http://www.mdpi.com/journal/marinedrugs Latest open access articles published in Mar. Drugs at http://www.mdpi.com/journal/marinedrugs http://www.mdpi.com/1660-3397/10/6/1203 Four new eunicellin-based diterpenes, simplexins P–S (1–4), and the known compound simplexin A (5), have been isolated from the soft coral Klyxum simplex. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly 1D and 2D NMR experiments. Compounds 1 and 3–5 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines, 3 being the most cytotoxic. http://www.mdpi.com/1660-3397/10/6/1203 Fri, 25 May 2012 00:00:00 CEST Marine Drugs 2012-05-25 10 6 Article 1203 1211 1660-3397 Simplexins P–S, Eunicellin-Based Diterpenes from the Soft Coral Klyxum simplex 2012-05-25 doi: 10.3390/md10061203 Shwu-Li Wu Jui-Hsin Su Chiung-Yao Huang Chi-Jen Tai Ping-Jyun Sung Chih-Chung Liaw Jyh-Horng Sheu http://www.mdpi.com/1660-3397/10/6/1192 Genomic mining revealed one major nonribosomal peptide synthetase (NRPS) phylogenetic cluster in 12 marine sponge species, one ascidian, an actinobacterial isolate and seawater. Phylogenetic analysis predicts its taxonomic affiliation to the actinomycetes and hydroxy-phenyl-glycine as a likely substrate. Additionally, a phylogenetically distinct NRPS gene cluster was discovered in the microbial metagenome of the sponge Aplysina aerophoba, which shows highest similarities to NRPS genes that were previously assigned, by ways of single cell genomics, to a Chloroflexi sponge symbiont. Genomic mining studies such as the one presented here for NRPS genes, contribute to on-going efforts to characterize the genomic potential of sponge-associated microbiota for secondary metabolite biosynthesis. http://www.mdpi.com/1660-3397/10/6/1192 Fri, 25 May 2012 00:00:00 CEST Marine Drugs 2012-05-25 10 6 Article 1192 1202 1660-3397 Diversity of Nonribosomal Peptide Synthetase Genes in the Microbial Metagenomes of Marine Sponges 2012-05-25 doi: 10.3390/md10061192 Sheila Marie Pimentel-Elardo Lubomir Grozdanov Sebastian Proksch Ute Hentschel http://www.mdpi.com/1660-3397/10/5/1180 To compare the chemical differences between the medicinal and cultured oyster shells, their chemical profiles were investigated. Using the ultra performance liquid chromatography-electron spraying ionization-mass spectrometry (UPLC-ESI-MS), combined with principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA), the discrimination of the chemical characteristics among the medicinal and cultured oyster shells was established. Moreover, the chemometric analysis revealed some potential key compounds. After a large-scale extraction and isolation, one target key compound was unambiguously identified as caffeine (1) based on extensive spectroscopic data analysis (1D and 2D NMR, MS, and UV) and comparison with literature data. http://www.mdpi.com/1660-3397/10/5/1180 Wed, 23 May 2012 00:00:00 CEST Marine Drugs 2012-05-23 10 5 Article 1180 1191 1660-3397 Chemical Profiles and Identification of Key Compound Caffeine in Marine-Derived Traditional Chinese Medicine Ostreae concha 2012-05-23 doi: 10.3390/md10051180 Xue Yang Shi-Lu Zhou Ai-Cui Ma Hai-Tao Xu Hua-Shi Guan Hong-Bing Liu http://www.mdpi.com/1660-3397/10/5/1169 A new labdane-type diterpenoid, echinolabdane A (1), and a new sterol, 6-epi-yonarasterol B (2), were isolated from a gorgonian coral identified as Echinomuricea sp. The structures of metabolites 1 and 2 were elucidated by spectroscopic methods. Echinolabdane A (1) possesses a novel tetracyclic skeleton with an oxepane ring jointed to an α,β-unsaturated-γ-lactone ring by a hemiketal moiety, and this compound is the first labdane-type diterpenoid to be obtained from marine organisms belonging to the phylum Cnidaria. 6-epi-Yonarasterol B (2) is the first steroid derivative to be isolated from gorgonian coral belonging to the genus Echinomuricea, and this compound displayed significant inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils. http://www.mdpi.com/1660-3397/10/5/1169 Wed, 23 May 2012 00:00:00 CEST Marine Drugs 2012-05-23 10 5 Article 1169 1179 1660-3397 Bioactive Compounds from a Gorgonian Coral Echinomuricea sp. (Plexauridae) 2012-05-23 doi: 10.3390/md10051169 Hsu-Ming Chung Pei-Han Hong Jui-Hsin Su Tsong-Long Hwang Mei-Chin Lu Lee-Shing Fang Yang-Chang Wu Jan-Jung Li Jih-Jung Chen Wei-Hsien Wang Ping-Jyun Sung http://www.mdpi.com/1660-3397/10/5/1156 Two new briarane diterpenoids, briarenolides, F (1) and G (2), were isolated from an octocoral identified as Briareum sp. The structures of briaranes 1 and 2 were established by spectroscopic methods and by comparison of the spectroscopic data with those of known briarane analogues. Briarenolide F was proven to be the first 6-hydroperoxybriarane derivative and this compound displayed a significant inhibitory effect on the generation of superoxide anion by human neutrophils. http://www.mdpi.com/1660-3397/10/5/1156 Wed, 23 May 2012 00:00:00 CEST Marine Drugs 2012-05-23 10 5 Article 1156 1168 1660-3397 Briarenolides F and G, New Briarane Diterpenoids from a Briareum sp. Octocoral 2012-05-23 doi: 10.3390/md10051156 Pei-Han Hong Yin-Di Su Jui-Hsin Su Yung-Husan Chen Tsong-Long Hwang Ching-Feng Weng Chia-Hung Lee Zhi-Hong Wen Jyh-Horng Sheu Nai-Cheng Lin Yueh-Hsiung Kuo Ping-Jyun Sung http://www.mdpi.com/1660-3397/10/5/1138 We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development. http://www.mdpi.com/1660-3397/10/5/1138 Wed, 23 May 2012 00:00:00 CEST Marine Drugs 2012-05-23 10 5 Article 1138 1155 1660-3397 Preclinical Evaluation of Anticancer Efficacy and Pharmacological Properties of FBA-TPQ, a Novel Synthetic Makaluvamine Analog 2012-05-23 doi: 10.3390/md10051138 Xiangrong Zhang Hongxia Xu Xu Zhang Sukesh Voruganti Srinivasan Murugesan Dwayaja H. Nadkarni Sadanandan E. Velu Ming-Hai Wang Wei Wang Ruiwen Zhang http://www.mdpi.com/1660-3397/10/5/1126 Lagunamides A (1) and