] Read more.
3-Alkyl pyridinium alkaloids (3-APAs) are common secondary metabolites in marine sponges of the order Haplosclerida. In recent years, our laboratory has isolated and synthesized several new members of this family such as haliclamines C–F, viscosamine, viscosaline and a cyclic monomer. All of them were isolated from the Arctic sponge Haliclona viscosa collected in Spitsbergen, Norway. In this article we report the syntheses of these secondary metabolites from Haliclona viscosa and related compounds and give a short overview of the bioactivity. Full article
(This article belongs to the Special Issue Synthesis around Marine Natural Products)
Open AccessReview Novel Anti-Infective Compounds from Marine Bacteria
Mar. Drugs 2010, 8(3), 498-518; doi:10.3390/md8030498
Received: 3 February 2010 / Revised: 1 March 2010 / Accepted: 2 March 2010 / Published: 5 March 2010
Cited by 52 | PDF Full-text (277 KB) | HTML Full-text | XML Full-text
Abstract
As a result of the continuous evolution of microbial pathogens towards antibiotic-resistance, there have been demands for the development of new and effective antimicrobial compounds. Since the 1960s, the scientific literature has accumulated many publications about novel pharmaceutical compounds produced by a [...] Read more.
As a result of the continuous evolution of microbial pathogens towards antibiotic-resistance, there have been demands for the development of new and effective antimicrobial compounds. Since the 1960s, the scientific literature has accumulated many publications about novel pharmaceutical compounds produced by a diverse range of marine bacteria. Indeed, marine micro-organisms continue to be a productive and successful focus for natural products research, with many newly isolated compounds possessing potentially valuable pharmacological activities. In this regard, the marine environment will undoubtedly prove to be an increasingly important source of novel antimicrobial metabolites, and selective or targeted approaches are already enabling the recovery of a significant number of antibiotic-producing micro-organisms. The aim of this review is to consider advances made in the discovery of new secondary metabolites derived from marine bacteria, and in particular those effective against the so called “superbugs”, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), which are largely responsible for the increase in numbers of hospital acquired, i.e., nosocomial, infections. Full article
(This article belongs to the Special Issue Marine Anti-infective Agents)
Open AccessReview Finding New Enzymes from Bacterial Physiology: A Successful Approach Illustrated by the Detection of Novel Oxidases in Marinomonas mediterranea
Mar. Drugs 2010, 8(3), 519-541; doi:10.3390/md8030519
Received: 10 February 2010 / Revised: 21 February 2010 / Accepted: 22 February 2010 / Published: 5 March 2010
Cited by 10 | PDF Full-text (934 KB) | HTML Full-text | XML Full-text
Abstract
The identification and study of marine microorganisms with unique physiological traits can be a very powerful tool discovering novel enzymes of possible biotechnological interest. This approach can complement the enormous amount of data concerning gene diversity in marine environments offered by metagenomic [...] Read more.
The identification and study of marine microorganisms with unique physiological traits can be a very powerful tool discovering novel enzymes of possible biotechnological interest. This approach can complement the enormous amount of data concerning gene diversity in marine environments offered by metagenomic analysis, and can help to place the activities associated with those sequences in the context of microbial cellular metabolism and physiology. Accordingly, the detection and isolation of microorganisms that may be a good source of enzymes is of great importance. Marinomonas mediterranea, for example, has proven to be one such useful microorganism. This Gram-negative marine bacterium was first selected because of the unusually high amounts of melanins synthesized in media containing the amino acid L-tyrosine. The study of its molecular biology has allowed the cloning of several genes encoding oxidases of biotechnological interest, particularly in white and red biotechnology. Characterization of the operon encoding the tyrosinase responsible for melanin synthesis revealed that a second gene in that operon encodes a protein, PpoB2, which is involved in copper transfer to tyrosinase. This finding made PpoB2 the first protein in the COG5486 group to which a physiological role has been assigned. Another enzyme of interest described in M. mediterranea is a multicopper oxidase encoding a membrane-associated enzyme that shows oxidative activity on a wide range of substrates typical of both laccases and tyrosinases. Finally, an enzyme very specific for L-lysine, which oxidises this amino acid in epsilon position and that has received a new EC number (1.4.3.20), has also been described for M. mediterranea. Overall, the studies carried out on this bacterium illustrate the power of exploring the physiology of selected microorganisms to discover novel enzymes of biotechnological relevance. Full article
(This article belongs to the Special Issue Enzymes from the Sea: Sources, Molecular Biology and Bioprocesses)
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Open AccessReview Cylindrospermopsin: A Decade of Progress on Bioaccumulation Research
Mar. Drugs 2010, 8(3), 542-564; doi:10.3390/md8030542
Received: 9 February 2010 / Revised: 3 March 2010 / Accepted: 8 March 2010 / Published: 9 March 2010
Cited by 75 | PDF Full-text (241 KB) | HTML Full-text | XML Full-text
Abstract
Cylindrospermopsin (CYN) is rapidly being recognised as one of the most globally important of the freshwater algal toxins. The ever-expanding distribution of CYN producers into temperate zones is heightening concern that this toxin will represent serious human, as well as environmental, health [...] Read more.
