Marine Drugs

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Open AccessArticle

PTP1B Inhibitory and Anti-Inflammatory Effects of Secondary Metabolites Isolated from the Marine-Derived Fungus Penicillium sp. JF-55

by Dong-Sung Lee, Jae-Hyuk Jang, Wonmin Ko, Kyoung-Su Kim, Jae Hak Sohn, Myeong-Suk Kang, Jong Seog Ahn, Youn-Chul Kim and Hyuncheol Oh

Mar. Drugs 2013, 11(4), 1409-1426; https://doi.org/10.3390/md11041409 - 23 Apr 2013

Cited by 58 | Viewed by 9165

Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures [...] Read more.

Protein tyrosine phosphatase 1B (PTP1B) plays a major role in the negative regulation of insulin signaling, and is thus considered as an attractive therapeutic target for the treatment of diabetes. Bioassay-guided investigation of the methylethylketone extract of marine-derived fungus Penicillium sp. JF-55 cultures afforded a new PTP1B inhibitory styrylpyrone-type metabolite named penstyrylpyrone (1), and two known metabolites, anhydrofulvic acid (2) and citromycetin (3). Compounds 1 and 2 inhibited PTP1B activity in a dose-dependent manner, and kinetic analyses of PTP1B inhibition suggested that these compounds inhibited PTP1B activity in a competitive manner. In an effort to gain more biological potential of the isolated compounds, the anti-inflammatory effects of compounds 1–3 were also evaluated. Among the tested compounds, only compound 1 inhibited the production of NO and PGE₂, due to the inhibition of the expression of iNOS and COX-2. Penstyrylpyrone (1) also reduced TNF-α and IL-1β production, and these anti-inflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of IκB-α, NF-κB nuclear translocation, and NF-κB DNA binding activity. In addition, using inhibitor tin protoporphyrin (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of penstyrylpyrone (1) on the pro-inflammatory mediators and NF-κB DNA binding activity were associated with the HO-1 expression. Therefore, these results suggest that penstyrylpyrone (1) suppresses PTP1B activity, as well as the production of pro-inflammatory mediators via NF-κB pathway, through expression of anti-inflammatory HO-1. Full article

(This article belongs to the Special Issue Bioactive Compounds from Marine Fungi)

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Open AccessArticle

Four New Chloro-Eremophilane Sesquiterpenes from an Antarctic Deep-Sea Derived Fungus, Penicillium sp. PR19N-1

by Guangwei Wu, Aiqun Lin, Qianqun Gu, Tianjiao Zhu and Dehai Li

Mar. Drugs 2013, 11(4), 1399-1408; https://doi.org/10.3390/md11041399 - 23 Apr 2013

Cited by 67 | Viewed by 8321

Abstract

A new chloro-trinoreremophilane sesquiterpene 1, three new chlorinated eremophilane sesquiterpenes 2–4, together with a known compound, eremofortine C (5), were isolated from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Structures were established using IR, HRMS, 1D [...] Read more.

A new chloro-trinoreremophilane sesquiterpene 1, three new chlorinated eremophilane sesquiterpenes 2–4, together with a known compound, eremofortine C (5), were isolated from an Antarctic deep-sea derived fungus, Penicillium sp. PR19N-1. Structures were established using IR, HRMS, 1D and 2D NMR techniques. In addition, the plausible metabolic network of these isolated products is proposed. Compound 1 showed moderate cytotoxic activity against HL-60 and A549 cancer cell lines. Full article

(This article belongs to the Special Issue Deep-Sea Natural Products)

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777 KiB

Open AccessReview

Natural Product Research in the Australian Marine Invertebrate Dicathais orbita

by Kirsten Benkendorff

Mar. Drugs 2013, 11(4), 1370-1398; https://doi.org/10.3390/md11041370 - 23 Apr 2013

Cited by 46 | Viewed by 9672

Abstract

The predatory marine gastropod Dicathais orbita has been the subject of a significant amount of biological and chemical research over the past five decades. Natural products research on D. orbita includes the isolation and identification of brominated indoles and choline esters as precursors [...] Read more.

The predatory marine gastropod Dicathais orbita has been the subject of a significant amount of biological and chemical research over the past five decades. Natural products research on D. orbita includes the isolation and identification of brominated indoles and choline esters as precursors of Tyrian purple, as well as the synthesis of structural analogues, bioactivity testing, biodistributional and biosynthetic studies. Here I also report on how well these compounds conform to Lipinski’s rule of five for druglikeness and their predicted receptor binding and enzyme inhibitor activity. The composition of mycosporine-like amino acids, fatty acids and sterols has also been described in the egg masses of D. orbita. The combination of bioactive compounds produced by D. orbita is of interest for further studies in chemical ecology, as well as for future nutraceutical development. Biological insights into the life history of this species, as well as ongoing research on the gene expression, microbial symbionts and biosynthetic capabilities, should facilitate sustainable production of the bioactive compounds. Knowledge of the phylogeny of D. orbita provides an excellent platform for novel research into the evolution of brominated secondary metabolites in marine molluscs. The range of polarities in the brominated indoles produced by D. orbita has also provided an effective model system used to develop a new method for biodistributional studies. The well characterized suite of chemical reactions that generate Tyrian purple, coupled with an in depth knowledge of the ecology, anatomy and genetics of D. orbita provide a good foundation for ongoing natural products research. Full article

(This article belongs to the Special Issue Marine Bioactive Natural Product Studies—A Southern Hemisphere Perspective)

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Open AccessArticle

Unusual Glycosaminoglycans from a Deep Sea Hydrothermal Bacterium Improve Fibrillar Collagen Structuring and Fibroblast Activities in Engineered Connective Tissues

by Karim Senni, Farida Gueniche, Sylvie Changotade, Dominique Septier, Corinne Sinquin, Jacqueline Ratiskol, Didier Lutomski, Gaston Godeau, Jean Guezennec and Sylvia Colliec-Jouault

Mar. Drugs 2013, 11(4), 1351-1369; https://doi.org/10.3390/md11041351 - 23 Apr 2013

Cited by 41 | Viewed by 8189

Abstract

Biopolymers produced by marine organisms can offer useful tools for regenerative medicine. Particularly, HE800 exopolysaccharide (HE800 EPS) secreted by a deep-sea hydrothermal bacterium displays an interesting glycosaminoglycan-like feature resembling hyaluronan. Previous studies demonstrated its effectiveness to enhance in vivo bone regeneration and to [...] Read more.

