Marine Drugs

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Open AccessArticle

Characterization of an Alginate Lyase, FlAlyA, from Flavobacterium sp. Strain UMI-01 and Its Expression in Escherichia coli

by Akira Inoue, Kohei Takadono, Ryuji Nishiyama, Kenji Tajima, Takanori Kobayashi and Takao Ojima

Mar. Drugs 2014, 12(8), 4693-4712; https://doi.org/10.3390/md12084693 - 22 Aug 2014

Cited by 70 | Viewed by 9967

Abstract

A major alginate lyase, FlAlyA, was purified from the periplasmic fraction of an alginate-assimilating bacterium, Flavobacterium sp. strain UMI-01. FlAlyA showed a single band of ~30 kDa on SDS-PAGE and exhibited the optimal temperature and pH at 55 °C and pH 7.7, respectively. [...] Read more.

A major alginate lyase, FlAlyA, was purified from the periplasmic fraction of an alginate-assimilating bacterium, Flavobacterium sp. strain UMI-01. FlAlyA showed a single band of ~30 kDa on SDS-PAGE and exhibited the optimal temperature and pH at 55 °C and pH 7.7, respectively. Analyses for substrate preference and reaction products indicated that FlAlyA was an endolytic poly(mannuronate) lyase (EC 4.2.2.3). A gene fragment encoding the amino-acid sequence of 288 residues for FlAlyA was amplified by inverse PCR. The N-terminal region of 21 residues except for the initiation Met in the deduced sequence was predicted as the signal peptide and the following region of six residues was regarded as propeptide, while the C-terminal region of 260 residues was regarded as the polysaccharide-lyase-family-7-type catalytic domain. The entire coding region for FlAlyA was subjected to the pCold I—Escherichia coli BL21(DE3) expression system and ~eight times higher yield of recombinant FlAlyA (recFlAlyA) than that of native FlAlyA was achieved. The recFlAlyA recovered in the periplasmic fraction of E. coli had lost the signal peptide region along with the N-terminal 3 residues of propeptide region. This suggested that the signal peptide of FlAlyA could function in part in E. coli. Full article

(This article belongs to the Special Issue Green Chemistry Approach to Marine Products)

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1198 KiB

Open AccessArticle

New Briarane Diterpenoids from Taiwanese Soft Coral Briareum violacea

by Chia-Ching Liaw, Yuan-Bin Cheng, Yun-Sheng Lin, Yao-Haur Kuo, Tsong-Long Hwang and Ya-Ching Shen

Mar. Drugs 2014, 12(8), 4677-4692; https://doi.org/10.3390/md12084677 - 22 Aug 2014

Cited by 17 | Viewed by 6693

Abstract

Ten new briarane diterpenoids, briaviolides A–J (1–10), together with six known briaranes, solenolides A and D, excavatolide A, briaexcavatolide I, 4β-acetoxy-9-deacetystylatulide lactone and 9-deacetylstylatulide lactone, were isolated from the Taiwanese soft coral, Briareum violacea. Their structures were determined [...] Read more.

Ten new briarane diterpenoids, briaviolides A–J (1–10), together with six known briaranes, solenolides A and D, excavatolide A, briaexcavatolide I, 4β-acetoxy-9-deacetystylatulide lactone and 9-deacetylstylatulide lactone, were isolated from the Taiwanese soft coral, Briareum violacea. Their structures were determined on the basis of spectroscopic data (¹H- and ¹³C-NMR, ¹H–¹H COSY, HSQC, HMBC and NOESY), HR-MS and chemical methods. The absolute configuration of briaviolide A (1) was determined by X-ray crystallographic analysis. Compounds 5, 9 and derivative 11 showed moderate inhibitory activities on superoxide-anion generation and elastase release by human neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine/ Cytochalasin B (fMLP/CB). Full article

(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)

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1282 KiB

Open AccessArticle

Localization and Characterization of Ferritin in Demospongiae: A Possible Role on Spiculogenesis

by Filipe Natalio, Stefanie Wiese, Norman Friedrich, Peter Werner and Muhammad Nawaz Tahir

Mar. Drugs 2014, 12(8), 4659-4676; https://doi.org/10.3390/md12084659 - 22 Aug 2014

Cited by 6 | Viewed by 7262

Abstract

Iron, as inorganic ion or as oxide, is widely used by biological systems in a myriad of biological functions (e.g., enzymatic, gene activation and/or regulation). In particular, marine organisms containing silica structures—diatoms and sponges—grow preferentially in the presence of iron. Using primary sponge [...] Read more.