Cylindrospermopsin (CYN) is rapidly being recognised as one of the most globally important of the freshwater algal toxins. The ever-expanding distribution of CYN producers into temperate zones is heightening concern that this toxin will represent serious human, as well as environmental, health risks across many countries. Since 1999, a number of studies have demonstrated the ability for CYN to bioaccumulate in freshwater organisms. This paper synthesizes the most current information on CYN accumulation, including notes on the global distribution of CYN producers, and a précis of CYN’s ecological and human effects. Studies on the bioaccumulation of CYN are systematically reviewed, together with an analysis of patterns of accumulation. A discussion on the factors influencing bioaccumulation rates and potential is also provided, along with notes on detection, monitoring and risk assessments. Finally, key gaps in the existing research are identified for future study. Full article
(This article belongs to the Special Issue Algal Toxins)
Open AccessReview The Chemical and Evolutionary Ecology of Tetrodotoxin (TTX) Toxicity in Terrestrial Vertebrates
Mar. Drugs 2010, 8(3), 577-593; doi:10.3390/md8030577
Received: 24 February 2010 / Revised: 3 March 2010 / Accepted: 8 March 2010 / Published: 10 March 2010
Cited by 51 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Tetrodotoxin (TTX) is widely distributed in marine taxa, however in terrestrial taxa it is limited to a single class of vertebrates (Amphibia). Tetrodotoxin present in the skin and eggs of TTX-bearing amphibians primarily serves as an antipredator defense and these taxa have [...] Read more.
Tetrodotoxin (TTX) is widely distributed in marine taxa, however in terrestrial taxa it is limited to a single class of vertebrates (Amphibia). Tetrodotoxin present in the skin and eggs of TTX-bearing amphibians primarily serves as an antipredator defense and these taxa have provided excellent models for the study of the evolution and chemical ecology of TTX toxicity. The origin of TTX present in terrestrial vertebrates is controversial. In marine organisms the accepted hypothesis is that the TTX present in metazoans results from either dietary uptake of bacterially produced TTX or symbiosis with TTX producing bacteria, but this hypothesis may not be applicable to TTX-bearing amphibians. Here I review the taxonomic distribution and evolutionary ecology of TTX in amphibians with some attention to the origin of TTX present in these taxa. Full article
(This article belongs to the Special Issue Tetrodotoxin)
Open AccessReview Structure and Function of Lactate Dehydrogenase from Hagfish
Mar. Drugs 2010, 8(3), 594-607; doi:10.3390/md8030594
Received: 8 January 2010 / Revised: 3 February 2010 / Accepted: 11 March 2010 / Published: 15 March 2010
Cited by 2 | PDF Full-text (1245 KB) | HTML Full-text | XML Full-text
Abstract
The lactate dehydrogenases (LDHs) in hagfish have been estimated to be the prototype of those in higher vertebrates. The effects of high hydrostatic pressure from 0.1 to 100 MPa on LDH activities from three hagfishes were examined. The LDH activities of Eptatretus [...] Read more.