Biopolymers produced by marine organisms can offer useful tools for regenerative medicine. Particularly, HE800 exopolysaccharide (HE800 EPS) secreted by a deep-sea hydrothermal bacterium displays an interesting glycosaminoglycan-like feature resembling hyaluronan. Previous studies demonstrated its effectiveness to enhance in vivo bone regeneration and to support osteoblastic cell metabolism in culture. Thus, in order to assess the usefulness of this high-molecular weight polymer in tissue engineering and tissue repair, in vitro reconstructed connective tissues containing HE800 EPS were performed. We showed that this polysaccharide promotes both collagen structuring and extracellular matrix settle by dermal fibroblasts. Furthermore, from the native HE800 EPS, a low-molecular weight sulfated derivative (HE800 DROS) displaying chemical analogy with heparan-sulfate, was designed. Thus, it was demonstrated that HE800 DROS mimics some properties of heparan-sulfate, such as promotion of fibroblast proliferation and inhibition of matrix metalloproteinase (MMP) secretion. Therefore, we suggest that the HE800EPS family can be considered as an innovative biotechnological source of glycosaminoglycan-like compounds useful to design biomaterials and drugs for tissue engineering and repair. Full article

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Open AccessArticle

Immunomodulatory Effect of Marine Cembrane-Type Diterpenoids on Dendritic Cells

by Ching-Yen Lin, Mei-Chin Lu, Jui-Hsin Su, Ching-Liang Chu, David Shiuan, Ching-Feng Weng, Ping-Jyun Sung and Kao-Jean Huang

Mar. Drugs 2013, 11(4), 1336-1350; https://doi.org/10.3390/md11041336 - 22 Apr 2013

Cited by 28 | Viewed by 7067

Abstract

Dendritic cells (DCs) are antigen presenting cells, which can present antigens to T-cells and play an important role in linking innate and adaptive immunity. DC maturation can be induced by many stimuli, including pro-inflammatory cytokines and bacterial products, such as lipopolysaccharides (LPS). Here, [...] Read more.

Dendritic cells (DCs) are antigen presenting cells, which can present antigens to T-cells and play an important role in linking innate and adaptive immunity. DC maturation can be induced by many stimuli, including pro-inflammatory cytokines and bacterial products, such as lipopolysaccharides (LPS). Here, we examined the immunomodulatory effects of marine cembrane compounds, (9E,13E)-5-acetoxy-6-hydroxy-9,13-dimethyl-3- methylene-3,3a,4,5,6,7,8,11,12,14a-decahydro-2H-cyclotrideca[b]furan-2-one (1), (9E,13E)- 5-acetoxy-6-acetyl-9,13-dimethyl-3-methylene-3,3a,4,5,6,7,8,11,12,14a-decahydro-2H-cyclotrideca[b]furan-2-one (2), lobocrassin B (3), (−)14-deoxycrassin (4), cembranolide B (5) and 13-acetoxysarcocrassolide (6) isolated from a soft coral, Lobophytum crassum, on mouse bone marrow-derived dendritic cells (BMDCs). The results revealed that cembrane-type diterpenoids, especially lobocrassin B, effectively inhibited LPS-induced BMDC activation by inhibiting the production of TNF-α. Pre-treatment of BMDCs with Lobocrassin B for 1 h is essential to prohibit the following activation induced by various toll-like receptor (TLR) agonists, such as LPS, zymosan, lipoteichoic acid (LTA) and Pam2CSK4. Inhibition of NF-κB nuclear translocation by lobocrassin B, which is a key transcription factor for cytokine production in TLR signaling, was evident as assayed by high-content image analysis. Lobocrassin B attenuated DC maturation and endocytosis as the expression levels of MHC class II and the co-stimulatory molecules were downregulated, which may affect the function of DCs to initiate the T-cell responses. Thus, lobocrassin B may have the potential in treatment of immune dysregulated diseases in the future. Full article

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

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Open AccessArticle

Chemoecological Screening Reveals High Bioactivity in Diverse Culturable Portuguese Marine Cyanobacteria

by Pedro N. Leão, Vitor Ramos, Patrício B. Gonçalves, Flávia Viana, Olga M. Lage, William H. Gerwick and Vitor M. Vasconcelos

Mar. Drugs 2013, 11(4), 1316-1335; https://doi.org/10.3390/md11041316 - 22 Apr 2013

Cited by 18 | Viewed by 8222

Abstract

Marine cyanobacteria, notably those from tropical regions, are a rich source of bioactive secondary metabolites. Tropical marine cyanobacteria often grow to high densities in the environment, allowing direct isolation of many secondary metabolites from field-collected material. However, in temperate environments culturing is usually [...] Read more.

Marine cyanobacteria, notably those from tropical regions, are a rich source of bioactive secondary metabolites. Tropical marine cyanobacteria often grow to high densities in the environment, allowing direct isolation of many secondary metabolites from field-collected material. However, in temperate environments culturing is usually required to produce enough biomass for investigations of their chemical constituents. In this work, we cultured a selection of novel and diverse cyanobacteria isolated from the Portuguese coast, and tested their organic extracts in a series of ecologically-relevant bioassays. The majority of the extracts showed activity in at least one of the bioassays, all of which were run in very small scale. Phylogenetically related isolates exhibited different activity profiles, highlighting the value of microdiversity for bioprospection studies. Furthermore, LC-MS analyses of selected active extracts suggested the presence of previously unidentified secondary metabolites. Overall, the screening strategy employed here, in which previously untapped cyanobacterial diversity was combined with multiple bioassays, proved to be a successful strategy and allowed the selection of several strains for further investigations based on their bioactivity profiles. Full article

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

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Open AccessArticle

Antimalarial Activity of Axidjiferosides, New β-Galactosylceramides from the African Sponge Axinyssa djiferi

by Fereshteh Farokhi, Philippe Grellier, Monique Clément, Christos Roussakis, Philippe M. Loiseau, Emilie Genin-Seward, Jean-Michel Kornprobst, Gilles Barnathan and Gaëtane Wielgosz-Collin

Mar. Drugs 2013, 11(4), 1304-1315; https://doi.org/10.3390/md11041304 - 17 Apr 2013

Cited by 21 | Viewed by 7294

Abstract

The marine sponge, Axinyssa djiferi, collected on mangrove tree roots in Senegal, was investigated for glycolipids. A mixture containing new glycosphingolipids, named axidjiferoside-A, -B and -C, accounted for 0.07% of sponge biomass (dry weight) and for 2.16% of total lipids. It showed [...] Read more.