Iron, as inorganic ion or as oxide, is widely used by biological systems in a myriad of biological functions (e.g., enzymatic, gene activation and/or regulation). In particular, marine organisms containing silica structures—diatoms and sponges—grow preferentially in the presence of iron. Using primary sponge cell culture from S. domuncula–primmorphs—as an in vitro model to study the Demospongiae spiculogenesis, we found the presence of agglomerates 50 nm in diameter exclusively inside sponge specialized cells called sclerocytes. A clear phase/material separation is observed between the agglomerates and the initial stages of intracellular spicule formation. STEM-HRTEM-EDX analysis of the agglomerates (30–100 nm) showed that they are composed of pseudohexagonal nanoparticles between 5 and 15 nm in size, displaying lattice parameters corresponding to hematite (Fe₂O₃) and mixed iron oxide phases typically attributed to ferritin. Further analysis, using western blotting, inductively coupled plasma mass spectrometry (ICP-MS), sequence alignment analysis, immunostaining and magnetic resonance imaging (MRI), of mature spicule filaments confirm the presence of ferritin within these organic structures. We suggest that S. domuncula can be classified as a dual biomineralizating organism, i.e., within the same cellular structure two distinct biomineralizing processes can occur as a result of the same cellular/metabolic function, spiculogenesis. Full article

(This article belongs to the Special Issue Marine Biomaterials)

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Open AccessArticle

The Effect of Substituent, Degree of Acetylation and Positioning of the Cationic Charge on the Antibacterial Activity of Quaternary Chitosan Derivatives

by Priyanka Sahariah, Vivek S. Gaware, Ramona Lieder, Sigríður Jónsdóttir, Martha Á. Hjálmarsdóttir, Olafur E. Sigurjonsson and Már Másson

Mar. Drugs 2014, 12(8), 4635-4658; https://doi.org/10.3390/md12084635 - 21 Aug 2014

Cited by 95 | Viewed by 11829

Abstract

A series of water-soluble cationic chitosan derivatives were prepared by chemoselective functionalization at the amino group of five different parent chitosans having varying degrees of acetylation and molecular weight. The quaternary moieties were introduced at different alkyl spacer lengths from the polymer backbone [...] Read more.

A series of water-soluble cationic chitosan derivatives were prepared by chemoselective functionalization at the amino group of five different parent chitosans having varying degrees of acetylation and molecular weight. The quaternary moieties were introduced at different alkyl spacer lengths from the polymer backbone (C-0, C-2 and C-6) with the aid of 3,6-di-O-tert-butyldimethylsilyl protection of the chitosan backbone, thus allowing full (100%) substitution of the free amino groups. All of the derivatives were characterized using ¹H-NMR, ¹H-¹H COSY and FT-IR spectroscopy, while molecular weight was determined by GPC. Antibacterial activity was investigated against Gram positive S. aureus and Gram negative E. coli. The relationship between structure and activity/toxicity was defined, considering the effect of the cationic group’s structure and its distance from the polymer backbone, as well as the degree of acetylation within a molecular weight range of 7–23 kDa for the final compounds. The N,N,N-trimethyl chitosan with 100% quaternization showed the highest antibacterial activity with moderate cytotoxicity, while increasing the spacer length reduced the activity. Trimethylammoniumyl quaternary ammonium moieties contributed more to activity than 1-pyridiniumyl moieties. In general, no trend in the antibacterial activity of the compounds with increasing molecular weight or degree of acetylation up to 34% was observed. Full article

(This article belongs to the Special Issue Advances in Marine Chitin and Chitosan)

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Open AccessArticle

Comparative Analysis of the Cytotoxic Effects of Okadaic Acid-Group Toxins on Human Intestinal Cell Lines

by Pierre-Jean Ferron, Kevin Hogeveen, Valérie Fessard and Ludovic Le Hégarat

Mar. Drugs 2014, 12(8), 4616-4634; https://doi.org/10.3390/md12084616 - 21 Aug 2014

Cited by 57 | Viewed by 7966

Abstract

The phycotoxin, okadaic acid (OA) and dinophysistoxin 1 and 2 (DTX-1 and -2) are protein phosphatase PP2A and PP1 inhibitors involved in diarrhetic shellfish poisoning (DSP). Data on the toxicity of the OA-group toxins show some differences with respect to the in vivo [...] Read more.

The phycotoxin, okadaic acid (OA) and dinophysistoxin 1 and 2 (DTX-1 and -2) are protein phosphatase PP2A and PP1 inhibitors involved in diarrhetic shellfish poisoning (DSP). Data on the toxicity of the OA-group toxins show some differences with respect to the in vivo acute toxicity between the toxin members. In order to investigate whether OA and congeners DTX-1 and -2 may induce different mechanisms of action during acute toxicity on the human intestine, we compared their toxicological effects in two in vitro intestinal cell models: the colorectal adenocarcinoma cell line, Caco-2, and the intestinal muco-secreting cell line, HT29-MTX. Using a high content analysis approach, we evaluated various cytotoxicity parameters, including apoptosis (caspase-3 activation), DNA damage (phosphorylation of histone H2AX), inflammation (translocation of NF-κB) and cell proliferation (Ki-67 production). Investigation of the kinetics of the cellular responses demonstrated that the three toxins induced a pro-inflammatory response followed by cell cycle disruption in both cell lines, leading to apoptosis. Our results demonstrate that the three toxins induce similar effects, as no major differences in the cytotoxic responses could be detected. However DTX-1 induced cytotoxic effects at five-fold lower concentrations than for OA and DTX-2. Full article