B (2) are potent cytotoxic cyclic depsipeptides isolated from the filamentous marine cyanobacterium, Lyngbya majuscula, from Pulau Hantu, Singapore. These compounds are structurally related to the aurilide-class of molecules, which have been reported to possess exquisite antiproliferative activities against cancer cells. The present study presents preliminary findings on the selectivity of lagunamides against various cancer cell lines as well as their mechanism of action by studying their effects on programmed cell death or apoptosis. Lagunamide A exhibited a selective growth inhibitory activity against a panel of cancer cell lines, including P388, A549, PC3, HCT8, and SK-OV3 cells, with IC50 values ranging from 1.6 nM to 6.4 nM. Morphological studies showed blebbing at the surface of cancer cells as well as cell shrinkage accompanied by loss of contact with the substratum and neighboring cells. Biochemical studies using HCT8 and MCF7 cancer cells suggested that the cytotoxic effect of 1 and 2 might act via induction of mitochondrial mediated apoptosis. Data presented in this study warrants further investigation on the mode of action and underscores the importance of the lagunamides as potential anticancer agents. http://www.mdpi.com/1660-3397/10/5/1126 Wed, 23 May 2012 00:00:00 CEST Marine Drugs 2012-05-23 10 5 Article 1126 1137 1660-3397 Biochemical Studies of the Lagunamides, Potent Cytotoxic Cyclic Depsipeptides from the Marine Cyanobacterium Lyngbya majuscula 2012-05-23 doi: 10.3390/md10051126 Ashootosh Tripathi Wanru Fang David Tai Leong Lik Tong Tan http://www.mdpi.com/1660-3397/10/5/1103 Drug-resistant Staphylococcus aureus is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple S. aureus strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga Chrysophaeum taylori that inhibit the growth of S. aureus and methicillin-resistant S. aureus (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in C. taylori located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse S. aureus strains. We find that the chrysophaentins show similar activity against all S. aureus strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs. http://www.mdpi.com/1660-3397/10/5/1103 Tue, 22 May 2012 00:00:00 CEST Marine Drugs 2012-05-22 10 5 Article 1103 1125 1660-3397 Geographic Variability and Anti-Staphylococcal Activity of the Chrysophaentins and Their Synthetic Fragments 2012-05-22 doi: 10.3390/md10051103 Jessica L. Keffer Jared T. Hammill John R. Lloyd Alberto Plaza Peter Wipf Carole A. Bewley http://www.mdpi.com/1660-3397/10/5/1092 The present study reports the identification of two new staurosporine derivatives, 2-hydroxy-7-oxostaurosporine (1) and 3-hydroxy-7-oxostaurosporine (2), obtained from mid-polar fractions of an aqueous methanol extract of the tunicate Eudistoma vannamei, endemic to the northeast coast of Brazil. The mixture of 1 and 2 displayed IC50 values in the nM range and was up to 14 times more cytotoxic than staurosporine across a panel of tumor cell lines, as evaluated using the MTT assay. http://www.mdpi.com/1660-3397/10/5/1092 Mon, 21 May 2012 00:00:00 CEST Marine Drugs 2012-05-21 10 5 Article 1092 1102 1660-3397 Structure Elucidation and Anticancer Activity of 7-Oxostaurosporine Derivatives from the Brazilian Endemic Tunicate Eudistoma vannamei 2012-05-21 doi: 10.3390/md10051092 Paula Christine Jimenez Diego Veras Wilke Elthon Gois Ferreira Renata Takeara Manoel Odorico de Moraes Edilberto Rocha Silveira Tito Monteiro da Cruz Lotufo Norberto Peporine Lopes Leticia Veras Costa-Lotufo http://www.mdpi.com/1660-3397/10/5/1081 Chemical investigation of the EtOAc extract of the endophytic fungus Bionectria ochroleuca, isolated from the inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae) from Hainan island (China), yielded two new peptides, pullularins E and F (1 and 2) together with three known compounds (3–5). The structures of the new compounds were unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of amino acids were determined by HPLC analysis of acid hydrolysates using Marfey’s method. The isolated compounds exhibited pronounced to moderate cytotoxic activity against the mouse lymphoma cells (L5178Y) with EC50 values ranging between 0.1 and 6.7 µg/mL. http://www.mdpi.com/1660-3397/10/5/1081 Fri, 18 May 2012 00:00:00 CEST Marine Drugs 2012-05-18 10 5 Article 1081 1091 1660-3397 Pullularins E and F, Two New Peptides from the Endophytic Fungus Bionectria ochroleuca Isolated from the Mangrove Plant Sonneratia caseolaris 2012-05-18 doi: 10.3390/md10051081 Weaam Ebrahim Julia Kjer Mustapha El Amrani Victor Wray Wenhan Lin Rainer Ebel Daowan Lai Peter Proksch http://www.mdpi.com/1660-3397/10/5/1066 Lizard fish (Saurida elongata) muscle protein was hydrolyzed using neutral protease to produce protein hydrolysate (LFPH), and the hydrolysis conditions were investigated using response-surface methodology. The optimum conditions for producing peptides with the highest angiotensin-I converting enzyme (ACE)-inhibitory activity were the following: enzyme-to-substrate ratio of 10,000 U/g, temperature of 48 °C, pH 7.0, and hydrolysis time of 2 h. Under these conditions, the ACE-inhibitory activity of LFPH and the degree of hydrolysis were 84% and 24%, respectively. A novel ACE-inhibitory peptide was isolated from LFPH using ultrafiltration, Sephadex G-15, and high-performance liquid chromatography. The amino acid sequence of the ACE-inhibitory peptide was identified as Ser-Pro-Arg-Cys-Arg (SPRCR), and its IC50 was 41 ± 1 µM. http://www.mdpi.com/1660-3397/10/5/1066 Fri, 18 May 2012 00:00:00 CEST Marine Drugs 2012-05-18 10 5 Article 1066 1080 1660-3397 Optimization of Hydrolysis Conditions for the Production of Angiotensin-I Converting Enzyme-Inhibitory Peptides and Isolation of a Novel Peptide from Lizard Fish (Saurida elongata) Muscle Protein Hydrolysate 2012-05-18 doi: 