The marine sponge, Axinyssa djiferi, collected on mangrove tree roots in Senegal, was investigated for glycolipids. A mixture containing new glycosphingolipids, named axidjiferoside-A, -B and -C, accounted for 0.07% of sponge biomass (dry weight) and for 2.16% of total lipids. It showed a significant antimalarial activity, with a 50% inhibitory concentration (IC₅₀) of 0.53 ± 0.2 μM against a chloroquine-resistant strain of Plasmodium falciparum. They were identified as homologous β-galactopyranosylceramides composed of 2-amino-(6E)-octadec-6-en-1,3,4-triol, and the major one, axidjiferoside-A (around 60%), contained 2-hydroxytetracosanoic acid. Cytotoxicity was studied in vitro on human cancer cell lines (multiple myeloma, colorectal adenocarcinoma, glioblastoma and two lung cancer NSCLC-N6 and A549). Results of this investigation showed that axidjiferosides are of interest, because they proved a good antiplasmodial activity, with only a low cytotoxicity against various human cell lines and no significant antitrypanosomal and antileishmanial activity. Thus, it seems that galactosylceramides with a β anomeric configuration may be suitable in searching for new antimalarial drugs. Full article

(This article belongs to the Special Issue Marine Lipids)

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244 KiB

Open AccessNew Book Received

Marine Nutraceuticals: Prospects and Perspectives. By Se-Kwon Kim, CRC Press, 2013; 464 Pages. Price £108.00, ISBN 978-1-4665-1351-8

by Shu-Kun Lin

Mar. Drugs 2013, 11(4), 1300-1303; https://doi.org/10.3390/md11041300 - 17 Apr 2013

Cited by 1 | Viewed by 5735

Abstract

The following paragraphs are reproduced from the publisher’s website [1]. There is a great deal of consumer interest in natural bioactive substances due to their health benefits. Offering the potential to provide valuable nutraceuticals and functional food ingredients, marine-derived compounds are an abundant [...] Read more.

The following paragraphs are reproduced from the publisher’s website [1]. There is a great deal of consumer interest in natural bioactive substances due to their health benefits. Offering the potential to provide valuable nutraceuticals and functional food ingredients, marine-derived compounds are an abundant source of nutritionally and pharmacologically active agents, with both chemical diversity and complexity. Functional ingredients derived from marine algae, invertebrates, vertebrates, and microorganisms can help fill the need for novel bioactives to treat chronic conditions such as cancer, microbial infections, and inflammatory processes. Full article

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Open AccessArticle

Differential in Gel Electrophoresis (DIGE) Comparative Proteomic Analysis of Macrophages Cell Cultures in Response to Perthamide C Treatment

by Annalisa Vilasi, Maria Chiara Monti, Alessandra Tosco, Simona De Marino, Luigi Margarucci, Raffaele Riccio and Agostino Casapullo

Mar. Drugs 2013, 11(4), 1288-1299; https://doi.org/10.3390/md11041288 - 17 Apr 2013

Cited by 7 | Viewed by 6920

Abstract

Secondary metabolites contained in marine organisms disclose diverse pharmacological activities, due to their intrinsic ability to recognize bio-macromolecules, which alter their expression and modulate their function. Thus, the identification of the cellular pathways affected by marine natural products is crucial to provide important [...] Read more.

Secondary metabolites contained in marine organisms disclose diverse pharmacological activities, due to their intrinsic ability to recognize bio-macromolecules, which alter their expression and modulate their function. Thus, the identification of the cellular pathways affected by marine natural products is crucial to provide important functional information concerning their mechanism of action at the molecular level. Perthamide C, a marine sponge metabolite isolated from the polar extracts of Theonella swinhoei and endowed with a broad and interesting anti-inflammatory profile, was found in a previous study to specifically interact with heat shock protein-90 and glucose regulated protein-94, also disclosing the ability to reduce cisplatin-mediated apoptosis. In this paper, we evaluated the effect of this compound on the whole proteome of murine macrophages cells by two-dimensional DIGE proteomics. Thirty-three spots were found to be altered in expression by at least 1.6-fold and 29 proteins were identified by LC ESI-Q/TOF-MS. These proteins are involved in different processes, such as metabolism, structural stability, protein folding assistance and gene expression. Among them, perthamide C modulates the expression of several chaperones implicated in the folding of proteins correlated to apoptosis, such as Hsp90 and T-complexes, and in this context our data shed more light on the cellular effects and pathways altered by this marine cyclo-peptide. Full article

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

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Open AccessArticle

Brominated Skeletal Components of the Marine Demosponges, Aplysina cavernicola and Ianthella basta: Analytical and Biochemical Investigations

by Kurt Kunze, Hendrik Niemann, Susanne Ueberlein, Renate Schulze, Hermann Ehrlich, Eike Brunner, Peter Proksch and Karl-Heinz Van Pée

Mar. Drugs 2013, 11(4), 1271-1287; https://doi.org/10.3390/md11041271 - 17 Apr 2013

Cited by 28 | Viewed by 7599

Abstract

Demosponges possess a skeleton made of a composite material with various organic constituents and/or siliceous spicules. Chitin is an integral part of the skeleton of different sponges of the order Verongida. Moreover, sponges of the order Verongida, such as Aplysina cavernicola or Ianthella [...] Read more.

Demosponges possess a skeleton made of a composite material with various organic constituents and/or siliceous spicules. Chitin is an integral part of the skeleton of different sponges of the order Verongida. Moreover, sponges of the order Verongida, such as Aplysina cavernicola or Ianthella basta, are well-known for the biosynthesis of brominated tyrosine derivates, characteristic bioactive natural products. It has been unknown so far whether these compounds are exclusively present in the cellular matrix or whether they may also be incorporated into the chitin-based skeletons. In the present study, we therefore examined the skeletons of A. cavernicola and I. basta with respect to the presence of bromotyrosine metabolites. The chitin-based-skeletons isolated from these sponges indeed contain significant amounts of brominated compounds, which are not easily extractable from the skeletons by common solvents, such as MeOH, as shown by HPLC analyses in combination with NMR and IR spectroscopic measurements. Quantitative potentiometric analyses confirm that the skeleton-associated bromine mainly withstands the MeOH-based extraction. This observation suggests that the respective, but yet unidentified, brominated compounds are strongly bound to the sponge skeletons, possibly by covalent bonding. Moreover, gene fragments of halogenases suggested to be responsible for the incorporation of bromine into organic molecules could be amplified from DNA isolated from sponge samples enriched for sponge-associated bacteria. Full article

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Open AccessArticle

Evaluation of the Antioxidant Activity of Cell Extracts from Microalgae

by A. Catarina Guedes, Maria S. Gião, Rui Seabra, A. C. Silva Ferreira, Paula Tamagnini, Pedro Moradas-Ferreira and F. Xavier Malcata

Mar. Drugs 2013, 11(4), 1256-1270; https://doi.org/10.3390/md11041256 - 17 Apr 2013

Cited by 69 | Viewed by 9349

Abstract

A growing market for novel antioxidants obtained from non-expensive sources justifies educated screening of microalgae for their potential antioxidant features. Characterization of the antioxidant profile of 18 species of cyanobacteria (prokaryotic microalgae) and 23 species of (eukaryotic) microalgae is accordingly reported in this [...] Read more.

