Marine Drugs

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Open AccessArticle

BMAA Inhibits Nitrogen Fixation in the Cyanobacterium Nostoc sp. PCC 7120

by Lotta Berntzon, Sven Erasmie, Narin Celepli, Johan Eriksson, Ulla Rasmussen and Birgitta Bergman

Mar. Drugs 2013, 11(8), 3091-3108; https://doi.org/10.3390/md11083091 - 21 Aug 2013

Cited by 51 | Viewed by 10556

Abstract

Cyanobacteria produce a range of secondary metabolites, one being the neurotoxic non-protein amino acid β-N-methylamino-L-alanine (BMAA), proposed to be a causative agent of human neurodegeneration. As for most cyanotoxins, the function of BMAA in cyanobacteria is unknown. Here, we examined the [...] Read more.

Cyanobacteria produce a range of secondary metabolites, one being the neurotoxic non-protein amino acid β-N-methylamino-L-alanine (BMAA), proposed to be a causative agent of human neurodegeneration. As for most cyanotoxins, the function of BMAA in cyanobacteria is unknown. Here, we examined the effects of BMAA on the physiology of the filamentous nitrogen-fixing cyanobacterium Nostoc sp. PCC 7120. Our data show that exogenously applied BMAA rapidly inhibits nitrogenase activity (acetylene reduction assay), even at micromolar concentrations, and that the inhibition was considerably more severe than that induced by combined nitrogen sources and most other amino acids. BMAA also caused growth arrest and massive cellular glycogen accumulation, as observed by electron microscopy. With nitrogen fixation being a process highly sensitive to oxygen species we propose that the BMAA effects found here may be related to the production of reactive oxygen species, as reported for other organisms. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Open AccessArticle

Double Strand Breaks and Cell-Cycle Arrest Induced by the Cyanobacterial Toxin Cylindrospermopsin in HepG2 Cells

by Štraser Alja, Metka Filipič, Matjaž Novak and Bojana Žegura

Mar. Drugs 2013, 11(8), 3077-3090; https://doi.org/10.3390/md11083077 - 21 Aug 2013

Cited by 44 | Viewed by 9284

Abstract

The newly emerging cyanobacterial cytotoxin cylindrospermopsin (CYN) is increasingly found in surface freshwaters, worldwide. It poses a potential threat to humans after chronic exposure as it was shown to be genotoxic in a range of test systems and is potentially carcinogenic. However, the [...] Read more.

The newly emerging cyanobacterial cytotoxin cylindrospermopsin (CYN) is increasingly found in surface freshwaters, worldwide. It poses a potential threat to humans after chronic exposure as it was shown to be genotoxic in a range of test systems and is potentially carcinogenic. However, the mechanisms of CYN toxicity and genotoxicity are not well understood. In the present study CYN induced formation of DNA double strand breaks (DSBs), after prolonged exposure (72 h), in human hepatoma cells, HepG2. CYN (0.1–0.5 µg/mL, 24–96 h) induced morphological changes and reduced cell viability in a dose and time dependent manner. No significant increase in lactate dehydrogenase (LDH) leakage could be observed after CYN exposure, indicating that the reduction in cell number was due to decreased cell proliferation and not due to cytotoxicity. This was confirmed by imunocytochemical analysis of the cell-proliferation marker Ki67. Analysis of the cell-cycle using flow-cytometry showed that CYN has an impact on the cell cycle, indicating G0/G1 arrest after 24 h and S-phase arrest after longer exposure (72 and 96 h). Our results provide new evidence that CYN is a direct acting genotoxin, causing DSBs, and these facts need to be considered in the human health risk assessment. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Open AccessArticle

Cytotoxic Anthranilic Acid Derivatives from Deep Sea Sediment-Derived Fungus Penicillium paneum SD-44

by Chun-Shun Li, Xiao-Ming Li, Shu-Shan Gao, Yan-Hua Lu and Bin-Gui Wang

Mar. Drugs 2013, 11(8), 3068-3076; https://doi.org/10.3390/md11083068 - 21 Aug 2013

Cited by 64 | Viewed by 8741

Abstract

Five new anthranilic acid derivatives, penipacids A–E (1–5), together with one known analogue (6), which was previously synthesized, were characterized from the ethyl acetate extract of the marine sediment-derived fungus Penicillium paneum SD-44. Their structures were elucidated [...] Read more.

Five new anthranilic acid derivatives, penipacids A–E (1–5), together with one known analogue (6), which was previously synthesized, were characterized from the ethyl acetate extract of the marine sediment-derived fungus Penicillium paneum SD-44. Their structures were elucidated mainly by extensive NMR spectroscopic and mass spectrometric analysis. The cytotoxicity and antimicrobial activity of the isolated compounds were evaluated. Compounds 1, and 5 exhibited inhibitory activity against human colon cancer RKO cell line, while compound 6 displayed cytotoxic activity against Hela cell line. Full article

(This article belongs to the Collection Marine Compounds and Cancer)

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Open AccessArticle

An Aeroplysinin-1 Specific Nitrile Hydratase Isolated from the Marine Sponge Aplysina cavernicola

by Bartosz Lipowicz, Nils Hanekop, Lutz Schmitt and Peter Proksch

Mar. Drugs 2013, 11(8), 3046-3067; https://doi.org/10.3390/md11083046 - 21 Aug 2013

Cited by 17 | Viewed by 7905

Abstract

A nitrile hydratase (NHase) that specifically accepts the nitrile aeroplysinin-1 (1) as a substrate and converts it into the dienone amide verongiaquinol (7) was isolated, partially purified and characterized from the Mediterranean sponge Aplysina cavernicola; although it is [...] Read more.