10.3390/md10051066 Shanguang Wu Jianhua Sun Zhangfa Tong Xiongdiao Lan Zhongxing Zhao Dankui Liao http://www.mdpi.com/1660-3397/10/5/1044 The dinoflagellate Gymnodinium catenatum produces paralyzing shellfish poisons that are consumed and accumulated by bivalves. We performed short-term feeding experiments to examine ingestion, accumulation, biotransformation, histopathology, and paralysis in the juvenile Pacific calico scallop Argopecten ventricosus that consume this dinoflagellate. Depletion of algal cells was measured in closed systems. Histopathological preparations were microscopically analyzed. Paralysis was observed and the time of recovery recorded. Accumulation and possible biotransformation of toxins were measured by HPLC analysis. Feeding activity in treated scallops showed that scallops produced pseudofeces, ingestion rates decreased at 8 h; approximately 60% of the scallops were paralyzed and melanin production and hemocyte aggregation were observed in several tissues at 15 h. HPLC analysis showed that the only toxins present in the dinoflagellates and scallops were the N-sulfo-carbamoyl toxins (C1, C2); after hydrolysis, the carbamate toxins (epimers GTX2/3) were present. C1 and C2 toxins were most common in the mantle, followed by the digestive gland and stomach-complex, adductor muscle, kidney and rectum group, and finally, gills. Toxin profiles in scallop tissue were similar to the dinoflagellate; biotransformations were not present in the scallops in this short-term feeding experiment. http://www.mdpi.com/1660-3397/10/5/1044 Wed, 09 May 2012 00:00:00 CEST Marine Drugs 2012-05-09 10 5 Article 1044 1065 1660-3397 Accumulation, Biotransformation, Histopathology and Paralysis in the Pacific Calico Scallop Argopecten ventricosus by the Paralyzing Toxins of the Dinoflagellate Gymnodinium catenatum 2012-05-09 doi: 10.3390/md10051044 Amada Y. Escobedo-Lozano Norma Estrada Felipe Ascencio Gerardo Contreras Rosalba Alonso-Rodriguez http://www.mdpi.com/1660-3397/10/5/1037 Chemical investigation of the cave sponge Xestospongia sp. resulted in the isolation of three new polyacetylenic long chain compounds along with two known metabolites. The structures of the new metabolites were established by NMR and MS analyses. The antibacterial activity of the new metabolites was also evaluated. http://www.mdpi.com/1660-3397/10/5/1037 Mon, 07 May 2012 00:00:00 CEST Marine Drugs 2012-05-07 10 5 Article 1037 1043 1660-3397 Antibacterial Secondary Metabolites from the Cave Sponge Xestospongia sp. 2012-05-07 doi: 10.3390/md10051037 Sridevi Ankisetty Marc Slattery http://www.mdpi.com/1660-3397/10/5/1027 Three new polyketides, woodylides A–C (1–3), were isolated from the ethanol extract of the South China Sea sponge Plakortis simplex. The structures were elucidated by spectroscopic data (IR, 1D and 2D NMR, and HRESIMS). The absolute configurations at C-3 of 1 and 3 were determined by the modified Mosher’s method. Antifungal, cytotoxic, and PTP1B inhibitory activities of these polyketides were evaluated. Compounds 1 and 3 showed antifungal activity against fungi Cryptococcus neoformans with IC50 values of 3.67 and 10.85 µg/mL, respectively. In the cytotoxicity test, compound 1 exhibited a moderate effect against the HeLa cell line with an IC50 value of 11.2 µg/mL, and compound 3 showed cytotoxic activity against the HCT-116 human colon tumor cell line and PTP1B inhibitory activity with IC50 values of 9.4 and 4.7 µg/mL, respectively. http://www.mdpi.com/1660-3397/10/5/1027 Mon, 07 May 2012 00:00:00 CEST Marine Drugs 2012-05-07 10 5 Article 1027 1036 1660-3397 Woodylides A–C, New Cytotoxic Linear Polyketides from the South China Sea Sponge Plakortis simplex 2012-05-07 doi: 10.3390/md10051027 Hao-Bing Yu Xiang-Fang Liu Ying Xu Jian-Hong Gan Wei-Hua Jiao Yang Shen Hou-Wen Lin http://www.mdpi.com/1660-3397/10/5/1019 In order to search for novel bioactive substances from marine organisms, we have investigated the organic extracts of the Taiwanese octocoral Briareum excavatum collected at Orchid Island. Three new briarane-type diterpenoids, briacavatolides A–C (1–3) as well as two known briaranes, briaexcavatolide U (4) and briaexcavatin L (5) were isolated from the acetone extract. The structures of these compounds were elucidated by extensive NMR spectroscopic analysis and physical data. The anti-HCMV (human cytomegalovirus) activity of 1–5 and their cytotoxicity against selected cancer cell lines were evaluated. http://www.mdpi.com/1660-3397/10/5/1019 Wed, 02 May 2012 00:00:00 CEST Marine Drugs 2012-05-02 10 5 Article 1019 1026 1660-3397 Briacavatolides A–C, New Briaranes from the Taiwanese Octocoral Briareum excavatum 2012-05-02 doi: 10.3390/md10051019 Tsun-Tai Yeh Shang-Kwei Wang Chang-Feng Dai Chang-Yih Duh http://www.mdpi.com/1660-3397/10/5/998 High irradiation and the presence of xenobiotics favor the formation of reactive oxygen species in marine environments. Organisms have developed antioxidant defenses, including the accumulation of carotenoids that must be obtained from the diet. Astaxanthin is the main carotenoid in marine crustaceans where, among other functions, it scavenges free radicals thus protecting cell compounds against oxidation. Four diets with different carotenoid composition were used to culture the meiobenthic copepod Amphiascoides atopus to assess how its astaxanthin content modulates the response to prooxidant stressors. A. atopus had the highest astaxanthin content when the carotenoid was supplied as astaxanthin esters (i.e., Haematococcus meal). Exposure to short wavelength UV light elicited a 77% to 92% decrease of the astaxanthin content of the copepod depending on the culture diet. The LC50 values of A. atopus exposed to copper were directly related to the initial astaxanthin content. The accumulation of carotenoids may ascribe competitive advantages to certain