A growing market for novel antioxidants obtained from non-expensive sources justifies educated screening of microalgae for their potential antioxidant features. Characterization of the antioxidant profile of 18 species of cyanobacteria (prokaryotic microalgae) and 23 species of (eukaryotic) microalgae is accordingly reported in this paper. The total antioxidant capacity, accounted for by both water- and lipid-soluble antioxidants, was evaluated by the (radical cation) ABTS method. For complementary characterization of cell extracts, a deoxyribose assay was carried out, as well as a bacteriophage P22/Salmonella-mediated approach. The microalga Scenedesmus obliquus strain M2-1 exhibited the highest (p > 0.05) total antioxidant capacity (149 ± 47 AAU) of intracellular extracts. Its scavenger activity correlated well with its protective effects against DNA oxidative damage induced by copper(II)-ascorbic acid; and against decay in bacteriophage infection capacity induced by H₂O₂. Finally, performance of an Ames test revealed no mutagenic effects of the said extract. Full article

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Open AccessArticle

Structural and Immunochemical Studies of the Lipopolysaccharide from the Fish Pathogen, Aeromonas bestiarum Strain K296, Serotype O18

by Anna Turska-Szewczuk, Buko Lindner, Iwona Komaniecka, Alicja Kozinska, Agnieszka Pekala, Adam Choma and Otto Holst

Mar. Drugs 2013, 11(4), 1235-1255; https://doi.org/10.3390/md11041235 - 17 Apr 2013

Cited by 16 | Viewed by 7449

Abstract

Chemical analyses and mass spectrometry were used to study the structure of the lipopolysaccharide (LPS) isolated from Aeromonas bestiarum strain K296, serotype O18. ESI-MS revealed that the most abundant A. bestiarum LPS glycoforms have a hexa-acylated or tetra-acylated lipid A with conserved architecture [...] Read more.

Chemical analyses and mass spectrometry were used to study the structure of the lipopolysaccharide (LPS) isolated from Aeromonas bestiarum strain K296, serotype O18. ESI-MS revealed that the most abundant A. bestiarum LPS glycoforms have a hexa-acylated or tetra-acylated lipid A with conserved architecture of the backbone, consisting of a 1,4′-bisphosphorylated β-(1→6)-linked d-GlcN disaccharide with an AraN residue as a non-stoichiometric substituent and a core oligosaccharide composed of Kdo₁Hep₆Hex₁HexN₁P₁. 1D and 2D NMR spectroscopy revealed that the O-specific polysaccharide (OPS) of A. bestiarum K296 consists of a branched tetrasaccharide repeating unit containing two 6-deoxy-l-talose (6dTalp), one Manp and one GalpNAc residues; thus, it is similar to that of the OPS of A. hydrophila AH-3 (serotype O34) in both the sugar composition and the glycosylation pattern. Moreover, 3-substituted 6dTalp was 2-O-acetylated and additional O-acetyl groups were identified at O-2 and O-4 (or O-3) positions of the terminal 6dTalp. Western blots with polyclonal rabbit sera showed that serotypes O18 and O34 share some epitopes in the LPS. The very weak reaction of the anti-O34 serum with the O-deacylated LPS of A. bestiarum K296 might have been due to the different O-acetylation pattern of the terminal 6dTalp. The latter suggestion was further confirmed by NMR. Full article

(This article belongs to the Special Issue Marine Lipopolysaccharides)

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Open AccessArticle

Antinociceptive Activity of Stephanolepis hispidus Skin Aqueous Extract Depends Partly on Opioid System Activation

by Vinicius Carvalho, Lohengrin Fernandes, Taline Conde, Helena Zamith, Ronald Silva, Andrea Surrage, Valber Frutuoso, Hugo Castro-Faria-Neto and Fabio Amendoeira

Mar. Drugs 2013, 11(4), 1221-1234; https://doi.org/10.3390/md11041221 - 10 Apr 2013

Cited by 10 | Viewed by 6226

Abstract

Stephanolepis hispidus is one of the most common filefish species in Brazil. Its skin is traditionally used as a complementary treatment for inflammatory disorders. However, there are very few studies on chemical and pharmacological properties using the skin of this fish. This study [...] Read more.

Stephanolepis hispidus is one of the most common filefish species in Brazil. Its skin is traditionally used as a complementary treatment for inflammatory disorders. However, there are very few studies on chemical and pharmacological properties using the skin of this fish. This study was undertaken in order to investigate the effect of aqueous crude extract of S. hispidus skin (SAE) in different nociception models. Here, we report that intraperitoneal administration of SAE inhibited the abdominal constrictions induced by acetic acid in mice. In addition to the effect seen in the abdominal constriction model, SAE was also able to inhibit the hyperalgesia induced by carrageenan and prostaglandin E2 (PGE2) in mice. This potent antinociceptive effect was observed in the hot plate model too, but not in tail-flick test. Naloxone, an opioid receptor antagonist, was able to block the antinociceptive effect of SAE in the abdominal constriction and hot plate models. In addition, SAE did not present cytotoxic or genotoxic effect in human peripheral blood cells. Our results suggest that aqueous crude extract from S. hispidus skin has antinociceptive activity in close relationship with the partial activation of opioid receptors in the nervous system. Moreover, aqueous crude extract from S. hispidus skin does not present toxicity and is therefore endowed with the potential for pharmacological control of pain. Full article

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Open AccessReview

A Therapeutic Potential for Marine Skeletal Proteins in Bone Regeneration

by David W. Green, Matthew P. Padula, Jerran Santos, Joshua Chou, Bruce Milthorpe and Besim Ben-Nissan

Mar. Drugs 2013, 11(4), 1203-1220; https://doi.org/10.3390/md11041203 - 10 Apr 2013

Cited by 33 | Viewed by 8353

Abstract

A vital ingredient for engineering bone tissue, in the culture dish, is the use of recombinant matrix and growth proteins to help accelerate the growth of cultivated tissues into clinically acceptable quantities. The skeletal organic matrices of calcifying marine invertebrates are an untouched [...] Read more.