The lactate dehydrogenases (LDHs) in hagfish have been estimated to be the prototype of those in higher vertebrates. The effects of high hydrostatic pressure from 0.1 to 100 MPa on LDH activities from three hagfishes were examined. The LDH activities of Eptatretus burgeri, living at 45–60 m, were completely lost at 5 MPa. In contrast, LDH-A and -B in Eptatretus okinoseanus maintained 70% of their activities even at 100 MPa. These results show that the deeper the habitat, the higher the tolerance to pressure. To elucidate the molecular mechanisms for adaptation to high pressure, we compared the amino acid sequences and three-dimensional structures of LDHs in these hagfish. There were differences in six amino acids (6, 10, 20, 156, 269, and 341). These amino acidresidues are likely to contribute to the stability of the E. okinoseanus LDH under high-pressure conditions. The amino acids responsible for the pressure tolerance of hagfish are the same in both human and hagfish LDHs, and one substitution that occurred as an adaptation during evolution is coincident with that observed in a human disease. Mutation of these amino acids can cause anomalies that may be implicated in the development of human diseases. Full article
(This article belongs to the Special Issue Enzymes from the Sea: Sources, Molecular Biology and Bioprocesses)
Open AccessReview Marine Metagenomics: New Tools for the Study and Exploitation of Marine Microbial Metabolism
Mar. Drugs 2010, 8(3), 608-628; doi:10.3390/md8030608
Received: 20 January 2010 / Revised: 4 February 2010 / Accepted: 12 March 2010 / Published: 15 March 2010
Cited by 59 | PDF Full-text (608 KB) | HTML Full-text | XML Full-text
Abstract
The marine environment is extremely diverse, with huge variations in pressure and temperature. Nevertheless, life, especially microbial life, thrives throughout the marine biosphere and microbes have adapted to all the divergent environments present. Large scale DNA sequence based approaches have recently been [...] Read more.
The marine environment is extremely diverse, with huge variations in pressure and temperature. Nevertheless, life, especially microbial life, thrives throughout the marine biosphere and microbes have adapted to all the divergent environments present. Large scale DNA sequence based approaches have recently been used to investigate the marine environment and these studies have revealed that the oceans harbor unprecedented microbial diversity. Novel gene families with representatives only within such metagenomic datasets represent a large proportion of the ocean metagenome. The presence of so many new gene families from these uncultured and highly diverse microbial populations represents a challenge for the understanding of and exploitation of the biology and biochemistry of the ocean environment. The application of new metagenomic and single cell genomics tools offers new ways to explore the complete metabolic diversity of the marine biome. Full article
(This article belongs to the Special Issue Enzymes from the Sea: Sources, Molecular Biology and Bioprocesses)
Open AccessReview Cyanobacterial Cyclopeptides as Lead Compounds to Novel Targeted Cancer Drugs
Mar. Drugs 2010, 8(3), 629-657; doi:10.3390/md8030629
Received: 4 January 2010 / Revised: 10 February 2010 / Accepted: 26 February 2010 / Published: 15 March 2010
Cited by 32 | PDF Full-text (583 KB) | HTML Full-text | XML Full-text
Abstract
Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via [...] Read more.
Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives. Full article
(This article belongs to the Special Issue Algal Toxins)
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Open AccessReview Targets and Effects of Yessotoxin, Okadaic Acid and Palytoxin: A Differential Review
Mar. Drugs 2010, 8(3), 658-677; doi:10.3390/md8030658
Received: 8 January 2010 / Revised: 9 February 2010 / Accepted: 10 February 2010 / Published: 16 March 2010
Cited by 18 | PDF Full-text (657 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we focus on processes, organs and systems targeted by the marine toxins yessotoxin (YTX), okadaic acid (OA) and palytoxin (PTX). The effects of YTX and their basis are analyzed from data collected in the mollusc Mytilus galloprovincialis, the [...] Read more.
In this review, we focus on processes, organs and systems targeted by the marine toxins yessotoxin (YTX), okadaic acid (OA) and palytoxin (PTX). The effects of YTX and their basis are analyzed from data collected in the mollusc Mytilus galloprovincialis, the annelid Enchytraeus crypticus, Swiss CD1 mice and invertebrate and vertebrate cell cultures. OA and PTX, two toxins with a better established mode of action, are analyzed with regard to their effects on development. The amphibian Xenopus laevis is used as a model, and the Frog Embryo Teratogenesis Assay-Xenopus (FETAX) as the experimental protocol. Full article
(This article belongs to the Special Issue Marine Biotoxins: Novel Issues about Old Compounds)
Open AccessReview Prymnesins: Toxic Metabolites of the Golden Alga, Prymnesium parvum Carter (Haptophyta)
Mar. Drugs 2010, 8(3), 678-704; doi:10.3390/md8030678
Received: 6 January 2010 / Revised: 9 March 2010 / Accepted: 10 March 2010 / Published: 16 March 2010
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Abstract
Increasingly over the past century, seasonal fish kills associated with toxic blooms of Prymnesium parvum have devastated aquaculture and native fish, shellfish, and mollusk populations worldwide. Protracted blooms of P. parvum can result in major disturbances to the local ecology and extensive [...] Read more.