species in areas subjected to pollution events by attenuating the detrimental effects of metals on survival, and possibly development and fecundity. Conversely, the loss of certain dietary items rich in carotenoids may be responsible for the amplification of the effects of metal exposure in consumers. http://www.mdpi.com/1660-3397/10/5/998 Fri, 27 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-27 10 5 Article 998 1018 1660-3397 Dietary Carotenoids Regulate Astaxanthin Content of Copepods and Modulate Their Susceptibility to UV Light and Copper Toxicity 2012-04-27 doi: 10.3390/md10050998 Maria-José Caramujo Carla C. C. R. de Carvalho Soraya J. Silva Kevin R. Carman http://www.mdpi.com/1660-3397/10/5/987 One new pentacyclic sesterterpene, hippospongide A (1), and one new scalarane sesterterpenoid, hippospongide B (2), along with six previously reported known scalarane–type sesterterpenes (3–8), were isolated from a sponge Hippospongia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. These metabolites are the first pentacyclic sesterterpene and scalarane-type sesterterpenes to be reported from this genus. Compounds 3–5 exhibited significant cytotoxicity against DLD-1, HCT-116, T-47D and K562 cancer cell lines. http://www.mdpi.com/1660-3397/10/5/987 Fri, 27 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-27 10 5 Article 987 997 1660-3397 Cytotoxic Sesterterpenoids from a Sponge Hippospongia sp. 2012-04-27 doi: 10.3390/md10050987 Yu-Chia Chang Shang-Wei Tseng Li-Lian Liu Yalan Chou Yuan-Shing Ho Mei-Chin Lu Jui-Hsin Su http://www.mdpi.com/1660-3397/10/5/963 Biologically active compounds with different modes of action, such as, antiproliferative, antioxidant, antimicrotubule, have been isolated from marine sources, specifically algae and cyanobacteria. Recently research has been focused on peptides from marine animal sources, since they have been found as secondary metabolites from sponges, ascidians, tunicates, and mollusks. The structural characteristics of these peptides include various unusual amino acid residues which may be responsible for their bioactivity. Moreover, protein hydrolysates formed by the enzymatic digestion of aquatic and marine by-products are an important source of bioactive peptides. Purified peptides from these sources have been shown to have antioxidant activity and cytotoxic effect on several human cancer cell lines such as HeLa, AGS, and DLD-1. These characteristics imply that the use of peptides from marine sources has potential for the prevention and treatment of cancer, and that they might also be useful as molecular models in anticancer drug research. This review focuses on the latest studies and critical research in this field, and evidences the immense potential of marine animals as bioactive peptide sources. http://www.mdpi.com/1660-3397/10/5/963 Thu, 26 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-26 10 5 Review 963 986 1660-3397 Bioactive Peptides and Depsipeptides with Anticancer Potential: Sources from Marine Animals 2012-04-26 doi: 10.3390/md10050963 Guadalupe-Miroslava Suarez-Jimenez Armando Burgos-Hernandez Josafat-Marina Ezquerra-Brauer http://www.mdpi.com/1660-3397/10/4/953 Infections caused by drug-resistant pathogens are on the rise. The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains exemplifies the urgent need for new antibiotics. The marine natural product, marinopyrrole A, was previously shown to have potent antibiotic activity against Gram-positive pathogens, including MRSA. However, its minimum inhibitory concentration (MIC) against MRSA was increased by >500 fold in the presence of 20% human serum, thus greatly limiting therapeutic potential. Here we report our discovery of a novel derivative of marinopyrrole A, designated 1a, featuring a 2–4 fold improved MIC against MRSA and significantly less susceptibility to serum inhibition. Importantly, compound 1a displayed rapid and concentration-dependent killing of MRSA. Compared to the natural product counterpart, compound 1a provides an important natural product based scaffold for further Structure Activity Relationship (SAR) and optimization. http://www.mdpi.com/1660-3397/10/4/953 Tue, 24 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-24 10 4 Article 953 962 1660-3397 Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (I) 2012-04-24 doi: 10.3390/md10040953 Yan Liu Nina M. Haste Wdee Thienphrapa Victor Nizet Mary Hensler Rongshi Li http://www.mdpi.com/1660-3397/10/4/932 A series of new derivatives (5–29) of marine-derived bostrycin (1) were synthesized. The in vitro cytotoxic activities of all compounds were evaluated against MCF-7, MDA-MB-435, A549, HepG2, HCT-116 and MCF-10A cells using the MTT method. The compounds 7, 8, 22, 23, 25, 28 and 29 of the total showed comparable activity to epirubicin, the positive control, against the tested cancer cell lines. However, these compounds also exhibited cytotoxicity towards MCF-10A cells. The structure-activity relationship (SAR) of bostrycin derivatives was also discussed based on the obtained experimental data. http://www.mdpi.com/1660-3397/10/4/932 Tue, 24 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-24 10 4 Article 932 952 1660-3397 Studies on the Synthesis of Derivatives of Marine-Derived Bostrycin and Their Structure-Activity Relationship against Tumor Cells 2012-04-24 doi: 10.3390/md10040932 Hong Chen Lili Zhong Yuhua Long Jia Li Jueheng Wu Lan Liu Shengping Chen Yongcheng Lin Mengfeng Li Xun Zhu Zhigang She http://www.mdpi.com/1660-3397/10/4/918 Glycolipids were extracted from the red alga Osmundaria obtusiloba from Southeastern Brazilian coast. The acetone insoluble material was extracted with chloroform/methanol and the lipids, enriched in glycolipids, were fractionated on a silica gel column eluted with chloroform, acetone and then methanol. Three major orcinol-positive bands were