A vital ingredient for engineering bone tissue, in the culture dish, is the use of recombinant matrix and growth proteins to help accelerate the growth of cultivated tissues into clinically acceptable quantities. The skeletal organic matrices of calcifying marine invertebrates are an untouched potential source of such growth inducing proteins. They have the advantage of being ready-made and retain the native state of the original protein. Striking evidence shows that skeleton building bone morphogenic protein-2/4 (BMP) and transforming growth factor beta (TGF-β) exist within various marine invertebrates such as, corals. Best practice mariculture and the latest innovations in long-term marine invertebrate cell cultivation can be implemented to ensure that these proteins are produced sustainably and supplied continuously. This also guarantees that coral reef habitats are not damaged during the collection of specimens. Potential proteins for bone repair, either extracted from the skeleton or derived from cultivated tissues, can be identified, evaluated and retrieved using chromatography, cell assays and proteomic methods. Due to the current evidence for bone matrix protein analogues in marine invertebrates, together with the methods established for their production and retrieval there is a genuine prospect that they can be used to regenerate living bone for potential clinical use. Full article

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Open AccessArticle

A Conus regularis Conotoxin with a Novel Eight-Cysteine Framework Inhibits Ca_V2.2 Channels and Displays an Anti-Nociceptive Activity

by Johanna Bernáldez, Sergio A. Román-González, Oscar Martínez, Samanta Jiménez, Oscar Vivas, Isabel Arenas, Gerardo Corzo, Roberto Arreguín, David E. García, Lourival D. Possani and Alexei Licea

Mar. Drugs 2013, 11(4), 1188-1202; https://doi.org/10.3390/md11041188 - 8 Apr 2013

Cited by 29 | Viewed by 9005

Abstract

A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40 [...] Read more.

A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40 amino acids and exhibits a novel arrangement of eight cysteine residues (C-C-C-C-CC-CC). Surprisingly, two loops of the novel peptide are highly identical to the amino acids sequence of ω-MVIIA. The total length and disulfide pairing of both peptides are quite different, although the two most important residues for the described function of ω-MVIIA (Lys2 and Tyr13) are also present in the peptide reported here. Electrophysiological analysis using superior cervical ganglion (SCG) neurons indicates that RsXXIVA inhibits Ca_V2.2 channel current in a dose-dependent manner with an EC₅₀ of 2.8 μM, whose effect is partially reversed after washing. Furthermore, RsXXIVA was tested in hot-plate assays to measure the potential anti-nociceptive effect to an acute thermal stimulus, showing an analgesic effect in acute thermal pain at 30 and 45 min post-injection. Also, the toxin shows an anti-nociceptive effect in a formalin chronic pain test. However, the low affinity for Ca_V2.2 suggests that the primary target of the peptide could be different from that of ω-MVIIA. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

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Open AccessArticle

Gene Cloning, Expression and Characterization of a Novel Xylanase from the Marine Bacterium, Glaciecola mesophila KMM241

by Bing Guo, Ping-Yi Li, Yong-Sheng Yue, Hui-Lin Zhao, Sheng Dong, Xiao-Yan Song, Cai-Yun Sun, Wei-Xin Zhang, Xiu-Lan Chen, Xi-Ying Zhang, Bai-Cheng Zhou and Yu-Zhong Zhang

Mar. Drugs 2013, 11(4), 1173-1187; https://doi.org/10.3390/md11041173 - 8 Apr 2013

Cited by 32 | Viewed by 7387

Abstract

Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase [...] Read more.

Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase (GH) family 8. The recombinant XynB comprises an N-terminal domain (NTD) with unknown function and a catalytic domain, which is structurally novel among the characterized xylanases of GH family 8. XynB has the highest identity (38%) to rXyn8 among the characterized xylanases. The recombinant XynB showed maximal activity at pH 6–7 and 35 °C. It is thermolabile and salt-tolerant. XynB is an endo-xylanase that demands at least five sugar moieties for effective cleavage and to hydrolyze xylohexaose and xylopentaose into xylotetraose, xylotriose and xylobiose. NTD was expressed in Escherichia coli to analyze its function. The recombinant NTD exhibited a high binding ability to insoluble xylan and avicel and little binding ability to chitosan and chitin. Since the NTD shows no obvious homology to any known carbohydrate-binding module (CBM) sequence in public databases, XynB may contain a new type of CBM. Full article

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Open AccessArticle

Cytotoxic and Antibacterial Cembranoids from a South China Sea Soft Coral, Lobophytum sp.

by Min Zhao, Jian Yin, Wei Jiang, Minshan Ma, Xinxiang Lei, Zheng Xiang, Jianyong Dong, Kexin Huang and Pengcheng Yan

Mar. Drugs 2013, 11(4), 1162-1172; https://doi.org/10.3390/md11041162 - 3 Apr 2013

Cited by 30 | Viewed by 6569

Abstract

Chemical examination of a South China Sea soft coral Lobophytum sp. led to the isolation of three new α-methylene-γ-lactone-containing cembranoids, (1R*,3R*, 4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide (1), (1R*,7S*,14S [...] Read more.

Chemical examination of a South China Sea soft coral Lobophytum sp. led to the isolation of three new α-methylene-γ-lactone-containing cembranoids, (1R*,3R*, 4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide (1), (1R*,7S*,14S*,3E, 11E)-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (2), and (1R*,7S*,14S*, 3E,11E)-18-acetoxy-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (3), along with eleven known analogues 4–14. The structures of the new compounds were elucidated through extensive spectroscopic analysis, including 1D and 2D NMR data. Compounds 1–3 exhibited moderate cytotoxic activity against the selected tumor cell lines. Moreover, 2 and 3 were found to be moderate inhibitors against the bacteria S. aureus and S. pneumoniae. Full article

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Open AccessArticle

Potential Chemopreventive Activity of a New Macrolide Antibiotic from a Marine-Derived Micromonospora sp.

by Skylar Carlson, Laura Marler, Sang-Jip Nam, Bernard D. Santarsiero, John M. Pezzuto and Brian T. Murphy

Mar. Drugs 2013, 11(4), 1152-1161; https://doi.org/10.3390/md11041152 - 3 Apr 2013

Cited by 27 | Viewed by 8562

Abstract

Agents capable of inducing phase II enzymes such as quinone reductase 1 (QR1) are known to have the potential of mediating cancer chemopreventive activity. As part of a program to discover novel phase II enzyme-inducing molecules, we identified a marine-derived actinomycete strain (CNJ-878) [...] Read more.