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Open AccessArticle

Echinochrome A Increases Mitochondrial Mass and Function by Modulating Mitochondrial Biogenesis Regulatory Genes

by Seung Hun Jeong, Hyoung Kyu Kim, In-Sung Song, Su Jin Noh, Jubert Marquez, Kyung Soo Ko, Byoung Doo Rhee, Nari Kim, Natalia P. Mishchenko, Sergey A. Fedoreyev, Valentin A. Stonik and Jin Han

Mar. Drugs 2014, 12(8), 4602-4615; https://doi.org/10.3390/md12084602 - 21 Aug 2014

Cited by 56 | Viewed by 9196

Abstract

Echinochrome A (Ech A) is a natural pigment from sea urchins that has been reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. In this study, we ascertained whether Ech A enhances the mitochondrial biogenesis and oxidative phosphorylation [...] Read more.

Echinochrome A (Ech A) is a natural pigment from sea urchins that has been reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. In this study, we ascertained whether Ech A enhances the mitochondrial biogenesis and oxidative phosphorylation in rat cardio myoblast H9c2 cells. To study the effects of Ech A on mitochondrial biogenesis, we measured mitochondrial mass, level of oxidative phosphorylation, and mitochondrial biogenesis regulatory gene expression. Ech A treatment did not induce cytotoxicity. However, Ech A treatment enhanced oxygen consumption rate and mitochondrial ATP level. Likewise, Ech A treatment increased mitochondrial contents in H9c2 cells. Furthermore, Ech A treatment up-regulated biogenesis of regulatory transcription genes, including proliferator-activated receptor gamma co-activator (PGC)-1α, estrogen-related receptor (ERR)-α, peroxisome proliferator-activator receptor (PPAR)-γ, and nuclear respiratory factor (NRF)-1 and such mitochondrial transcription regulatory genes as mitochondrial transcriptional factor A (TFAM), mitochondrial transcription factor B2 (TFB2M), mitochondrial DNA direct polymerase (POLMRT), single strand binding protein (SSBP) and Tu translation elongation factor (TUFM). In conclusion, these data suggest that Ech A is a potentiated marine drug which enhances mitochondrial biogenesis. Full article

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589 KiB

Open AccessCommunication

Tricyclic Guanidine Alkaloids from the Marine Sponge Acanthella cavernosa that Stabilize the Tumor Suppressor PDCD4

by Tanja Grkovic, Johanna S. Blees, Magdalena M. Bayer, Nancy H. Colburn, Cheryl L. Thomas, Curtis J. Henrich, Megan L. Peach, James B. McMahon, Tobias Schmid and Kirk R. Gustafson

Mar. Drugs 2014, 12(8), 4593-4601; https://doi.org/10.3390/md12084593 - 21 Aug 2014

Cited by 17 | Viewed by 6964

Abstract

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G ( [...] Read more.

A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC₅₀ values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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689 KiB

Open AccessArticle

Lipids and Fatty Acids of Nudibranch Mollusks: Potential Sources of Bioactive Compounds

by Natalia V. Zhukova

Mar. Drugs 2014, 12(8), 4578-4592; https://doi.org/10.3390/md12084578 - 19 Aug 2014

Cited by 42 | Viewed by 9693

Abstract

The molecular diversity of chemical compounds found in marine animals offers a good chance for the discovery of novel bioactive compounds of unique structures and diverse biological activities. Nudibranch mollusks, which are not protected by a shell and produce chemicals for various ecological [...] Read more.

The molecular diversity of chemical compounds found in marine animals offers a good chance for the discovery of novel bioactive compounds of unique structures and diverse biological activities. Nudibranch mollusks, which are not protected by a shell and produce chemicals for various ecological uses, including defense against predators, have attracted great interest for their lipid composition. Lipid analysis of eight nudibranch species revealed dominant phospholipids, sterols and monoalkyldiacylglycerols. Among polar lipids, 1-alkenyl-2-acyl glycerophospholipids (plasmalogens) and ceramide-aminoethyl phosphonates were found in the mollusks. The fatty acid compositions of the nudibranchs differed greatly from those of other marine gastropods and exhibited a wide diversity: very long chain fatty acids known as demospongic acids, a series of non-methylene-interrupted fatty acids, including unusual 21:2∆7,13, and an abundance of various odd and branched fatty acids typical of bacteria. Symbiotic bacteria revealed in some species of nudibranchs participate presumably in the production of some compounds serving as a chemical defense for the mollusks. The unique fatty acid composition of the nudibranchs is determined by food supply, inherent biosynthetic activities and intracellular symbiotic microorganisms. The potential of nudibranchs as a source of biologically active lipids and fatty acids is also discussed. Full article

(This article belongs to the Special Issue Advances and New Perspectives in Marine Biotechnology)

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Open AccessReview

Marine Sponge Derived Natural Products between 2001 and 2010: Trends and Opportunities for Discovery of Bioactives

by Mohammad Ferdous Mehbub, Jie Lei, Christopher Franco and Wei Zhang

Mar. Drugs 2014, 12(8), 4539-4577; https://doi.org/10.3390/md12084539 - 19 Aug 2014

Cited by 340 | Viewed by 24315

Abstract

Marine sponges belonging to the phylum Porifera (Metazoa), evolutionarily the oldest animals are the single best source of marine natural products. The present review presents a comprehensive overview of the source, taxonomy, country of origin or geographical position, chemical class, and biological activity [...] Read more.