found in the acetone and methanol fractions, being detected by thin layer chromatography. The structures of the corresponding glycolipids were elucidated by ESI-MS and 1H/13C NMR analysis, on the basis of their tandem-MS behavior and HSQC, TOCSY fingerprints. For the first time, the structure of sulfoquinovosyldiacylglycerol from the red alga Osmundaria obtusiloba was characterized. This molecule exhibited potent antiviral activity against HSV-1 and HSV-2 with EC50 values of 42 µg/mL to HSV-1 and 12 µg/mL to HSV-2, respectively. Two other glycolipids, mono- and digalactosyldiacylglycerol, were also found in the alga, being characterized by ESI-MS/MS. The structural elucidation of algae glycolipids is a first step for a better understanding of the relation between these structures and their biological activities. http://www.mdpi.com/1660-3397/10/4/918 Mon, 23 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-23 10 4 Article 918 931 1660-3397 Structural Characterization and Anti-HSV-1 and HSV-2 Activity of Glycolipids from the Marine Algae Osmundaria obtusiloba Isolated from Southeastern Brazilian Coast 2012-04-23 doi: 10.3390/md10040918 Lauro M. de Souza Guilherme L. Sassaki Maria Teresa Villela Romanos Eliana Barreto-Bergter http://www.mdpi.com/1660-3397/10/4/900 Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC50 0.36–13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC50 12.2–26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ0 cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G2/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells. http://www.mdpi.com/1660-3397/10/4/900 Mon, 16 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-16 10 4 Article 900 917 1660-3397 Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole 2012-04-16 doi: 10.3390/md10040900 Kirsten J. Meyer A. Jonathan Singh Alanna Cameron An S. Tan Dora C. Leahy David O’Sullivan Praneta Joshi Anne C. La Flamme Peter T. Northcote Michael V. Berridge John H. Miller http://www.mdpi.com/1660-3397/10/4/890 It has been suggested that oxidative stress activates various intracellular signaling pathways leading to secretion of a variety of pro-inflammatory cytokines and chemokines. SHP-1 is a protein tyrosine phosphatase (PTP) which acts as a negative regulator of immune cytokine signaling. However, intracellular hydrogen peroxide (H2O2), generated endogenously upon stimulation and exogenously from environmental oxidants, has been known to be involved in the process of intracellular signaling through inhibiting various PTPs, including SHP-1. In this study, we investigated the potential role of astaxanthin, an antioxidant marine carotenoid, in re-establishing SHP-1 negative regulation on pro-inflammatory cytokines secretion in U-937 cell line stimulated with oxidative stimulus. ELISA measurement suggested that ASTA treatment (10 µM) reduced pro-inflammatory cytokines secretion (IL-1β, IL-6 and TNF-α) induced through H2O2, (100 µM). Furthermore, this property is elicited by restoration of basal SHP-1 protein expression level and reduced NF-κB (p65) nuclear expression, as showed by western blotting experiments. http://www.mdpi.com/1660-3397/10/4/890 Tue, 10 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-10 10 4 Article 890 899 1660-3397 Astaxanthin Treatment Reduced Oxidative Induced Pro-Inflammatory Cytokines Secretion in U937: SHP-1 as a Novel Biological Target 2012-04-10 doi: 10.3390/md10040890 Lorenza Speranza Mirko Pesce Antonia Patruno Sara Franceschelli Maria Anna de Lutiis Alfredo Grilli Mario Felaco http://www.mdpi.com/1660-3397/10/4/881 4-Amino-7-(5′-deoxy-β-d-xylofuranosyl)-5-iodo-pyrrolo[2,3-d]pyrimidine 1, an unusual naturally occurring marine nucleoside isolated from an ascidan, Diplosoma sp., was synthesized from d-xylose in seven steps with 28% overall yield on 10 g scale. The key step was Vorbrüggen glycosylation of 5-iodo-pyrrolo[2,3-d]pyrimidine with 5-deoxy-1, 2-O-diacetyl-3-O-benzoyl-d-xylofuranose. Its absolute configuration was confirmed. http://www.mdpi.com/1660-3397/10/4/881 Tue, 10 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-10 10 4 Communication 881 889 1660-3397 First Total Synthesis of a Naturally Occurring Iodinated 5′-Deoxyxylofuranosyl Marine Nucleoside 2012-04-10 doi: 10.3390/md10040881 Jianyun Sun Yanhui Dou Haixin Ding Ruchun Yang Qi Sun Qiang Xiao http://www.mdpi.com/1660-3397/10/4/849 Marine systems are very diverse and recognized as being sources of a wide range of biomolecules. This review provides an overview of metabolite profiling based on mass spectrometry (MS) approaches in marine organisms and their environments, focusing on recent advances in the field. We also point out some of the technical challenges that need to be overcome in order to increase applications of metabolomics in marine systems, including extraction of chemical compounds from different matrices and data management. Metabolites being important links between genotype and phenotype, we describe added value provided by integration of data from metabolite profiling with other layers of omics, as well as their importance for the development of systems biology approaches in marine systems to study several biological processes, and to analyze interactions between organisms within communities. The growing importance of MS-based metabolomics in chemical ecology studies in marine ecosystems is also illustrated. http://www.mdpi.com/1660-3397/10/4/849 Thu, 05 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-05 10 4 Review 849 880 1660-3397 Mass Spectrometry-Based Metabolomics to Elucidate Functions in Marine Organisms and Ecosystems 2012-04-05 doi: 10.3390/md10040849 Sophie Goulitquer Philippe Potin Thierry Tonon http://www.mdpi.com/1660-3397/10/4/834 Cerium binding activity of three different water soluble pectin compounds of different origin was studied in a batch sorption