Increasingly over the past century, seasonal fish kills associated with toxic blooms of Prymnesium parvum have devastated aquaculture and native fish, shellfish, and mollusk populations worldwide. Protracted blooms of P. parvum can result in major disturbances to the local ecology and extensive monetary losses. Toxicity of this alga is attributed to a collection of compounds known as prymnesins, which exhibit potent cytotoxic, hemolytic, neurotoxic and ichthyotoxic effects. These secondary metabolites are especially damaging to gill-breathing organisms and they are believed to interact directly with plasma membranes, compromising integrity by permitting ion leakage. Several factors appear to function in the activation and potency of prymnesins including salinity, pH, ion availability, and growth phase. Prymnesins may function as defense compounds to prevent herbivory and some investigations suggest that they have allelopathic roles. Since the last extensive review was published, two prymnesins have been chemically characterized and ongoing investigations are aimed at the purification and analysis of numerous other toxic metabolites from this alga. More information is needed to unravel the mechanisms of prymnesin synthesis and the significance of these metabolites. Such work should greatly improve our limited understanding of the physiology and biochemistry of P. parvum and how to mitigate its blooms. Full article
(This article belongs to the Special Issue Algal Toxins)
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Open AccessReview Production of Metabolites as Bacterial Responses to the Marine Environment
Mar. Drugs 2010, 8(3), 705-727; doi:10.3390/md8030705
Received: 28 January 2010 / Revised: 26 February 2010 / Accepted: 16 March 2010 / Published: 17 March 2010
Cited by 45 | PDF Full-text (196 KB) | HTML Full-text | XML Full-text
Abstract
Bacteria in marine environments are often under extreme conditions of e.g., pressure, temperature, salinity, and depletion of micronutrients, with survival and proliferation often depending on the ability to produce biologically active compounds. Some marine bacteria produce biosurfactants, which help to transport hydrophobic [...] Read more.
Bacteria in marine environments are often under extreme conditions of e.g., pressure, temperature, salinity, and depletion of micronutrients, with survival and proliferation often depending on the ability to produce biologically active compounds. Some marine bacteria produce biosurfactants, which help to transport hydrophobic low water soluble substrates by increasing their bioavailability. However, other functions related to heavy metal binding, quorum sensing and biofilm formation have been described. In the case of metal ions, bacteria developed a strategy involving the release of binding agents to increase their bioavailability. In the particular case of the Fe3+ ion, which is almost insoluble in water, bacteria secrete siderophores that form soluble complexes with the ion, allowing the cells to uptake the iron required for cell functioning. Adaptive changes in the lipid composition of marine bacteria have been observed in response to environmental variations in pressure, temperature and salinity. Some fatty acids, including docosahexaenoic and eicosapentaenoic acids, have only been reported in prokaryotes in deep-sea bacteria. Cell membrane permeability can also be adapted to extreme environmental conditions by the production of hopanoids, which are pentacyclic triterpenoids that have a function similar to cholesterol in eukaryotes. Bacteria can also produce molecules that prevent the attachment, growth and/or survival of challenging organisms in competitive environments. The production of these compounds is particularly important in surface attached strains and in those in biofilms. The wide array of compounds produced by marine bacteria as an adaptive response to demanding conditions makes them suitable candidates for screening of compounds with commercially interesting biological functions. Biosurfactants produced by marine bacteria may be helpful to increase mass transfer in different industrial processes and in the bioremediation of hydrocarbon-contaminated sites. Siderophores are necessary e.g., in the treatment of diseases with metal ion imbalance, while antifouling compounds could be used to treat man-made surfaces that are used in marine environments. New classes of antibiotics could efficiently combat bacteria resistant to the existing antibiotics. The present work aims to provide a comprehensive review of the metabolites produced by marine bacteria in order to cope with intrusive environments, and to illustrate how such metabolites can be advantageously used in several relevant areas, from bioremediation to health and pharmaceutical sectors. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Microbes)
Open AccessReview Effects of Tetrodotoxin on the Mammalian Cardiovascular System
Mar. Drugs 2010, 8(3), 741-762; doi:10.3390/md8030741
Received: 3 February 2010 / Revised: 11 February 2010 / Accepted: 18 March 2010 / Published: 19 March 2010
Cited by 21 | PDF Full-text (115 KB) | HTML Full-text | XML Full-text
Abstract
The human genome encodes nine functional voltage-gated Na+ channels. Three of them, namely Nav1.5, Nav1.8, and Nav1.9, are resistant to nanomolar concentrations of tetrodotoxin (TTX; IC50 ≥ 1 μM). The other isoforms, which are [...] Read more.