Marine sponges belonging to the phylum Porifera (Metazoa), evolutionarily the oldest animals are the single best source of marine natural products. The present review presents a comprehensive overview of the source, taxonomy, country of origin or geographical position, chemical class, and biological activity of sponge-derived new natural products discovered between 2001 and 2010. The data has been analyzed with a view to gaining an outlook on the future trends and opportunities in the search for new compounds and their sources from marine sponges. Full article

(This article belongs to the Special Issue Advances and New Perspectives in Marine Biotechnology)

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Open AccessArticle

Paper Synthesis, Cytotoxicity and Apoptosis Induction in Human Tumor Cells by Galaxamide and Its Analogues

by Xi Xiao, Xiaojian Liao, Shaoling Qiu, Zihao Liu, Bin Du and Shihai Xu

Mar. Drugs 2014, 12(8), 4521-4538; https://doi.org/10.3390/md12084521 - 18 Aug 2014

Cited by 19 | Viewed by 6073 | Correction

Abstract

Our previous study reported that galaxamide, which is a cyclo-pentapeptide containing five leucines that was extracted from Galaxaura filamentosa, displayed remarkable anticancer cytotoxicity. This novel cyclo-peptide provided a new skeleton for the structural modifications used in finding new drugs with better anticancer [...] Read more.

Our previous study reported that galaxamide, which is a cyclo-pentapeptide containing five leucines that was extracted from Galaxaura filamentosa, displayed remarkable anticancer cytotoxicity. This novel cyclo-peptide provided a new skeleton for the structural modifications used in finding new drugs with better anticancer properties. In this study, five analogues were synthesized based on changing the number of d/l amino acids by adding a new amino acid, phenylalanine. Galaxamide and five of its analogues were evaluated through MTT assays to examine their cytotoxic activities. We found that modified analogue 5, which is referred to as A5, displayed broad spectrum cytotoxic activity toward every cell line tested; in addition, the IC₅₀ of A5 was lower than that of galaxamide and the other analogues. Furthermore, we used flow cytometry and western blot assays to investigate whether galaxamide and A5 could induce cancer cell apoptosis. The flow cytometric studies showed that HepG2 cells treated with different concentrations of galaxamide or A5 over 72 h displayed significant and dose-dependent increases in the percentages of early-stage apoptotic cells. Western blotting revealed that both compounds induce caspase-dependent apoptosis in HepG2 cells through a mitochondria-mediated pathway. The results demonstrate that galaxamide and its analogues have potential applications as clinical anticancer drugs. Full article

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Open AccessArticle

Accumulation of Astaxanthin by a New Haematococcus pluvialis Strain BM1 from the White Sea Coastal Rocks (Russia)

by Konstantin Chekanov, Elena Lobakova, Irina Selyakh, Larisa Semenova, Roman Sidorov and Alexei Solovchenko

Mar. Drugs 2014, 12(8), 4504-4520; https://doi.org/10.3390/md12084504 - 15 Aug 2014

Cited by 103 | Viewed by 14934

Abstract

We report on a novel arctic strain BM1 of a carotenogenic chlorophyte from a coastal habitat with harsh environmental conditions (wide variations in solar irradiance, temperature, salinity and nutrient availability) identified as Haematococcus pluvialis Flotow. Increased (25‰) salinity exerted no adverse effect on [...] Read more.

We report on a novel arctic strain BM1 of a carotenogenic chlorophyte from a coastal habitat with harsh environmental conditions (wide variations in solar irradiance, temperature, salinity and nutrient availability) identified as Haematococcus pluvialis Flotow. Increased (25‰) salinity exerted no adverse effect on the growth of the green BM1 cells. Under stressful conditions (high light, nitrogen and phosphorus deprivation), green vegetative cells of H. pluvialis BM1 grown in BG11 medium formed non-motile palmelloid cells and, eventually, hematocysts capable of a massive accumulation of the keto-carotenoid astaxanthin with a high nutraceutical and therapeutic potential. Routinely, astaxanthin was accumulated at the level of 4% of the cell dry weight (DW), reaching, under prolonged stress, 5.5% DW. Astaxanthin was predominantly accumulated in the form of mono- and diesters of fatty acids from C16 and C18 families. The palmelloids and hematocysts were characterized by the formation of red-colored cytoplasmic lipid droplets, increasingly large in size and number. The lipid droplets tended to merge and occupied almost the entire volume of the cell at the advanced stages of stress-induced carotenogenesis. The potential application of the new strain for the production of astaxanthin is discussed in comparison with the H. pluvialis strains currently employed in microalgal biotechnology. Full article