system. The Langmuir, Freundlich and BET sorption models were adopted to describe the binding reactions between metal ions and pectin molecules. The Langmuir model provided the best fit. Within the pH range from 4.0 to 6.0, the largest amount of the cerium ions was bound by pectin isolated from the seagrass Phylospadix iwatensis in comparison to pectin extracted from the seagrass Zostera marina and pectin obtained from citrus peel (commercial grade). The Langmuir constants were also highest for the pectin samples isolated from the seagrass P. iwatensis. The results obtained from this study suggest that pectin is a prospective source for the development of radioisotope-removing pharmaceuticals. http://www.mdpi.com/1660-3397/10/4/834 Thu, 05 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-05 10 4 Article 834 848 1660-3397 Cerium Binding Activity of Pectins Isolated from the Seagrasses Zostera marina and Phyllospadix iwatensis 2012-04-05 doi: 10.3390/md10040834 Yuri Khotimchenko Elena Khozhaenko Valeri Kovalev Maxim Khotimchenko http://www.mdpi.com/1660-3397/10/4/812 Inflammation is a hot topic in medical research, because it plays a key role in inflammatory diseases: rheumatoid arthritis (RA) and other forms of arthritis, diabetes, heart diseases, irritable bowel syndrome, Alzheimer’s disease, Parkinson’s disease, allergies, asthma, even cancer and many others. Over the past few decades, it was realized that the process of inflammation is virtually the same in different disorders, and a better understanding of inflammation may lead to better treatments for numerous diseases. Inflammation is the activation of the immune system in response to infection, irritation, or injury, with an influx of white blood cells, redness, heat, swelling, pain, and dysfunction of the organs involved. Although the pathophysiological basis of these conditions is not yet fully understood, reactive oxygen species (ROS) have often been implicated in their pathogenesis. In fact, in inflammatory diseases the antioxidant defense system is compromised, as evidenced by increased markers of oxidative stress, and decreased levels of protective antioxidant enzymes in patients with rheumatoid arthritis (RA). An enriched diet containing antioxidants, such as vitamin E, vitamin C, β-carotene and phenolic substances, has been suggested to improve symptoms by reducing disease-related oxidative stress. In this respect, the marine world represents a largely untapped reserve of bioactive ingredients, and considerable potential exists for exploitation of these bioactives as functional food ingredients. Substances such as n-3 oils, carotenoids, vitamins, minerals and peptides provide a myriad of health benefits, including reduction of cardiovascular diseases, anticarcinogenic and anti-inflammatory activities. New marine bioactives are recently gaining attention, since they could be helpful in combating chronic inflammatory degenerative conditions. The aim of this review is to examine the published studies concerning the potential pharmacological properties and application of many marine bioactives against inflammatory diseases. http://www.mdpi.com/1660-3397/10/4/812 Thu, 05 Apr 2012 00:00:00 CEST Marine Drugs 2012-04-05 10 4 Review 812 833 1660-3397 Marine Bioactives: Pharmacological Properties and Potential Applications against Inflammatory Diseases 2012-04-05 doi: 10.3390/md10040812 Nicolantonio D’Orazio Maria Alessandra Gammone Eugenio Gemello Massimo De Girolamo Salvatore Cusenza Graziano Riccioni http://www.mdpi.com/1660-3397/10/4/793 Glycomics turned out to be a very extensive project where its subdivision is consequently emerging. This is seen by the growing number of terminologies used to define subprojects concerning particular classes of bioactive carbohydrates. Sulfated fucans (SFs) and sulfated galactans (SGs) are relatively new classes of sulfated polysaccharides (SPs) that occur mostly in marine organisms, and exhibit a broad range of medicinal effects. Their structures are taxonomically dependent, and their therapeutic actions include benefits in inflammation, coagulation, thrombosis, angiogenesis, cancer, oxidation, and infections. Some red algae, marine angiosperm and invertebrates express SPs of unique structures composed of regular repeating oligomeric units of well-defined sulfation patterns. This fine pattern of structural regularity is quite rare among any naturally occurring long SPs, and enables accurate structure-biofunction correlations. Seeing that, fucanomics and galactanomics may comprise distinguished glycomics subprojects. We hereby discuss the relevance that justifies the international recognition of these subprojects in the current glycomics age associated with the beneficial outcomes that these glycans may offer in drug development. http://www.mdpi.com/1660-3397/10/4/793 Thu, 29 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-29 10 4 Review 793 811 1660-3397 Fucanomics and Galactanomics: Marine Distribution, Medicinal Impact, Conceptions, and Challenges 2012-03-29 doi: 10.3390/md10040793 Vitor H. Pomin http://www.mdpi.com/1660-3397/10/4/775 Several marine and freshwater diatoms produce polyunsaturated aldehydes (PUA) in wound-activated processes. These metabolites are also released by intact diatom cells during algal blooms. Due to their activity in laboratory experiments, PUA are considered as potential mediators of diatom-bacteria interactions. Here, we tested the hypothesis that PUA mediate such processes in a close-to-field mesocosm experiment. Natural plankton communities enriched with Skeletonema marinoi strains that differ in their PUA production, a plankton control, and a plankton control supplemented with PUA at natural and elevated concentrations were observed. We monitored bacterial and viral abundance as well as bacterial community composition and did not observe any