A nitrile hydratase (NHase) that specifically accepts the nitrile aeroplysinin-1 (1) as a substrate and converts it into the dienone amide verongiaquinol (7) was isolated, partially purified and characterized from the Mediterranean sponge Aplysina cavernicola; although it is currently not known whether the enzyme is of sponge origin or produced by its symbiotic microorganisms. The formation of aeroplysinin-1 and of the corresponding dienone amide is part of the chemical defence system of A. cavernicola. The latter two compounds that show strong antibiotic activity originate from brominated isoxazoline alkaloids that are thought to protect the sponges from invasion of bacterial pathogens. The sponge was shown to contain at least two NHases as two excised protein bands from a non denaturating Blue Native gel showed nitrile hydratase activity, which was not observed for control samples. The enzymes were shown to be manganese dependent, although cobalt and nickel ions were also able to recover the activity of the nitrile hydratases. The temperature and pH optimum of the studied enzymes were found at 41 °C and pH 7.8. The enzymes showed high substrate specificity towards the physiological substrate aeroplysinin-1 (1) since none of the substrate analogues that were prepared either by partial or by total synthesis were converted in an in vitro assay. Moreover de-novo sequencing by mass spectrometry was employed to obtain information about the primary structure of the studied NHases, which did not reveal any homology to known NHases. Full article

(This article belongs to the Special Issue Enzymes from the Sea: Sources, Molecular Biology and Bioprocesses)

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Open AccessArticle

Structural Characterization of New Microcystins Containing Tryptophan and Oxidized Tryptophan Residues

by Jonathan Puddick, Michèle R. Prinsep, Susanna A. Wood, Christopher O. Miles, Frode Rise, Stephen Craig Cary, David P. Hamilton and Alistair L. Wilkins

Mar. Drugs 2013, 11(8), 3025-3045; https://doi.org/10.3390/md11083025 - 21 Aug 2013

Cited by 22 | Viewed by 13018

Abstract

Microcystins are cyclic peptides produced by cyanobacteria, which can be harmful to humans and animals when ingested. Eight of the (more than) 90 microcystin variants presently characterized, contain the amino acid tryptophan. The well-researched oxidation products of tryptophan; kynurenine, oxindolylalanine, and N-formylkynurenine, [...] Read more.

Microcystins are cyclic peptides produced by cyanobacteria, which can be harmful to humans and animals when ingested. Eight of the (more than) 90 microcystin variants presently characterized, contain the amino acid tryptophan. The well-researched oxidation products of tryptophan; kynurenine, oxindolylalanine, and N-formylkynurenine, have been previously identified in intact polypeptides but microcystin congeners containing oxidized tryptophan moieties have not been reported. Liquid chromatography-tandem mass spectrometric analysis of an extract of Microcystis CAWBG11 led to the tentative identification of two new tryptophan-containing microcystins (MC‑WAba and MC-WL), as well as eight other microcystin analogs containing kynurenine, oxindolylalanine and N‑formylkynurenine (Nfk). Investigation of one of these congeners (MC‑NfkA) by nuclear magnetic resonance spectroscopy was used to verify the presence of Nfk in the microcystin. Liquid chromatography-mass spectrometry analysis of a tryptophan oxidation experiment demonstrated that tryptophan-containing microcystins could be converted into oxidized tryptophan analogs and that low levels of oxidized tryptophan congeners were present intracellularly in CAWBG11. MC-NfkR and MC-LNfk were detected in standards of MC-WR and MC-LW, indicating that care during storage of tryptophan-containing microcystins is required. Full article

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Open AccessArticle

Bouillonamide: A Mixed Polyketide–Peptide Cytotoxin from the Marine Cyanobacterium Moorea bouillonii

by Lik Tong Tan, Tatsufumi Okino and William H. Gerwick

Mar. Drugs 2013, 11(8), 3015-3024; https://doi.org/10.3390/md11083015 - 19 Aug 2013

Cited by 18 | Viewed by 8211

Abstract

The tropical marine cyanobacterium, Moorea bouillonii, has gained recent attention as a rich source of bioactive natural products. Continued chemical investigation of this cyanobacterium, collected from New Britain, Papua New Guinea, yielded a novel cytotoxic cyclic depsipeptide, bouillonamide (1), along [...] Read more.

The tropical marine cyanobacterium, Moorea bouillonii, has gained recent attention as a rich source of bioactive natural products. Continued chemical investigation of this cyanobacterium, collected from New Britain, Papua New Guinea, yielded a novel cytotoxic cyclic depsipeptide, bouillonamide (1), along with previously reported molecules, ulongamide A and apratoxin A. Planar structure of bouillonamide was established by extensive 1D and 2D NMR experiments, including multi-edited HSQC, TOCSY, HBMC, and ROESY experiments. In addition to the presence of α-amino acid residues, compound 1 contained two unique polyketide-derived moieties, namely a 2-methyl-6-methylamino-hex-5-enoic acid (Mmaha) residue and a unit of 3-methyl-5-hydroxy-heptanoic acid (Mhha). Absolute stereochemistry of the α-amino acid units in bouillonamide was determined mainly by Marfey’s analysis. Compound 1 exhibited mild toxicity with IC₅₀’s of 6.0 µM against the neuron 2a mouse neuroblastoma cells. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Open AccessArticle

Fucoidans as Potential Inhibitors of HIV-1

by Maria M. Prokofjeva, Tatyana I. Imbs, Natalya M. Shevchenko, Pavel V. Spirin, Stefan Horn, Boris Fehse, Tatyana N. Zvyagintseva and Vladimir S. Prassolov

Mar. Drugs 2013, 11(8), 3000-3014; https://doi.org/10.3390/md11083000 - 19 Aug 2013

Cited by 65 | Viewed by 8124

Abstract

The antiviral activity of different structure fucoidans (α-l-fucans and galactofucans) was studied using two model viral systems based on a lentiviral vectors and a replication competent Moloney murine leukemia virus (Mo-MuLV). It was found that investigated fucoidans have no cytotoxic effects on Jurkat [...] Read more.