(This article belongs to the Special Issue Marine Carotenoids (Special Issue))

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553 KiB

Open AccessArticle

Oxygenated Eremophilane- and Neolemnane-Derived Sesquiterpenoids from the Soft Coral Lemnalia philippinensis

by Yun-Jie Xio, Jui-Hsin Su, Yen-Ju Tseng, Bo-Wei Chen, Wangta Liu and Jyh-Horng Sheu

Mar. Drugs 2014, 12(8), 4495-4503; https://doi.org/10.3390/md12084495 - 15 Aug 2014

Cited by 12 | Viewed by 5924

Abstract

Five sesquiterpene-related metabolites (1–5), including two new eremophilane-type compounds, philippinlins C and D (1 and 2) and a 4,5-seconeolemnane philippinlin E (3), were isolated from the organic extract of a Taiwanese soft coral Lemnalia philippinensis [...] Read more.

Five sesquiterpene-related metabolites (1–5), including two new eremophilane-type compounds, philippinlins C and D (1 and 2) and a 4,5-seconeolemnane philippinlin E (3), were isolated from the organic extract of a Taiwanese soft coral Lemnalia philippinensis. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis and by comparison of NMR data with those of related metabolites. Compound 3 was suggested to be derived from the neolemnane skeleton. Full article

(This article belongs to the Special Issue Terpenoids of Marine Origin)

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Open AccessReview

Effects of Estrogens and Estrogenic Disrupting Compounds on Fish Mineralized Tissues

by Patricia I. S. Pinto, Maria D. Estêvão and Deborah M. Power

Mar. Drugs 2014, 12(8), 4474-4494; https://doi.org/10.3390/md12084474 - 15 Aug 2014

Cited by 53 | Viewed by 14384

Abstract

Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs), regulating the transcription of responsive genes, but rapid [...] Read more.

Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs), regulating the transcription of responsive genes, but rapid non-genomic actions initiated by binding to plasma membrane receptors were recently described. A wide range of structurally diverse compounds from natural and anthropogenic sources have been shown to interact with and disrupt the normal functions of the estrogen system, and fish are particularly vulnerable to endocrine disruption, as these compounds are frequently discharged or run-off into waterways. The effect of estrogen disruptors in fish has mainly been assessed in relation to reproductive endpoints, and relatively little attention has been given to other disruptive actions. This review will overview the actions of estrogens in fish, including ER isoforms, their expression, structure and mechanisms of action. The estrogen functions will be considered in relation to mineral homeostasis and actions on mineralized tissues. The impact of estrogenic endocrine disrupting compounds on fish mineralized tissues will be reviewed, and the potential adverse outcomes of exposure to such compounds will be discussed. Current lacunae in knowledge are highlighted along with future research priorities. Full article

(This article belongs to the Special Issue Marine Fish Endocrine Disruption)

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Open AccessArticle

Structural Elucidation of Novel Saponins in the Sea Cucumber Holothuria lessoni

by Yadollah Bahrami, Wei Zhang, Tim Chataway and Chris Franco

Mar. Drugs 2014, 12(8), 4439-4473; https://doi.org/10.3390/md12084439 - 8 Aug 2014

Cited by 46 | Viewed by 11522

Abstract

Sea cucumbers are prolific producers of a wide range of bioactive compounds. This study aimed to purify and characterize one class of compound, the saponins, from the viscera of the Australian sea cucumber Holothuria lessoni. The saponins were obtained by ethanolic extraction [...] Read more.

Sea cucumbers are prolific producers of a wide range of bioactive compounds. This study aimed to purify and characterize one class of compound, the saponins, from the viscera of the Australian sea cucumber Holothuria lessoni. The saponins were obtained by ethanolic extraction of the viscera and enriched by a liquid-liquid partition process and adsorption column chromatography. A high performance centrifugal partition chromatography (HPCPC) was applied to the saponin-enriched mixture to obtain saponins with high purity. The resultant purified saponins were profiled using MALDI-MS/MS and ESI-MS/MS which revealed the structure of isomeric saponins to contain multiple aglycones and/or sugar residues. We have elucidated the structure of five novel saponins, Holothurins D/E and Holothurinosides X/Y/Z, along with seven reported triterpene glycosides, including sulfated and non-sulfated saponins containing a range of aglycones and sugar moieties, from the viscera of H. lessoni. The abundance of novel compounds from this species holds promise for biotechnological applications. Full article

(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)

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Open AccessArticle

The Skeletal Amino Acid Composition of the Marine Demosponge Aplysina cavernicola

by Susanne Ueberlein, Susanne Machill, Hendrik Niemann, Peter Proksch and Eike Brunner

Mar. Drugs 2014, 12(8), 4417-4438; https://doi.org/10.3390/md12084417 - 8 Aug 2014

Cited by 11 | Viewed by 7598

Abstract

It has been discovered during the past few years that demosponges of the order Verongida such as Aplysina cavernicola exhibit chitin-based skeletons. Verongida sponges are well known to produce bioactive brominated tyrosine derivatives. We could recently demonstrate that brominated compounds do not exclusively [...] Read more.