influence of PUA on these parameters even at elevated concentrations. We rather detected an alternation of the bacterial diversity over time and differences between the two S. marinoi strains, indicating unique dynamic bacterial communities in these algal blooms. These results suggest that factors other than PUA are of significance for interactions between diatoms and bacteria. http://www.mdpi.com/1660-3397/10/4/775 Wed, 28 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-28 10 4 Article 775 792 1660-3397 Diatom Derived Polyunsaturated Aldehydes Do Not Structure the Planktonic Microbial Community in a Mesocosm Study 2012-03-28 doi: 10.3390/md10040775 Carsten Paul Anna Reunamo Elin Lindehoff Johanna Bergkvist Michaela A. Mausz Henrik Larsson Hannes Richter Sten-Åke Wängberg Piia Leskinen Ulf Båmstedt Georg Pohnert http://www.mdpi.com/1660-3397/10/4/762 Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC90 of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC90 of 437 µM, representing a 90% inhibition therapeutic index (TI90 = IC90 A459/IC90 P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM). http://www.mdpi.com/1660-3397/10/4/762 Wed, 28 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-28 10 4 Article 762 774 1660-3397 Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii 2012-03-28 doi: 10.3390/md10040762 Jeremy Beau Nida Mahid Whittney N. Burda Lacey Harrington Lindsey N. Shaw Tina Mutka Dennis E. Kyle Betty Barisic Alberto van Olphen Bill J. Baker http://www.mdpi.com/1660-3397/10/4/744 Hepatitis C virus (HCV) is a causative agent of acute and chronic hepatitis, leading to the development of hepatic cirrhosis and hepatocellular carcinoma. We prepared extracts from 61 marine organisms and screened them by an in vitro fluorescence assay targeting the viral helicase (NS3), which plays an important role in HCV replication, to identify effective candidates for anti-HCV agents. An ethyl acetate-soluble fraction of the feather star Alloeocomatella polycladia exhibited the strongest inhibition of NS3 helicase activity, with an IC50 of 11.7 µg/mL. The extract of A. polycladia inhibited interaction between NS3 and RNA but not ATPase of NS3. Furthermore, the replication of the replicons derived from three HCV strains of genotype 1b in cultured cells was suppressed by the extract with an EC50 value of 23 to 44 µg/mL, which is similar to the IC50 value of the NS3 helicase assay. The extract did not induce interferon or inhibit cell growth. These results suggest that the unknown compound(s) included in A. polycladia can inhibit HCV replication by suppressing the helicase activity of HCV NS3. This study may present a new approach toward the development of a novel therapy for chronic hepatitis C. http://www.mdpi.com/1660-3397/10/4/744 Wed, 28 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-28 10 4 Article 744 761 1660-3397 Inhibition of Hepatitis C Virus Replication and Viral Helicase by Ethyl Acetate Extract of the Marine Feather Star Alloeocomatella polycladia 2012-03-28 doi: 10.3390/md10040744 Atsuya Yamashita Kazi Abdus Salam Atsushi Furuta Yasuyoshi Matsuda Osamu Fujita Hidenori Tani Yoshihisa Fujita Yuusuke Fujimoto Masanori Ikeda Nobuyuki Kato Naoya Sakamoto Shinya Maekawa Nobuyuki Enomoto Masamichi Nakakoshi Masayoshi Tsubuki Yuji Sekiguchi Satoshi Tsuneda Nobuyoshi Akimitsu Naohiro Noda Junichi Tanaka Kohji Moriishi http://www.mdpi.com/1660-3397/10/4/727 Cancer represents a set of more than 100 diseases, including malignant tumors from different locations. Strategies inducing differentiation have had limited success in the treatment of established cancers. Marine sponges are a biological reservoir of bioactive molecules, especially lectins. Several animal and plant lectins were purified with antitumor activity, mitogenic, anti-inflammatory and antiviral, but there are few reports in the literature describing the mechanism of action of lectins purified from marine sponges to induce apoptosis in human tumor cells. In this work, a lectin purified from the marine sponge Cinachyrella apion (CaL) was evaluated with respect to its hemolytic, cytotoxic and antiproliferative properties, besides the ability to induce cell death in tumor cells. The antiproliferative activity of CaL was tested against HeLa, PC3 and 3T3 cell lines, with highest growth inhibition for HeLa, reducing cell growth at a dose dependent manner (0.5–10 µg/mL). Hemolytic activity and toxicity against peripheral blood cells were tested using the concentration of IC50 (10 µg/mL) for both trials and twice the IC50 for analysis in flow cytometry, indicating that CaL is not toxic to these cells. To assess the mechanism of cell death caused by CaL in HeLa cells, we performed flow cytometry and western blotting. Results showed that lectin probably induces cell death by apoptosis activation by pro-apoptotic protein Bax, promoting mitochondrial membrane permeabilization, cell cycle arrest in S phase and acting as both dependent and/or independent of caspases pathway. These results indicate the potential of CaL in studies of medicine for treating cancer. http://www.mdpi.com/1660-3397/10/4/727 Wed, 28 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-28 10 4 Article 727 743 1660-3397 A Lactose-Binding Lectin from the Marine Sponge Cinachyrella Apion (Cal) Induces Cell Death in Human Cervical Adenocarcinoma Cells 2012-03-28 doi: 10.3390/md10040727 Luciana Rabelo Norberto Monteiro Raphael Serquiz Paula Santos Ruth Oliveira Adeliana Oliveira Hugo Rocha Ana Heloneida Morais Adriana Uchoa Elizeu Santos http://www.mdpi.com/1660-3397/10/4/712 Tetrodotoxin is a potent low weight marine toxin found in warm waters, especially of the Indian and Pacific Oceans. Intoxications are usually linked to the consumption of the puffer fish, although TTX was already detected in several different edible taxa. Benthic organisms