The antiviral activity of different structure fucoidans (α-l-fucans and galactofucans) was studied using two model viral systems based on a lentiviral vectors and a replication competent Moloney murine leukemia virus (Mo-MuLV). It was found that investigated fucoidans have no cytotoxic effects on Jurkat and SC-1cell at the concentration range of 0.001–100 µg/mL. Fucoidans with different efficiency suppressed transduction of Jurkat cell line by pseudo-HIV-1 particles carrying the envelope protein of HIV-1 and infection of SC-1 cells by Mo-MuLV. According to our data, all natural fucoidans can be considered as potential anti-HIV agents regardless of their carbohydrate backbone and degree of sulfating, since their activity is shown at low concentrations (0.001–0.05 µg/mL). High molecular weight fucoidans isolated from Saccharina cichorioides (1.3-α-l-fucan), and S. japonica (galactofucan) were the most effective inhibitors. Full article

(This article belongs to the Special Issue Selected Papers from the 1st Symposium on Marine Enzymes and Polysaccharides)

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Open AccessArticle

The Anticancer Effect of Fucoidan in PC-3 Prostate Cancer Cells

by Hye-Jin Boo, Ji-Young Hong, Sang-Cheol Kim, Jung-Il Kang, Min-Kyoung Kim, Eun-Ji Kim, Jin-Won Hyun, Young-Sang Koh, Eun-Sook Yoo, Jung-Mi Kwon and Hee-Kyoung Kang

Mar. Drugs 2013, 11(8), 2982-2999; https://doi.org/10.3390/md11082982 - 19 Aug 2013

Cited by 117 | Viewed by 12272

Abstract

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from [...] Read more.

Fucoidan, a sulfated polysaccharide, has a variety of biological activities, such as anti-cancer, anti-angiogenic and anti-inflammatory. However, the mechanisms of action of fucoidan as an anti-cancer agent have not been fully elucidated. The present study examined the anti-cancer effect of fucoidan obtained from Undaria pinnatifida in PC-3 cells, human prostate cancer cells. Fucoidan induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways. The induction of apoptosis was accompanied by the activation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK1/2 MAPK) and the inactivation of p38 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, fucoidan also induced the up-regulation of p21^Cip1/Waf and down-regulation of E2F-1 cell-cycle-related proteins. Furthermore, in the Wnt/β-catenin pathway, fucoidan activated GSK-3β that resulted in the decrease of β-catenin level, followed by the decrease of c-myc and cyclin D1 expressions, target genes of β-catenin in PC-3 cells. These results suggested that fucoidan treatment could induce intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, the inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the down-regulation of Wnt/β-catenin signaling pathway in PC-3 prostate cancer cells. These data support that fucoidan might have potential for the treatment of prostate cancer. Full article

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Open AccessArticle

Climate Variability and Oceanographic Settings Associated with Interannual Variability in the Initiation of Dinophysis acuminata Blooms

by Patricio A. Díaz, Beatriz Reguera, Manuel Ruiz-Villarreal, Yolanda Pazos, Lourdes Velo-Suárez, Henrick Berger and Marc Sourisseau

Mar. Drugs 2013, 11(8), 2964-2981; https://doi.org/10.3390/md11082964 - 16 Aug 2013

Cited by 47 | Viewed by 8837

Abstract

In 2012, there were exceptional blooms of D. acuminata in early spring in what appeared to be a mesoscale event affecting Western Iberia and the Bay of Biscay. The objective of this work was to identify common climatic patterns to explain the observed [...] Read more.

In 2012, there were exceptional blooms of D. acuminata in early spring in what appeared to be a mesoscale event affecting Western Iberia and the Bay of Biscay. The objective of this work was to identify common climatic patterns to explain the observed anomalies in two important aquaculture sites, the Galician Rías Baixas (NW Spain) and Arcachon Bay (SW France). Here, we examine climate variability through physical-biological couplings, Sea Surface Temperature (SST) anomalies and time of initiation of the upwelling season and its intensity over several decades. In 2012, the mesoscale features common to the two sites were positive anomalies in SST and unusual wind patterns. These led to an atypical predominance of upwelling in winter in the Galician Rías, and increased haline stratification associated with a southward advection of the Gironde plume in Arcachon Bay. Both scenarios promoted an early phytoplankton growth season and increased stability that enhanced D. acuminata growth. Therefore, a common climate anomaly caused exceptional blooms of D. acuminata in two distant regions through different triggering mechanisms. These results increase our capability to predict intense diarrhetic shellfish poisoning outbreaks in the early spring from observations in the preceding winter. Full article

(This article belongs to the Special Issue Selected Papers from Canadian Diarrhetic Shellfish Poisoning Symposium)

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Open AccessArticle

Growth and Saxitoxin Production by Cylindrospermopsis raciborskii (Cyanobacteria) Correlate with Water Hardness

by Ronaldo Leal Carneiro, Ana Beatriz Furlanetto Pacheco and Sandra Maria Feliciano De Oliveira e Azevedo

Mar. Drugs 2013, 11(8), 2949-2963; https://doi.org/10.3390/md11082949 - 15 Aug 2013

Cited by 36 | Viewed by 9061

Abstract

The cosmopolitan and increasing distribution of Cylindrospermopsis raciborskii can be attributed to its ecophysiological plasticity and tolerance to changing environmental factors in water bodies. In reservoirs in the semi-arid region of Brazil, the presence and common dominance of C. raciborskii have been described [...] Read more.