It has been discovered during the past few years that demosponges of the order Verongida such as Aplysina cavernicola exhibit chitin-based skeletons. Verongida sponges are well known to produce bioactive brominated tyrosine derivatives. We could recently demonstrate that brominated compounds do not exclusively occur in the cellular matrix but also in the skeletons of the marine sponges Aplysina cavernicola and Ianthella basta. Our measurements imply that these yet unknown compounds are strongly, possibly covalently bound to the sponge skeletons. In the present work, we determined the skeletal amino acid composition of the demosponge A. cavernicola especially with respect to the presence of halogenated amino acids. The investigations of the skeletons before and after MeOH extraction confirmed that only a small amount of the brominated skeleton-bound compounds dissolves in MeOH. The main part of the brominated compounds is strongly attached to the skeletons but can be extracted for example by using Ba(OH)₂. Various halogenated tyrosine derivatives were identified by GC-MS and LC-MS in these Ba(OH)₂ extracts of the skeletons. Full article

(This article belongs to the Special Issue Bioactive Halogenated Metabolites of Marine Origin)

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Open AccessArticle

Relative and Absolute Stereochemistry of Diacarperoxides: Antimalarial Norditerpene Endoperoxides from Marine Sponge Diacarnus megaspinorhabdosa

by Fan Yang, Yike Zou, Ru-Ping Wang, Mark T. Hamann, Hong-Jun Zhang, Wei-Hua Jiao, Bing-Nan Han, Shao-Jiang Song and Hou-Wen Lin

Mar. Drugs 2014, 12(8), 4399-4416; https://doi.org/10.3390/md12084399 - 8 Aug 2014

Cited by 19 | Viewed by 6846

Abstract

Five new norditerpene endoperoxides, named diacarperoxides H–L (1–5), and a new norditerpene diol, called diacardiol B (6), were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined [...] Read more.

Five new norditerpene endoperoxides, named diacarperoxides H–L (1–5), and a new norditerpene diol, called diacardiol B (6), were isolated from the South China Sea sponge, Diacarnus megaspinorhabdosa. Their structures, including conformations and absolute configurations, were determined by using spectroscopic analyses, computational approaches and chemical degradation. Diacarperoxides H–J (1–3) showed some interesting stereochemical issues, as well as antimalarial activity. Full article

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Open AccessArticle

Preparation and Characterization of Antioxidant Nanoparticles Composed of Chitosan and Fucoidan for Antibiotics Delivery

by Yi-Cheng Huang and Rou-Ying Li

Mar. Drugs 2014, 12(8), 4379-4398; https://doi.org/10.3390/md12084379 - 31 Jul 2014

Cited by 102 | Viewed by 9895

Abstract

In this study, we developed novel chitosan/fucoidan nanoparticles (CS/F NPs) using a simple polyelectrolyte self-assembly method and evaluated their potential to be antioxidant carriers. As the CS/F weight ratio was 5/1, the CS/F NPs were spherical and exhibited diameters of approximately 230–250 nm, [...] Read more.

In this study, we developed novel chitosan/fucoidan nanoparticles (CS/F NPs) using a simple polyelectrolyte self-assembly method and evaluated their potential to be antioxidant carriers. As the CS/F weight ratio was 5/1, the CS/F NPs were spherical and exhibited diameters of approximately 230–250 nm, as demonstrated by TEM. These CS/F NPs maintained compactness and stability for 25 day in phosphate-buffered saline (pH 6.0–7.4). The CS/F NPs exhibited highly potent antioxidant effects by scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH), reducing the concentration of intracellular reactive oxygen species (ROS) and superoxide anion (O₂⁻) in stimulated macrophages. The DPPH scavenging effect of CS/F NPs primarily derives from fucoidan. Furthermore, these CS/F NPs activated no host immune cells into inflammation-mediated cytotoxic conditions induced by IL-6 production and NO generation. The MTT cell viability assay revealed an absence of toxicity in A549 cells after exposure to the formulations containing 0.375 mg NPs/mL to 3 mg NPs/mL. Gentamicin (GM), an antibiotic, was used as a model drug for an in vitro releasing test. The CS/F NPs controlled the release of GM for up to 72 h, with 99% of release. The antioxidant CS/F NPs prepared in this study could thus be effective in delivering antibiotics to the lungs, particularly for airway inflammatory diseases. Full article

(This article belongs to the Special Issue Marine Biomaterials)

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Open AccessArticle

Synthesis and Biological Evaluation of Novel 3-Alkylpyridine Marine Alkaloid Analogs with Promising Anticancer Activity

by Alessandra Mirtes Marques Neves Gonçalves, Aline Brito De Lima, Maria Cristina Da Silva Barbosa, Luiz Fernando De Camargos, Júlia Teixeira De Oliveira, Camila De Souza Barbosa, José Augusto Ferreira Perez Villar, André Carvalho Costa, Isabella Viana Gomes da Silva, Luciana Maria Silva, Fernando De Pilla Varotti, Fabio Vieira Dos Santos and Gustavo Henrique Ribeiro Viana

Mar. Drugs 2014, 12(8), 4361-4378; https://doi.org/10.3390/md12084361 - 31 Jul 2014

Cited by 18 | Viewed by 7144

Abstract

Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action [...] Read more.