Agents capable of inducing phase II enzymes such as quinone reductase 1 (QR1) are known to have the potential of mediating cancer chemopreventive activity. As part of a program to discover novel phase II enzyme-inducing molecules, we identified a marine-derived actinomycete strain (CNJ-878) that exhibited activity with cultured Hepa 1c1c7 cells. Based on this activity, a new macrolide, juvenimicin C (1), as well as 5-O-α-l-rhamnosyltylactone (2), were isolated from the culture broth of a Micromonospora sp. Compound 1 enhanced QR1 enzyme activity and glutathione levels by two-fold with CD values of 10.1 and 27.7 μM, respectively. In addition, glutathione reductase and glutathione peroxidase activities were elevated. This is the first reported member of the macrolide class of antibiotics found to mediate these responses. Full article

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

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Open AccessArticle

Spongiatriol Inhibits Nuclear Factor Kappa B Activation and Induces Apoptosis in Pancreatic Cancer Cells

by Esther Guzmán, Michael Maher, Alexis Temkin, Tara Pitts and Amy Wright

Mar. Drugs 2013, 11(4), 1140-1151; https://doi.org/10.3390/md11041140 - 2 Apr 2013

Cited by 16 | Viewed by 7211

Abstract

Pancreatic cancer, the fourth leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear [...] Read more.

Pancreatic cancer, the fourth leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear Factor Kappa B (NFκB), a signal transduction molecule that promotes cell survival, proliferation and angiogenesis. In an effort to identify novel inhibitors of NFκB, the HBOI library of pure compounds was screened using a reporter cell line that produces luciferin under the transcriptional control of NFκB. Seven compounds were identified through this screen, but in the case of five of them, their reported mechanism of action made them unlikely to be specific NFκB inhibitors. Spongiatriol, a marine furanoditerpenoid that was first isolated in the 1970s, is shown here to inhibit NFκB transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NFκB in the AsPC-1 cell line, to have an IC₅₀ for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 pancreatic cancer cell lines, and to induce moderate but significant apoptosis in both the AsPC-1 and the Panc-1 cell lines. Full article

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Open AccessArticle

Biological Activities of Ethanolic Extracts from Deep-Sea Antarctic Marine Sponges

by Tom Turk, Jerneja Ambrožič Avguštin, Urška Batista, Gašper Strugar, Rok Kosmina, Sandra Čivović, Dorte Janussen, Silke Kauferstein, Dietrich Mebs and Kristina Sepčić

Mar. Drugs 2013, 11(4), 1126-1139; https://doi.org/10.3390/md11041126 - 2 Apr 2013

Cited by 29 | Viewed by 7801

Abstract

We report on the screening of ethanolic extracts from 33 deep-sea Antarctic marine sponges for different biological activities. We monitored hemolysis, inhibition of acetylcholinesterase, cytotoxicity towards normal and transformed cells and growth inhibition of laboratory, commensal and clinically and ecologically relevant bacteria. The [...] Read more.

We report on the screening of ethanolic extracts from 33 deep-sea Antarctic marine sponges for different biological activities. We monitored hemolysis, inhibition of acetylcholinesterase, cytotoxicity towards normal and transformed cells and growth inhibition of laboratory, commensal and clinically and ecologically relevant bacteria. The most prominent activities were associated with the extracts from sponges belonging to the genus Latrunculia, which show all of these activities. While most of these activities are associated to already known secondary metabolites, the extremely strong acetylcholinesterase inhibitory potential appears to be related to a compound unknown to date. Extracts from Tetilla leptoderma, Bathydorus cf. spinosus, Xestospongia sp., Rossella sp., Rossella cf. racovitzae and Halichondria osculum were hemolytic, with the last two also showing moderate cytotoxic potential. The antibacterial tests showed significantly greater activities of the extracts of these Antarctic sponges towards ecologically relevant bacteria from sea water and from Arctic ice. This indicates their ecological relevance for inhibition of bacterial microfouling. Full article

(This article belongs to the Special Issue Deep-Sea Natural Products)

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Open AccessArticle

An HPLC Method for Microanalysis and Pharmacokinetics of Marine Sulfated Polysaccharide PSS-Loaded Poly Lactic-co-Glycolic Acid (PLGA) Nanoparticles in Rat Plasma

by Peng-Li Li, Chun-Xia Li, Yi-Ting Xue, Hai-Hua Li, Hong-Bing Liu, Xiao-Xi He, Guang-Li Yu and Hua-Shi Guan

Mar. Drugs 2013, 11(4), 1113-1125; https://doi.org/10.3390/md11041113 - 2 Apr 2013

Cited by 16 | Viewed by 7212

Abstract

This study was aimed at developing a sensitive and selective HPLC method with postcolumn fluorescence derivatization for the detection of propylene glycol alginate sodium sulfate (PSS) in rat plasma. Plasma samples were prepared by a simple and fast ultrafiltration method. PSS was extracted [...] Read more.

This study was aimed at developing a sensitive and selective HPLC method with postcolumn fluorescence derivatization for the detection of propylene glycol alginate sodium sulfate (PSS) in rat plasma. Plasma samples were prepared by a simple and fast ultrafiltration method. PSS was extracted from rat plasma with d-glucuronic acid as internal standard. Isocratic chromatographic separation was performed on a TSKgel G2500 PWxL column with the mobile phase of 0.1 M sodium sulfate at a flow rate of 0.5 mL/min. Analyte detection was achieved by fluorescence detection (FLD) at 250 nm (excitation) and 435 nm (emission) using guanidine hydrochloride as postcolumn derivatizing reagent in an alkaline medium at 120 °C. The calibration curve was linear over a concentration range of 1–500 μg/mL, and the lower limit of detection (LLOD) was found to be 250 ng/mL. This validated method was applied successfully to the pharmacokinetic study of PSS and PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (PSS-NP) in rat plasma after a single intravenous (PSS only) and oral administration (PSS and PSS-NP). Significant differences in the main pharmacokinetic parameters of PSS and PSS-NP were observed. The relative bioavailability of PSS-NP was 190.10% compared with PSS which shows that PSS-NP can improve oral bioavailability. Full article

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Open AccessArticle

Isolation and Structure Elucidation of Three New Dolastanes from the Brown Alga Dilophus spiralis

by Efstathia Ioannou, Constantinos Vagias and Vassilios Roussis

Mar. Drugs 2013, 11(4), 1104-1112; https://doi.org/10.3390/md11041104 - 2 Apr 2013

Cited by 8 | Viewed by 5413

Abstract

Three new dolastane diterpenes (1–3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis. The structure elucidation and the assignment of the relative configurations of the isolated natural products were [...] Read more.