The cosmopolitan and increasing distribution of Cylindrospermopsis raciborskii can be attributed to its ecophysiological plasticity and tolerance to changing environmental factors in water bodies. In reservoirs in the semi-arid region of Brazil, the presence and common dominance of C. raciborskii have been described in waters that are considered hard. We investigated the response of a Brazilian C. raciborskii strain to water hardness by evaluating its growth and saxitoxin production. Based on environmental data, a concentration of 5 mM of different carbonate salts was tested. These conditions affected growth either positively (MgCO₃) or negatively (CaCO₃ and Na₂CO₃). As a control for the addition of cations, MgCl₂, CaCl₂ and NaCl were tested at 5 or 10 mM, and MgCl₂ stimulated growth, NaCl slowed but sustained growth, and CaCl₂ inhibited growth. Most of the tested treatments increased the saxitoxin (STX) cell quota after six days of exposure. After 12 days, STX production returned to concentrations similar to that of the control, indicating an adaptation to the altered water conditions. In the short term, cell exposure to most of the tested conditions favored STX production over neoSTX production. These results support the noted plasticity of C. raciborskii and highlight its potential to thrive in hard waters. Additionally, the observed relationship between saxitoxin production and water ion concentrations characteristic of the natural environments can be important for understanding toxin content variation in other harmful algae that produce STX. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Open AccessArticle

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (II)

by Chunwei Cheng, Yan Liu, Hao Song, Lili Pan, Jerry Li, Yong Qin and Rongshi Li

Mar. Drugs 2013, 11(8), 2927-2948; https://doi.org/10.3390/md11082927 - 15 Aug 2013

Cited by 23 | Viewed by 8753

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel [...] Read more.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed. Marinopyrrole A was reported to show antibiotic activity against MRSA in 2008. After we reported the first total synthesis of (±)-marinopyrrole A, we designed and synthesized a series of marinopyrrole derivatives. Our structure activity relationship (SAR) studies of these novel derivatives against a panel of Gram-positive pathogens in antibacterial assays have revealed that a para-trifluoromethyl analog (33) of marinopyrrole A is ≥63-, 8-, and 4-fold more potent than vancomycin against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA, respectively. The results provide valuable information in the search for new-generation antibiotics. Full article

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Open AccessArticle

Anti-Inflammatory Components of the Starfish Astropecten polyacanthus

by Nguyen Phuong Thao, Nguyen Xuan Cuong, Bui Thi Thuy Luyen, Tran Hong Quang, Tran Thi Hong Hanh, Sohyun Kim, Young-Sang Koh, Nguyen Hoai Nam, Phan Van Kiem, Chau Van Minh and Young Ho Kim

Mar. Drugs 2013, 11(8), 2917-2926; https://doi.org/10.3390/md11082917 - 13 Aug 2013

Cited by 32 | Viewed by 9620

Abstract

Inflammation is important in biomedical research, because it plays a key role in inflammatory diseases including rheumatoid arthritis and other forms of arthritis, diabetes, heart disease, irritable bowel syndrome, Alzheimer’s disease, Parkinson’s disease, allergies, asthma, and even cancer. In the present study, we [...] Read more.

Inflammation is important in biomedical research, because it plays a key role in inflammatory diseases including rheumatoid arthritis and other forms of arthritis, diabetes, heart disease, irritable bowel syndrome, Alzheimer’s disease, Parkinson’s disease, allergies, asthma, and even cancer. In the present study, we describe the inhibitory effect of crude extracts and steroids isolated from the starfish Astropecten polyacanthus on pro-inflammatory cytokine (Interleukin-12 (IL-12) p40, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α)) production in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs). Among those tested, compounds 5 and 7 showed potent inhibitory effects on the production of all three pro-inflammatory cytokines with IC₅₀ values ranging from 1.82 ± 0.11 to 7.00 ± 0.16 μM. Potent inhibitory activities were also observed for compound 1 on the production of IL-12 p40 and IL-6 with values of 3.96 ± 0.12 and 4.07 ± 0.13 μM, respectively, and for compounds 3 and 4 on the production of IL-12 p40 with values of 6.55 ± 0.18 and 5.06 ± 0.16 μM, respectively. Moreover, compounds 2 (IC₅₀ = 34.86 ± 0.31 μM) and 6 (IC₅₀ = 79.05 ± 2.05 μM) exhibited moderate inhibitory effects on the production of IL-12 p40, whereas compounds 3 (IC₅₀ = 22.80 ± 0.21 μM) and 4 (IC₅₀ = 16.73 ± 0.25 μM) moderately inhibited the production of TNF-α and IL-6, respectively. Full article

(This article belongs to the Special Issue Marine Compounds and Inflammation)

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Open AccessReview

Development of Synechocystis sp. PCC 6803 as a Phototrophic Cell Factory

by Yi Yu, Le You, Dianyi Liu, Whitney Hollinshead, Yinjie J. Tang and Fuzhong Zhang

Mar. Drugs 2013, 11(8), 2894-2916; https://doi.org/10.3390/md11082894 - 13 Aug 2013

Cited by 112 | Viewed by 21412

Abstract

Cyanobacteria (blue-green algae) play profound roles in ecology and biogeochemistry. One model cyanobacterial species is the unicellular cyanobacterium Synechocystis sp. PCC 6803. This species is highly amenable to genetic modification. Its genome has been sequenced and many systems biology and molecular biology tools [...] Read more.