Cancer continues to be one of the most important health problems worldwide, and the identification of novel drugs and treatments to address this disease is urgent. During recent years, marine organisms have proven to be a promising source of new compounds with action against tumoral cell lines. Here, we describe the synthesis and anticancer activity of eight new 3-alkylpyridine alkaloid (3-APA) analogs in four steps and with good yields. The key step for the synthesis of these compounds is a Williamson etherification under phase-transfer conditions. We investigated the influence of the length of the alkyl chain attached to position 3 of the pyridine ring on the cytotoxicity of these compounds. Biological assays demonstrated that compounds with an alkyl chain of ten carbon atoms (4c and 5c) were the most active against two tumoral cell lines: RKO-AS-45-1 and HeLa. Micronucleus and TUNEL assays showed that both compounds are mutagenic and induce apoptosis. In addition, Compound 5c altered the cellular actin cytoskeleton in RKO-AS-45-1 cells. The results suggest that Compounds 4c and 5c may be novel prototype anticancer agents. Full article

(This article belongs to the Special Issue Alkaloid Analogs)

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Open AccessCommunication

New Antioxidative Secondary Metabolites from the Fruits of a Beibu Gulf Mangrove, Avicennia marina

by Cheng-Hai Gao, Xiang-Xi Yi, Wen-Pei Xie, Yin-Ning Chen, Ming-Ben Xu, Zhi-Wei Su, Lian Yu and Ri-Ming Huang

Mar. Drugs 2014, 12(8), 4353-4360; https://doi.org/10.3390/md12084353 - 29 Jul 2014

Cited by 17 | Viewed by 5575

Abstract

Further chemical investigation of the fruits of the mangrove, Avicennia marina, afforded three new phenylethyl glycosides, marinoids J–L (1–3), and a new cinnamoyl glycoside, marinoid M (4). The structures of isolates were elucidated on the basis [...] Read more.

Further chemical investigation of the fruits of the mangrove, Avicennia marina, afforded three new phenylethyl glycosides, marinoids J–L (1–3), and a new cinnamoyl glycoside, marinoid M (4). The structures of isolates were elucidated on the basis of extensive spectroscopic analysis and by comparison of the data with those of related secondary metabolites. The antioxidant activity of the isolates was evaluated using the cellular antioxidant assay (CAA), and compounds 1–4 showed antioxidant activities, with EC₅₀ values ranging from 23.0 ± 0.71 μM to 247.8 ± 2.47 μM. Full article

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Open AccessArticle

Activation of Dormant Secondary Metabolite Production by Introducing Neomycin Resistance into the Deep-Sea Fungus, Aspergillus versicolor ZBY-3

by Yuan Dong, Cheng-Bin Cui, Chang-Wei Li, Wei Hua, Chang-Jing Wu, Tian-Jiao Zhu and Qian-Qun Gu

Mar. Drugs 2014, 12(8), 4326-4352; https://doi.org/10.3390/md12084326 - 29 Jul 2014

Cited by 44 | Viewed by 8183

Abstract

A new ultrasound-mediated approach has been developed to introduce neomycin-resistance to activate silent pathways for secondary metabolite production in a bio-inactive, deep-sea fungus, Aspergillus versicolor ZBY-3. Upon treatment of the ZBY-3 spores with a high concentration of neomycin by proper ultrasound irradiation, a [...] Read more.

A new ultrasound-mediated approach has been developed to introduce neomycin-resistance to activate silent pathways for secondary metabolite production in a bio-inactive, deep-sea fungus, Aspergillus versicolor ZBY-3. Upon treatment of the ZBY-3 spores with a high concentration of neomycin by proper ultrasound irradiation, a total of 30 mutants were obtained by single colony isolation. The acquired resistance of the mutants to neomycin was confirmed by a resistance test. In contrast to the ZBY-3 strain, the EtOAc extracts of 22 of the 30 mutants inhibited the human cancer K562 cells, indicating that these mutants acquired a capability to produce antitumor metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses of the EtOAc extracts of seven bioactive mutants and the ZBY-3 strain indicated that diverse secondary metabolites have been newly produced in the mutant extracts in contrast to the ZBY-3 extract. The followed isolation and characterization demonstrated that six metabolites, cyclo(d-Pro-d-Phe) (1), cyclo(d-Tyr-d-Pro) (2), phenethyl 5-oxo-l-prolinate (3), cyclo(l-Ile-l-Pro) (4), cyclo(l-Leu-l-Pro) (5) and 3β,5α,9α-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (6), were newly produced by the mutant u2n2h3-3 compared to the parent ZBY-3 strain. Compound 3 was a new compound; 2 was isolated from a natural source for the first time, and all of these compounds were also not yet found in the metabolites of other A. versicolor strains. Compounds 1–6 inhibited the K562 cells, with inhibition rates of 54.6% (1), 72.9% (2), 23.5% (3), 29.6% (4), 30.9% (5) and 51.1% (6) at 100 μg/mL, and inhibited also other human cancer HL-60, BGC-823 and HeLa cells, to some extent. The present study demonstrated the effectiveness of the ultrasound-mediated approach to activate silent metabolite production in fungi by introducing acquired resistance to aminoglycosides and its potential for discovering new compounds from silent fungal metabolic pathways. This approach could be applied to elicit the metabolic potentials of other fungal isolates to discover new compounds from cryptic secondary metabolites. Full article