Three new dolastane diterpenes (1–3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis. The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on extensive analyses of their spectroscopic data, whereas the absolute configuration of metabolite 2 was determined through its chemical conversion to a previously isolated compound of known configuration. Full article

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Open AccessArticle

6″-Debromohamacanthin A, a Bis (Indole) Alkaloid, Inhibits Angiogenesis by Targeting the VEGFR2-Mediated PI3K/AKT/mTOR Signaling Pathways

by Gi Dae Kim, Oug Jae Cheong, Song Yi Bae, Jongheon Shin and Sang Kook Lee

Mar. Drugs 2013, 11(4), 1087-1103; https://doi.org/10.3390/md11041087 - 2 Apr 2013

Cited by 35 | Viewed by 7491

Abstract

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present [...] Read more.

Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6″-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells. Full article

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Open AccessArticle

Sponge-Derived Kocuria and Micrococcus spp. as Sources of the New Thiazolyl Peptide Antibiotic Kocurin

by Sara Palomo, Ignacio González, Mercedes De la Cruz, Jesús Martín, José Rubén Tormo, Matthew Anderson, Russell T. Hill, Francisca Vicente, Fernando Reyes and Olga Genilloud

Mar. Drugs 2013, 11(4), 1071-1086; https://doi.org/10.3390/md11041071 - 28 Mar 2013

Cited by 89 | Viewed by 11630

Abstract

Forty four marine actinomycetes of the family Microccocaceae isolated from sponges collected primarily in Florida Keys (USA) were selected from our strain collection to be studied as new sources for the production of bioactive natural products. A 16S rRNA gene based phylogenetic analysis [...] Read more.

Forty four marine actinomycetes of the family Microccocaceae isolated from sponges collected primarily in Florida Keys (USA) were selected from our strain collection to be studied as new sources for the production of bioactive natural products. A 16S rRNA gene based phylogenetic analysis showed that the strains are members of the genera Kocuria and Micrococcus. To assess their biosynthetic potential, the strains were PCR screened for the presence of secondary metabolite genes encoding nonribosomal synthetase (NRPS) and polyketide synthases (PKS). A small extract collection of 528 crude extracts generated from nutritional microfermentation arrays was tested for the production of bioactive secondary metabolites against clinically relevant strains (Bacillus subtilis, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and Candida albicans). Three independent isolates were shown to produce a new anti-MRSA bioactive compound that was identified as kocurin, a new member of the thiazolyl peptide family of antibiotics emphasizing the role of this family as a prolific resource for novel drugs. Full article

(This article belongs to the Special Issue Marine Antibiotics)

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Open AccessArticle

Bioactive Compounds from the Red Sea Marine Sponge Hyrtios Species

by Diaa T. A. Youssef, Lamiaa A. Shaala and Hani Z. Asfour

Mar. Drugs 2013, 11(4), 1061-1070; https://doi.org/10.3390/md11041061 - 28 Mar 2013

Cited by 39 | Viewed by 10154

Abstract

In continuation of our search for drug leads from Red Sea sponges we have investigated the ethyl acetate fraction of the organic extract of the Red Sea sponge Hyrtios species. Bioassay-directed fractionation of the active fraction resulted into the identification of three new [...] Read more.

In continuation of our search for drug leads from Red Sea sponges we have investigated the ethyl acetate fraction of the organic extract of the Red Sea sponge Hyrtios species. Bioassay-directed fractionation of the active fraction resulted into the identification of three new alkaloids, hyrtioerectines D–F (1–3). Hyrtioerectines D–F belong to the rare marine alkaloids in which the indole and β-carboline fragments of the molecule are linked through C-3/C-3 of both moieties. The structures of the isolated compounds were established based on different spectroscopic data including UV, IR, 1D and 2D NMR (COSY, HSQC, and HMBC) and high-resolution mass spectral studies. The antimicrobial activity against several pathogens and the free radical scavenging activity of the compounds using DPPH reagent were evaluated. In addition, the growth inhibitory activity of the compounds against three cancer cell lines was also evaluated. Hyrtioerectines D–F (1–3) displayed variable antimicrobial, free radical scavenging and cancer growth inhibition activities. Generally, compounds 1 and 3 were more active than compound 2. Full article

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Open AccessArticle

(±)-Pestalachloride D, an Antibacterial Racemate of Chlorinated Benzophenone Derivative from a Soft Coral-Derived Fungus Pestalotiopsis sp.

by Mei-Yan Wei, Dan Li, Chang-Lun Shao, Dong-Sheng Deng and Chang-Yun Wang

Mar. Drugs 2013, 11(4), 1050-1060; https://doi.org/10.3390/md11041050 - 28 Mar 2013

Cited by 60 | Viewed by 7892

Abstract

A new antibacterial chlorinated benzophenone derivative, (±)-pestalachloride D (1), along with a related analog, (±)-pestalachloride C (2), was recently isolated from the marine-derived fungus Pestalotiopsis sp. isolated from a soft coral Sarcophyton sp. collected from Yongxing Island in the [...] Read more.

A new antibacterial chlorinated benzophenone derivative, (±)-pestalachloride D (1), along with a related analog, (±)-pestalachloride C (2), was recently isolated from the marine-derived fungus Pestalotiopsis sp. isolated from a soft coral Sarcophyton sp. collected from Yongxing Island in the South China Sea. Both chiral HPLC analysis and single-crystal X-ray data indicated that 1 is a racemic mixture. Interestingly, 1 did not exhibit any effect in the zebrafish embryo teratogenicity assay, while 2 led to abnormal growth. The potential impact on zebrafish embryo growth is discussed based on their crystal structures. The main difference of crystal structures between 1 and 2 is that the six-member non-aromatic ring (O4, C10, C9, C8, C2′, and C3′) in 1 exhibits a distorted chair conformation, while 2 shows a distorted boat conformation. Moreover, compounds 1 and 2 both exhibited moderate antibacterial activity. Full article

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Open AccessCommunication

Diketopiperazine Derivatives from the Marine-Derived Actinomycete Streptomyces sp. FXJ7.328

by Pei Wang, Lijun Xi, Peipei Liu, Yi Wang, Wei Wang, Ying Huang and Weiming Zhu

Mar. Drugs 2013, 11(4), 1035-1049; https://doi.org/10.3390/md11041035 - 28 Mar 2013

Cited by 49 | Viewed by 9061

Abstract

Five new diketopiperazine derivatives, (3Z,6E)-1-N-methyl-3-benzy lidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione (1), (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione (2), (3Z,6Z)-3- (4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione (3), (3Z,6Z)-3-((1 [...] Read more.