Cyanobacteria (blue-green algae) play profound roles in ecology and biogeochemistry. One model cyanobacterial species is the unicellular cyanobacterium Synechocystis sp. PCC 6803. This species is highly amenable to genetic modification. Its genome has been sequenced and many systems biology and molecular biology tools are available to study this bacterium. Recently, researchers have put significant efforts into understanding and engineering this bacterium to produce chemicals and biofuels from sunlight and CO₂. To demonstrate our perspective on the application of this cyanobacterium as a photosynthesis-based chassis, we summarize the recent research on Synechocystis 6803 by focusing on five topics: rate-limiting factors for cell cultivation; molecular tools for genetic modifications; high-throughput system biology for genome wide analysis; metabolic modeling for physiological prediction and rational metabolic engineering; and applications in producing diverse chemicals. We also discuss the particular challenges for systems analysis and engineering applications of this microorganism, including precise characterization of versatile cell metabolism, improvement of product rates and titers, bioprocess scale-up, and product recovery. Although much progress has been achieved in the development of Synechocystis 6803 as a phototrophic cell factory, the biotechnology for “Compounds from Synechocystis” is still significantly lagging behind those for heterotrophic microbes (e.g., Escherichia coli). Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Open AccessArticle

Separacenes A–D, Novel Polyene Polyols from the Marine Actinomycete, Streptomyces sp.

by Munhyung Bae, Heegyu Kim, Yoonho Shin, Byung Yong Kim, Sang Kook Lee, Ki-Bong Oh, Jongheon Shin and Dong-Chan Oh

Mar. Drugs 2013, 11(8), 2882-2893; https://doi.org/10.3390/md11082882 - 13 Aug 2013

Cited by 21 | Viewed by 7334

Abstract

Separacenes A–D (1–4), novel polyene polyols, were isolated from Streptomyces sp. collected from the southern area of Jeju Island, Korea. The chemical structures of 1–4 were established by NMR, mass, UV, and IR spectroscopy as well as [...] Read more.

Separacenes A–D (1–4), novel polyene polyols, were isolated from Streptomyces sp. collected from the southern area of Jeju Island, Korea. The chemical structures of 1–4 were established by NMR, mass, UV, and IR spectroscopy as well as the modified Mosher’s method. Separacenes A–B (1–2), which share an identical planar structure but possess different relative configurations, bear tetraene units flanked by two diol moieties, whereas the stereoisomeric separacenes C–D (3–4) possess a triene moiety between two diol substructures. Separacenes A–D each contain a terminal olefinic methylene. Separacene A displayed inhibitory activity against Candida albicans isocitrate lyase and weak cytotoxicity against both the colon carcinoma cell line HCT-116 and the lung cancer cell line A549. Full article

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Open AccessCommunication

Insights into the Toxicological Properties of a Low Molecular Weight Fraction from Zoanthus sociatus (Cnidaria)

by Dany Domínguez-Pérez, Carlos Manlio Diaz-Garcia, Neivys García-Delgado, Yusvel Sierra-Gómez, Olga Castañeda and Agostinho Antunes

Mar. Drugs 2013, 11(8), 2873-2881; https://doi.org/10.3390/md11082873 - 13 Aug 2013

Cited by 6 | Viewed by 6698

Abstract

The phylum Cnidaria is an ancient group of venomous animals, specialized in the production and delivery of toxins. Many species belonging to the class Anthozoa have been studied and their venoms often contain a group of peptides, less than 10 kDa, that act [...] Read more.

The phylum Cnidaria is an ancient group of venomous animals, specialized in the production and delivery of toxins. Many species belonging to the class Anthozoa have been studied and their venoms often contain a group of peptides, less than 10 kDa, that act upon ion channels. These peptides and their targets interact with high affinity producing neurotoxic and cardiotoxic effects, and even death, depending on the dose and the administration pathway. Zoanthiniaria is an order of the Subclass Hexacorallia, class Anthozoa, and unlike sea anemone (order Actiniaria), neither its diversity of toxins nor the in vivo effects of the venoms has been exhaustively explored. In this study we assessed some toxicological tests on mice with a low molecular weight fraction obtained by gel filtration in Sephadex G-50 from Zoanthus sociatus crude extract. The gel filtration chromatogram at 280 nm revealed two major peaks, the highest absorbance corresponding to the low molecular weight fraction. The toxicological effects seem to be mostly autonomic and cardiotoxic, causing death in a dose dependent manner with a LD₅₀ of 792 μg/kg. Moreover, at a dose of 600 μg/kg the active fraction accelerated the KCl-induced lethality in mice. Full article

(This article belongs to the Special Issue Marine Peptides and Their Mimetics)

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Open AccessReview

Diversity of Secondary Metabolites from Marine Bacillus Species: Chemistry and Biological Activity

by Muhammad Abdul Mojid Mondol, Hee Jae Shin and Mohammad Tofazzal Islam

Mar. Drugs 2013, 11(8), 2846-2872; https://doi.org/10.3390/md11082846 - 12 Aug 2013

Cited by 189 | Viewed by 16463

Abstract

Marine Bacillus species produce versatile secondary metabolites including lipopeptides, polypeptides, macrolactones, fatty acids, polyketides, and isocoumarins. These structurally diverse compounds exhibit a wide range of biological activities, such as antimicrobial, anticancer, and antialgal activities. Some marine Bacillus strains can detoxify heavy metals through [...] Read more.

Marine Bacillus species produce versatile secondary metabolites including lipopeptides, polypeptides, macrolactones, fatty acids, polyketides, and isocoumarins. These structurally diverse compounds exhibit a wide range of biological activities, such as antimicrobial, anticancer, and antialgal activities. Some marine Bacillus strains can detoxify heavy metals through reduction processes and have the ability to produce carotenoids. The present article reviews the chemistry and biological activities of secondary metabolites from marine isolates. Side by side, the potential for application of these novel natural products from marine Bacillus strains as drugs, pesticides, carotenoids, and tools for the bioremediation of heavy metal toxicity are also discussed. Full article

(This article belongs to the Special Issue Marine Secondary Metabolites)

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Open AccessReview

Okadaic Acid Meet and Greet: An Insight into Detection Methods, Response Strategies and Genotoxic Effects in Marine Invertebrates

by María Verónica Prego-Faraldo, Vanessa Valdiglesias, Josefina Méndez and José M. Eirín-López

Mar. Drugs 2013, 11(8), 2829-2845; https://doi.org/10.3390/md11082829 - 9 Aug 2013

Cited by 34 | Viewed by 10510

Abstract

Harmful Algal Blooms (HABs) constitute one of the most important sources of contamination in the oceans, producing high concentrations of potentially harmful biotoxins that are accumulated across the food chains. One such biotoxin, Okadaic Acid (OA), is produced by marine dinoflagellates and subsequently [...] Read more.