The human genome encodes nine functional voltage-gated Na+ channels. Three of them, namely Nav1.5, Nav1.8, and Nav1.9, are resistant to nanomolar concentrations of tetrodotoxin (TTX; IC50 ≥ 1 μM). The other isoforms, which are predominantly expressed in the skeletal muscle and nervous system, are highly sensitive to TTX (IC50 ~ 10 nM). During the last two decades, it has become evident that in addition to the major cardiac isoform Nav1.5, several of those TTX sensitive isoforms are expressed in the mammalian heart. Whereas immunohistochemical and electrophysiological methods demonstrated functional expression in various heart regions, the physiological importance of those isoforms for cardiac excitation in higher mammals is still debated. This review summarizes our knowledge on the systemic cardiovascular effects of TTX in animals and humans, with a special focus on cardiac excitation and performance at lower concentrations of this marine drug. Altogether, these data strongly suggest that TTX sensitive Na+ channels, detected more recently in various heart tissues, are not involved in excitation phenomena in the healthy adult heart of higher mammals. Full article
(This article belongs to the Special Issue Tetrodotoxin)
Open AccessReview Synthesis of Marine Polycyclic Polyethers via Endo-Selective Epoxide-Opening Cascades
Mar. Drugs 2010, 8(3), 763-809; doi:10.3390/md8030763
Received: 25 February 2010 / Revised: 11 March 2010 / Accepted: 18 March 2010 / Published: 19 March 2010
Cited by 26 | PDF Full-text (3185 KB) | HTML Full-text | XML Full-text
Abstract
The proposed biosynthetic pathways to ladder polyethers of polyketide origin and oxasqualenoids of terpenoid origin share a dramatic epoxide-opening cascade as a key step. Polycyclic structures generated in these biosynthetic pathways display biological effects ranging from potentially therapeutic properties to extreme lethality. [...] Read more.
The proposed biosynthetic pathways to ladder polyethers of polyketide origin and oxasqualenoids of terpenoid origin share a dramatic epoxide-opening cascade as a key step. Polycyclic structures generated in these biosynthetic pathways display biological effects ranging from potentially therapeutic properties to extreme lethality. Much of the structural complexity of ladder polyether and oxasqualenoid natural products can be traced to these hypothesized cascades. In this review we summarize how such epoxide-opening cascade reactions have been used in the synthesis of ladder polyethers and oxasqualenoid natural products. Full article
(This article belongs to the Special Issue Marine Dinoflagellates)
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Open AccessReview Cyclodepsipeptides from Marine Sponges: Natural Agents for Drug Research
Mar. Drugs 2010, 8(3), 810-834; doi:10.3390/md8030810
Received: 5 February 2010 / Revised: 4 March 2010 / Accepted: 19 March 2010 / Published: 22 March 2010
Cited by 50 | PDF Full-text (180 KB) | HTML Full-text | XML Full-text
Abstract
A number of natural products from marine sponges, such as cyclodepsipeptides, have been identified. The structural characteristics of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of [...] Read more.
A number of natural products from marine sponges, such as cyclodepsipeptides, have been identified. The structural characteristics of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of marine sponge derived cyclic depsipeptides, including callipeltin A, celebesides A and B, homophymine A, mirabamides, microspinosamide, neamphamide A and theopapuamides. They are thought to have cytoprotective activity against HIV-1 in vitro by inhibiting viral entry. Jasplakinolide, a representative member of marine sponge-derived cyclodepsipeptides that include arenastatin A, geodiamolides, homophymines, spongidepsin and theopapuamides, is a potent inducer of actin polymerization in vitro. Although actin dynamics is essential for tumor metasasis, no actin targeting drugs have been used in clinical trials due to their severe cytotoxicity. Nonetheless, the actin cytoskeleton remains a potential target for anti-cancer drug development. These features imply the use of cyclodepsipeptides as molecular models in drug research. Full article
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)

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