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Open AccessArticle

Marinopyrrole Derivatives with Sulfide Spacers as Selective Disruptors of Mcl-1 Binding to Pro-Apoptotic Protein Bim

by Chunwei Cheng, Yan Liu, Maria E. Balasis, Thomas P. Garner, Jerry Li, Nicholas L. Simmons, Norbert Berndt, Hao Song, Lili Pan, Yong Qin, K. C. Nicolaou, Evripidis Gavathiotis, Said M. Sebti and Rongshi Li

Mar. Drugs 2014, 12(8), 4311-4325; https://doi.org/10.3390/md12084311 - 29 Jul 2014

Cited by 11 | Viewed by 8548

Abstract

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct [...] Read more.

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl- and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC₅₀ values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation. Full article

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Open AccessArticle

Astaxanthin Alleviates Early Brain Injury Following Subarachnoid Hemorrhage in Rats: Possible Involvement of Akt/Bad Signaling

by Xiang-Sheng Zhang, Xin Zhang, Qi Wu, Wei Li, Qing-Rong Zhang, Chun-Xi Wang, Xiao-Ming Zhou, Hua Li, Ji-Xin Shi and Meng-Liang Zhou

Mar. Drugs 2014, 12(8), 4291-4310; https://doi.org/10.3390/md12084291 - 28 Jul 2014

Cited by 71 | Viewed by 8347

Abstract

Apoptosis has been proven to play a crucial role in early brain injury pathogenesis and to represent a target for the treatment of subarachnoid hemorrhage (SAH). Previously, we demonstrated that astaxanthin (ATX) administration markedly reduced neuronal apoptosis in the early period after SAH. [...] Read more.

Apoptosis has been proven to play a crucial role in early brain injury pathogenesis and to represent a target for the treatment of subarachnoid hemorrhage (SAH). Previously, we demonstrated that astaxanthin (ATX) administration markedly reduced neuronal apoptosis in the early period after SAH. However, the underlying molecular mechanisms remain obscure. In the present study, we tried to investigate whether ATX administration is associated with the phosphatidylinositol 3-kinase-Akt (PI3K/Akt) pathway, which can play an important role in the signaling of apoptosis. Our results showed that post-SAH treatment with ATX could cause a significant increase of phosphorylated Akt and Bad levels, along with a significant decrease of cleaved caspase-3 levels in the cortex after SAH. In addition to the reduced neuronal apoptosis, treatment with ATX could also significantly reduce secondary brain injury characterized by neurological dysfunction, cerebral edema and blood-brain barrier disruption. In contrast, the PI3K/Akt inhibitor, LY294002, could partially reverse the neuroprotection of ATX in the early period after SAH by downregulating ATX-induced activation of Akt/Bad and upregulating cleaved caspase-3 levels. These results provided the evidence that ATX could attenuate apoptosis in a rat SAH model, potentially, in part, through modulating the Akt/Bad pathway. Full article

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Open AccessArticle

Cytotoxic and Apoptosis-Inducing Activity of Triterpene Glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 Cells

by Juanjuan Wang, Hua Han, Xiangfeng Chen, Yanghua Yi and Hongxiang Sun

Mar. Drugs 2014, 12(8), 4274-4290; https://doi.org/10.3390/md12084274 - 24 Jul 2014

Cited by 45 | Viewed by 7655

Abstract

The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in [...] Read more.

The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in HepG2 cells was further investigated by determining its effect on the morphology, mitochondrial transmembrane potential (Δψ_m) and mRNA expression levels of the apoptosis-related genes. The results showed that the number of glycosyl residues in sugar chains and the side chain of aglycone could affect their cytotoxicity towards tumor cells and selective cytotoxicity. 1 significantly inhibited cell viability and induced apoptosis in HepG2 cells. 1 also markedly decreased the Δψ_m and Bcl-2/Bax mRNA express ratio, and up-regulated the mRNA expression levels of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. Therefore, 1 induced apoptosis in HepG2 cells through both intrinsic and extrinsic pathway. These findings could potentially promote the usage of these glycosides as leading compounds for developing new antitumor drugs. Full article

(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)

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Mar. Drugs, Volume 12, Issue 8 (August 2014) – 23 articles , Pages 4274-4712

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