Harmful Algal Blooms (HABs) constitute one of the most important sources of contamination in the oceans, producing high concentrations of potentially harmful biotoxins that are accumulated across the food chains. One such biotoxin, Okadaic Acid (OA), is produced by marine dinoflagellates and subsequently accumulated within the tissues of filtering marine organisms feeding on HABs, rapidly spreading to their predators in the food chain and eventually reaching human consumers causing Diarrhetic Shellfish Poisoning (DSP) syndrome. While numerous studies have thoroughly evaluated the effects of OA in mammals, the attention drawn to marine organisms in this regard has been scarce, even though they constitute primary targets for this biotoxin. With this in mind, the present work aimed to provide a timely and comprehensive insight into the current literature on the effect of OA in marine invertebrates, along with the strategies developed by these organisms to respond to its toxic effect together with the most important methods and techniques used for OA detection and evaluation. Full article

(This article belongs to the Special Issue Cytogenetic and Molecular Effects of Marine Compounds)

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Open AccessReview

Evolution and Distribution of Saxitoxin Biosynthesis in Dinoflagellates

by Russell J. S. Orr, Anke Stüken, Shauna A. Murray and Kjetill S. Jakobsen

Mar. Drugs 2013, 11(8), 2814-2828; https://doi.org/10.3390/md11082814 - 8 Aug 2013

Cited by 55 | Viewed by 13692

Abstract

Numerous species of marine dinoflagellates synthesize the potent environmental neurotoxic alkaloid, saxitoxin, the agent of the human illness, paralytic shellfish poisoning. In addition, certain freshwater species of cyanobacteria also synthesize the same toxic compound, with the biosynthetic pathway and genes responsible being recently [...] Read more.

Numerous species of marine dinoflagellates synthesize the potent environmental neurotoxic alkaloid, saxitoxin, the agent of the human illness, paralytic shellfish poisoning. In addition, certain freshwater species of cyanobacteria also synthesize the same toxic compound, with the biosynthetic pathway and genes responsible being recently reported. Three theories have been postulated to explain the origin of saxitoxin in dinoflagellates: The production of saxitoxin by co-cultured bacteria rather than the dinoflagellates themselves, convergent evolution within both dinoflagellates and bacteria and horizontal gene transfer between dinoflagellates and bacteria. The discovery of cyanobacterial saxitoxin homologs in dinoflagellates has enabled us for the first time to evaluate these theories. Here, we review the distribution of saxitoxin within the dinoflagellates and our knowledge of its genetic basis to determine the likely evolutionary origins of this potent neurotoxin. Full article

(This article belongs to the Special Issue Marine Shellfish Toxins)

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Open AccessArticle

First Identification of 5,11-Dideoxytetrodotoxin in Marine Animals, and Characterization of Major Fragment Ions of Tetrodotoxin and Its Analogs by High Resolution ESI-MS/MS

by Mari Yotsu-Yamashita, Yuka Abe, Yuta Kudo, Raphael Ritson-Williams, Valerie J. Paul, Keiichi Konoki, Yuko Cho, Masaatsu Adachi, Takuya Imazu, Toshio Nishikawa and Minoru Isobe

Mar. Drugs 2013, 11(8), 2799-2813; https://doi.org/10.3390/md11082799 - 6 Aug 2013

Cited by 96 | Viewed by 10080

Abstract

Even though tetrodotoxin (TTX) is a widespread toxin in marine and terrestrial organisms, very little is known about the biosynthetic pathway used to produce it. By describing chemical structures of natural analogs of TTX, we can start to identify some of the precursors [...] Read more.

Even though tetrodotoxin (TTX) is a widespread toxin in marine and terrestrial organisms, very little is known about the biosynthetic pathway used to produce it. By describing chemical structures of natural analogs of TTX, we can start to identify some of the precursors that might be important for TTX biosynthesis. In the present study, an analog of TTX, 5,11-dideoxyTTX, was identified for the first time in natural sources, the ovary of the pufferfish and the pharynx of a flatworm (planocerid sp. 1), by comparison with totally synthesized (−)-5,11-dideoxyTTX, using high resolution ESI-LC-MS. Based on the presence of 5,11-dideoxyTTX together with a series of known deoxy analogs, 5,6, 11-trideoxyTTX, 6,11-dideoxyTTX, 11-deoxyTTX, and 5-deoxyTTX, in these animals, we predicted two routes of stepwise oxidation pathways in the late stages of biosynthesis of TTX. Furthermore, high resolution masses of the major fragment ions of TTX, 6,11-dideoxyTTX, and 5,6,11-trideoxyTTX were also measured, and their molecular formulas and structures were predicted to compare them with each other. Although both TTX and 5,6,11-trideoxyTTX give major fragment ions that are very close, m/z 162.0660 and 162.1020, respectively, they are distinguishable and predicted to be different molecular formulas. These data will be useful for identification of TTXs using high resolution LC-MS/MS. Full article

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Open AccessArticle

Magnetic Resonance Imaging for Rapid Screening for the Nephrotoxic and Hepatotoxic Effects of Microcystins

by Aleksandra Milutinović, Ruda Zorc-Pleskovič, Marko Živin, Andrej Vovk, Igor Serša and Dušan Šuput

Mar. Drugs 2013, 11(8), 2785-2798; https://doi.org/10.3390/md11082785 - 5 Aug 2013

Cited by 6 | Viewed by 6997

Abstract

In vivo visualization of kidney and liver damage by Magnetic Resonance Imaging (MRI) may offer an advantage when there is a need for a simple, non-invasive and rapid method for screening of the effects of potential nephrotoxic and hepatotoxic substances in chronic experiments. [...] Read more.