Five new diketopiperazine derivatives, (3Z,6E)-1-N-methyl-3-benzy lidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione (1), (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione (2), (3Z,6Z)-3- (4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione (3), (3Z,6Z)-3-((1H-imidazol-5-yl)-methylene)-6-isobutylidenepiperazine-2,5-dione (4), and (3Z,6S)-3-benzylidene-6-(2S-but-2-yl)piperazine-2,5-dione (5), were isolated from the marine-derived actinomycete Streptomyces sp. FXJ7.328. The structures of 1–5 were determined by spectroscopic analysis, CD exciton chirality, the modified Mosher’s, Marfey’s and the C₃ Marfey’s methods. Compound 3 showed modest antivirus activity against influenza A (H1N1) virus with an IC₅₀ value of 41.5 ± 4.5 μM. In addition, compound 6 and 7 displayed potent anti-H1N1 activity with IC₅₀ value of 28.9 ± 2.2 and 6.8 ± 1.5 μM, respectively. Due to the lack of corresponding data in the literature, the ¹³C NMR data of (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione (6) were also reported here for the first time. Full article

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Open AccessArticle

Astaxanthin Suppresses MPP⁺-Induced Oxidative Damage in PC12 Cells through a Sp1/NR1 Signaling Pathway

by Qinyong Ye, Xiaodong Zhang, Bixia Huang, Yuangui Zhu and Xiaochun Chen

Mar. Drugs 2013, 11(4), 1019-1034; https://doi.org/10.3390/md11041019 - 28 Mar 2013

Cited by 55 | Viewed by 8477

Abstract

Objective: To investigate astaxanthin (ATX) neuroprotection, and its mechanism, on a 1-methyl-4-phenyl-pyridine ion (MPP⁺)-induced cell model of Parkinson’s disease. Methods: Mature, differentiated PC12 cells treated with MPP⁺ were used as an in vitro cell model. The MTT assay was used [...] Read more.

Objective: To investigate astaxanthin (ATX) neuroprotection, and its mechanism, on a 1-methyl-4-phenyl-pyridine ion (MPP⁺)-induced cell model of Parkinson’s disease. Methods: Mature, differentiated PC12 cells treated with MPP⁺ were used as an in vitro cell model. The MTT assay was used to investigate cell viability after ATX treatment, and western blot analysis was used to observe Sp1 (activated transcription factor 1) and NR1 (NMDA receptor subunit 1) protein expression, real-time PCR was used to monitor Sp1 and NR1 mRNA, and cell immunofluorescence was used to determine the location of Sp1 and NR1 protein and the nuclear translocation of Sp1. Results: PC12 cell viability was significantly reduced by MPP⁺ treatment. The expression of Sp1 and NR1 mRNA and protein were increased compared with the control (p < 0.01). Following co-treatment with ATX and MPP⁺, cell viability was significantly increased, and Sp1 and NR1 mRNA and protein were decreased, compared with the MPP⁺ groups (p < 0.01). In addition, mithracycin A protected PC12 cells from oxidative stress caused by MPP⁺ by specifically inhibiting the expression of Sp1. Moreover, cell immunofluorescence revealed that ATX could suppress Sp1 nuclear transfer. Conclusion: ATX inhibited oxidative stress induced by MPP⁺ in PC12 cells, via the SP1/NR1 signaling pathway. Full article

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Open AccessReview

An Overview on the Marine Neurotoxin, Saxitoxin: Genetics, Molecular Targets, Methods of Detection and Ecological Functions

by Kathleen D. Cusick and Gary S. Sayler

Mar. Drugs 2013, 11(4), 991-1018; https://doi.org/10.3390/md11040991 - 27 Mar 2013

Cited by 238 | Viewed by 17791

Abstract

Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine [...] Read more.

Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin’s ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxin research are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

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Open AccessArticle

Evidence of Anti-Proliferative Activities in Blue Mussel (Mytilus edulis) By-Products

by Lucie Beaulieu, Jacinthe Thibodeau, Claudie Bonnet, Piotr Bryl and Marie-Elise Carbonneau

Mar. Drugs 2013, 11(4), 975-990; https://doi.org/10.3390/md11040975 - 27 Mar 2013

Cited by 40 | Viewed by 6361

Abstract

Shellfish waste components contain significant levels of high quality protein and are therefore a potential source for biofunctional high-value peptides. The feasibility of applying a pilot scale enzymatic hydrolysis process to whole Mytilus edulis and, by fractionation, recover hydrolysates presenting a biological activity [...] Read more.

Shellfish waste components contain significant levels of high quality protein and are therefore a potential source for biofunctional high-value peptides. The feasibility of applying a pilot scale enzymatic hydrolysis process to whole Mytilus edulis and, by fractionation, recover hydrolysates presenting a biological activity of interest, was evaluated. Fractions were tested on four immortalized cancerous cell lines: A549, BT549, HCT15 and PC3. The 50 kDa fraction, enriched in peptides, presented anti-proliferative activity with all cell lines and results suggest a bioactive molecule synergy within the fraction. At a protein concentration of 44 µg/mL, the 50 kDa fraction induced a mortality of 90% for PC3, 89% for A549, 85% for HCT15 and of 81% for BT549 cell lines. At the low protein concentration of only 11 µg/mL the 50 kDa fraction still entails a cell mortality of 76% for A549 and 87% for PC3 cell lines. The 50 kDa fraction contains 56% of proteins, 3% of lipids and 6% of minerals on a dry weight basis and the lowest levels detected of taurine and methionine and highest levels of threonine, proline and glycine amino acids. The enzymatic hydrolysis process suggests that Mytilus edulis by-products should be viewed as high-valued products with strong potential as anti-proliferative agent and promising active ingredients in functional foods. Full article

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Mar. Drugs, Volume 11, Issue 4 (April 2013) – 30 articles , Pages 975-1426

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