In vivo visualization of kidney and liver damage by Magnetic Resonance Imaging (MRI) may offer an advantage when there is a need for a simple, non-invasive and rapid method for screening of the effects of potential nephrotoxic and hepatotoxic substances in chronic experiments. Here, we used MRI for monitoring chronic intoxication with microcystins (MCs) in rat. Male adult Wistar rats were treated every other day for eight months, either with MC-LR (10 μg/kg i.p.) or MC-YR (10 μg/kg i.p.). Control groups were treated with vehicle solutions. T₁-weighted MR-images were acquired before and at the end of the eight months experimental period. Kidney injury induced by the MCs presented with the increased intensity of T₁-weighted MR-signal of the kidneys and liver as compared to these organs from the control animals treated for eight months, either with the vehicle solution or with saline. The intensification of the T1-weighted MR-signal correlated with the increased volume density of heavily injured tubuli (R² = 0.77), with heavily damaged glomeruli (R² = 0.84) and with volume density of connective tissue (R² = 0.72). The changes in the MR signal intensity probably reflect the presence of an abundant proteinaceous material within the dilated nephrons and proliferation of the connective tissue. T₁-weighted MRI-is a valuable method for the in vivo screening of kidney and liver damage in rat models of intoxication with hepatotoxic and nephrotoxic agents, such as microcystins. Full article

(This article belongs to the Special Issue Compounds from Cyanobacteria)

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Cellular Antioxidant Effect of Four Bromophenols from the Red Algae, Vertebrata lanosa

by Elisabeth K. Olsen, Espen Hansen, Johan Isaksson and Jeanette H. Andersen

Mar. Drugs 2013, 11(8), 2769-2784; https://doi.org/10.3390/md11082769 - 5 Aug 2013

Cited by 52 | Viewed by 7786

Abstract

Three known bromophenols, 2,3-dibromo-4,5-dihydroxybenzylaldehyde (1), 2,2′,3-tribromo-3′,4,4′,5-tetrahydroxy-6′-hydroxymethyldiphenylmethane (2) and bis(2, 3-dibromo-4,5-dihydroxylbenzyl) ether (3), and one new one, 5,5″-oxybis(methylene)bis (3-bromo-4-(2′,3′-dibromo-4′,5′-dihydroxylbenzyl)benzene-1,2-diol) (4), were isolated from an extract of the red alga, Vertebrata lanosa. The antioxidant activity of [...] Read more.

Three known bromophenols, 2,3-dibromo-4,5-dihydroxybenzylaldehyde (1), 2,2′,3-tribromo-3′,4,4′,5-tetrahydroxy-6′-hydroxymethyldiphenylmethane (2) and bis(2, 3-dibromo-4,5-dihydroxylbenzyl) ether (3), and one new one, 5,5″-oxybis(methylene)bis (3-bromo-4-(2′,3′-dibromo-4′,5′-dihydroxylbenzyl)benzene-1,2-diol) (4), were isolated from an extract of the red alga, Vertebrata lanosa. The antioxidant activity of these four bromophenols was examined using one biochemical and two cellular assays: Oxygen Radical Absorbance Capacity (ORAC), Cellular Antioxidant Activity (CAA) and Cellular Lipid Peroxidation Antioxidant Activity (CLPAA) assays. Compound 2 distinguished itself by showing potent activity, having a better antioxidant effect than luteolin in both the CAA and CLPAA assays and of quercetin in the CLPAA assay. Although several bromophenols are known to be potent antioxidants in biochemical assays, this is the first time their cellular antioxidant activity has been demonstrated. Full article

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Hepatotoxic Seafood Poisoning (HSP) Due to Microcystins: A Threat from the Ocean?

by Katerina Vareli, Walter Jaeger, Anastasia Touka, Stathis Frillingos, Evangelos Briasoulis and Ioannis Sainis

Mar. Drugs 2013, 11(8), 2751-2768; https://doi.org/10.3390/md11082751 - 5 Aug 2013

Cited by 34 | Viewed by 8074

Abstract

Cyanobacterial blooms are a major and growing problem for freshwater ecosystems worldwide that increasingly concerns public health, with an average of 60% of blooms known to be toxic. The most studied cyanobacterial toxins belong to a family of cyclic heptapeptide hepatotoxins, called microcystins. [...] Read more.

Cyanobacterial blooms are a major and growing problem for freshwater ecosystems worldwide that increasingly concerns public health, with an average of 60% of blooms known to be toxic. The most studied cyanobacterial toxins belong to a family of cyclic heptapeptide hepatotoxins, called microcystins. The microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cell damage following cellular uptake via organic anion-transporting proteins (OATP). Their intracellular biologic effects presumably involve inhibition of catalytic subunits of protein phosphatases (PP1 and PP2A) and glutathione depletion. The microcystins produced by cyanobacteria pose a serious problem to human health, if they contaminate drinking water or food. These toxins are collectively responsible for human fatalities, as well as continued and widespread poisoning of wild and domestic animals. Although intoxications of aquatic organisms by microcystins have been widely documented for freshwater ecosystems, such poisonings in marine environments have only occasionally been reported. Moreover, these poisonings have been attributed to freshwater cyanobacterial species invading seas of lower salinity (e.g., the Baltic) or to the discharge of freshwater microcystins into the ocean. However, recent data suggest that microcystins are also being produced in the oceans by a number of cosmopolitan marine species, so that Hepatotoxic Seafood Poisoning (HSP) is increasingly recognized as a major health risk that follows consumption of contaminated seafood. Full article

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Krempfielins J-M, New Eunicellin-Based Diterpenoids from the Soft Coral Cladiella krempfi

by Yan-Ning Lee, Chi-Jen Tai, Tsong-Long Hwang and Jyh-Horng Sheu

Mar. Drugs 2013, 11(8), 2741-2750; https://doi.org/10.3390/md11082741 - 2 Aug 2013

Cited by 25 | Viewed by 6596

Abstract

New four eunicellin-based diterpenoids, krempfielins J–M (1–4) 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. The structure of [...] Read more.

New four eunicellin-based diterpenoids, krempfielins J–M (1–4) 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. The structure of compound 2 is rare due to the presence of the highly oxygenated pattern. Anti-inflammatory activity of 1–6 to inhibit the superoxide anion generation and elastase release in FMLP/CB-induced human neutrophils was also evaluated, and 2 and 4 were shown to possess the ability to inhibit the elastase release. Full article

(This article belongs to the Special Issue Marine Compounds and Inflammation)

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Evaluation of Anti-Nociceptive and Anti-Inflammatory Activities of a Heterofucan from Dictyota menstrualis

by Ivan Rui Lopes Albuquerque, Sara Lima Cordeiro, Dayanne Lopes Gomes, Juliana Luporini Dreyfuss, Luciana Guimarães Alves Filgueira, Edda Lisboa Leite, Helena Bonciani Nader and Hugo Alexandre Oliveira Rocha

Mar. Drugs 2013, 11(8), 2722-2740; https://doi.org/10.3390/md11082722 - 2 Aug 2013

Cited by 49 | Viewed by 8997

Abstract

Fucan is a term that defines a family of homo- and hetero-polysaccharides containing sulfated l-fucose in its structure. In this work, a heterofucan (F2.0v) from the seaweed, Dictyota menstrualis, was evaluated as an antinociceptive and anti-inflammatory agent. F2.0v (20.0 mg/kg) inhibits 100% [...] Read more.

Fucan is a term that defines a family of homo- and hetero-polysaccharides containing sulfated l-fucose in its structure. In this work, a heterofucan (F2.0v) from the seaweed, Dictyota menstrualis, was evaluated as an antinociceptive and anti-inflammatory agent. F2.0v (20.0 mg/kg) inhibits 100% of leukocyte migration into the peritoneal cavity after chemical stimulation. However, F2.0v does not alter the expression of interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), as well as tumor necrosis factor alpha (TNF-α). F2.0v (20.0 mg/kg) has peripheral antinociceptive activity with potency similar to dipyrone. On the other hand, it had no effect on pain response on the hot plate test. Confocal microscopy analysis and flow cytometry showed that F2.0v binds to the surface of leucocytes, which leads us to suggest that the mechanism of action of anti-inflammatory and antinociceptive F2.0v is related to its ability to inhibit the migration of leukocytes to the site of tissue injury. In summary, the data show that F2.0v compound has great potential as an antinociceptive and anti-inflammatory, and future studies will be performed to further characterize the mechanism of action of F2.0v. Full article

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Two Novel Tyrosinase Inhibitory Sesquiterpenes Induced by CuCl₂ from a Marine-Derived Fungus Pestalotiopsis sp. Z233

by Bin Wu, Xiaodan Wu, Min Sun and Minhui Li

Mar. Drugs 2013, 11(8), 2713-2721; https://doi.org/10.3390/md11082713 - 2 Aug 2013

Cited by 48 | Viewed by 7237

Abstract

Two new sesquiterpenes, 1β,5α,6α,14-tetraacetoxy-9α-benzoyloxy-7β H-eudesman-2β,11-diol (1) and 4α,5α-diacetoxy-9α-benzoyloxy-7βH-eudesman-1β,2β,11, 14-tetraol (2), were produced as stress metabolites in the cultured mycelia of Pestalotiopsis sp. Z233 isolated from the algae Sargassum horneri in response to abiotic stress elicitation by [...] Read more.

Two new sesquiterpenes, 1β,5α,6α,14-tetraacetoxy-9α-benzoyloxy-7β H-eudesman-2β,11-diol (1) and 4α,5α-diacetoxy-9α-benzoyloxy-7βH-eudesman-1β,2β,11, 14-tetraol (2), were produced as stress metabolites in the cultured mycelia of Pestalotiopsis sp. Z233 isolated from the algae Sargassum horneri in response to abiotic stress elicitation by CuCl₂. Their structures were established by spectroscopic means. New compounds 1 and 2 showed tyrosinase inhibitory activities with IC₅₀ value of 14.8 µM and 22.3 µM. Full article

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Diversity and Biosynthetic Potential of Culturable Microbes Associated with Toxic Marine Animals

by Rocky Chau, John A. Kalaitzis, Susanna A. Wood and Brett A. Neilan

Mar. Drugs 2013, 11(8), 2695-2712; https://doi.org/10.3390/md11082695 - 2 Aug 2013

Cited by 31 | Viewed by 9166

Abstract

Tetrodotoxin (TTX) is a neurotoxin that has been reported from taxonomically diverse organisms across 14 different phyla. The biogenic origin of tetrodotoxin is still disputed, however, TTX biosynthesis by host-associated bacteria has been reported. An investigation into the culturable microbial populations from the [...] Read more.

Tetrodotoxin (TTX) is a neurotoxin that has been reported from taxonomically diverse organisms across 14 different phyla. The biogenic origin of tetrodotoxin is still disputed, however, TTX biosynthesis by host-associated bacteria has been reported. An investigation into the culturable microbial populations from the TTX-associated blue-ringed octopus Hapalochlaena sp. and sea slug Pleurobranchaea maculata revealed a surprisingly high microbial diversity. Although TTX was not detected among the cultured isolates, PCR screening identifiedsome natural product biosynthesis genes putatively involved in its assembly. This study is the first to report on the microbial diversity of culturable communities from H. maculosa and P. maculata and common natural product biosynthesis genes from their microbiota. We also reassess the production of TTX reported from three bacterial strains isolated from the TTX-containing gastropod Nassarius semiplicatus. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

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Mar. Drugs, Volume 11, Issue 8 (August 2013) – 26 articles , Pages 2695-3108

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