such as mollusks and echinoderms, with different feeding habits, were collected monthly along the Portuguese coast from the summer of 2009 until the end of 2010. The extraction and analysis techniques were optimized and TTX and some analogues were detected for the first time in two intertidal gastropod species—Gibbula umbilicalis and Monodonta lineata by LC-MS/MS and UPLC-MS/MS. Although the levels are low, these findings suggest that monitoring of TTX and analogues in North Atlantic species should be implemented so as to detect potentially new toxin vectors and seasonal and/or geographical patterns. http://www.mdpi.com/1660-3397/10/4/712 Mon, 26 Mar 2012 00:00:00 CEST Marine Drugs 2012-03-26 10 4 Article 712 726 1660-3397 New Gastropod Vectors and Tetrodotoxin Potential Expansion in Temperate Waters of the Atlantic Ocean 2012-03-26 doi: 10.3390/md10040712 Marisa Silva Joana Azevedo Paula Rodriguez Amparo Alfonso Luis M. Botana Vítor Vasconcelos http://www.mdpi.com/1660-3397/10/4/694 Breast cancer remains a major health problem worldwide. While chemotherapy represents an important therapeutic modality against breast cancer, limitations in the clinical use of chemotherapy remain formidable because of chemoresistance. The HER2/PI-3K/Akt pathway has been demonstrated to play a causal role in conferring a broad chemoresistance in breast cancer cells and thus justified to be a target for enhancing the effects of anti-breast cancer chemotherapies, such as adriamycin (ADR). Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance are urgently needed for the treatment of breast cancer. In this context, SZ-685C, an agent that has been previously shown, as such, to suppress Akt signaling, is expected to increase the efficacy of chemotherapy. Our current study investigated whether SZ-685C can override chemoresistance through inhibiting Akt signaling in human breast cancer cells. ADR-resistant cells derived from human breast cancer cell lines MCF-7, MCF-7/ADR and MCF-7/Akt, were used as models to test the effects of SZ-685C. We found that SZ-685C suppressed the Akt pathway and induced apoptosis in MCF-7/ADR and MCF-7/Akt cells that are resistant to ADR treatment, leading to antitumor effects both in vitro and in vivo. Our data suggest that use of SZ-685C might represent a potentially promising approach to the treatment of ADR-resistant breast cancer. http://www.mdpi.com/1660-3397/10/4/694 Fri, 23 Mar 2012 00:00:00 CET Marine Drugs 2012-03-23 10 4 Article 694 711 1660-3397 A Marine Anthraquinone SZ-685C Overrides Adriamycin-Resistance in Breast Cancer Cells through Suppressing Akt Signaling 2012-03-23 doi: 10.3390/md10040694 Xun Zhu Zhenjian He Jueheng Wu Jie Yuan Weitao Wen Yiwen Hu Yi Jiang Cuiji Lin Qianhui Zhang Min Lin Henan Zhang Wan Yang Hong Chen Lili Zhong Zhigang She Shengping Chen Yongcheng Lin Mengfeng Li http://www.mdpi.com/1660-3397/10/4/677 Temporal changes in the production of secondary metabolites are far from being fully understood. Our study quantified, over a two-year period, the concentrations of brominated alkaloids in the ectosome and the choanosome of Aplysina aerophoba, and examined the temporal patterns of these natural products. Based on standard curves, we quantified the concentrations of aerophobin-2, aplysinamisin-1, and isofistularin-3: three of the four major peaks obtained through chemical profiling with high-performance liquid chromatography. Our results showed a striking variation in compound abundance between the outer and inner layers of the sponge. The ectosome showed high concentrations of bromocompounds during the summer months, while the choanosome followed no pattern. Additionally, we found that, from the outer layer of the sponge, aerophobin-2 and isofistularin-3 were significantly correlated with water temperature. The present study is one of the first to document quantitative seasonal variations in individual compounds over multiple years. Further studies will clarify the role of environmental, biological, and physiological factors in determining the seasonal patterns in the concentration of brominated alkaloids. http://www.mdpi.com/1660-3397/10/4/677 Fri, 23 Mar 2012 00:00:00 CET Marine Drugs 2012-03-23 10 4 Article 677 693 1660-3397 Temporal Trends in the Secondary Metabolite Production of the Sponge Aplysina aerophoba 2012-03-23 doi: 10.3390/md10040677 Oriol Sacristán-Soriano Bernard Banaigs Mikel A. Becerro http://www.mdpi.com/1660-3397/10/3/668 Two new antimycin A analogues, antimycin B1 and B2 (1–2), were isolated from a spent broth of a marine-derived bacterium, Streptomyces lusitanus. The structures of 1 and 2 were established on the basis of spectroscopic analyses and chemical methods. The isolated compounds were tested for their anti-bacterial potency. Compound 1 was found to be inactive against the bacteria Bacillus subtilis, Staphyloccocus aureus, and Loktanella hongkongensis. Compound 2 showed antibacterial activities against S. aureus and L. hongkongensis with MIC values of 32.0 and 8.0 μg/mL, respectively. http://www.mdpi.com/1660-3397/10/3/668 Thu, 22 Mar 2012 00:00:00 CET Marine Drugs 2012-03-22 10 3 Article 668 676 1660-3397 Two Antimycin A Analogues from Marine-Derived Actinomycete Streptomyces lusitanus 2012-03-22 doi: 10.3390/md10030668 Zhuang Han Ying Xu Oliver McConnell Lingli Liu Yongxin Li Shuhua Qi Xiangzhong Huang Peiyuan Qian http://www.mdpi.com/1660-3397/10/3/655 Identification of new tetrodotoxin (TTX) analogs from TTX-possessing animals might provide insight into its biosynthesis and metabolism. In this study, four new analogs, 8-epi-5,6,11-trideoxyTTX, 4,9-anhydro-8-epi-5,6,11-trideoxyTTX, 1-hydroxy-8-epi-5,6,11-trideoxyTTX, and 1-hydroxy-4,4a-anhydro-8-epi-5,6,11-trideoxyTTX, were isolated from the newt, Cynops ensicauda popei, and their structures were determined using spectroscopic methods. These are the first 8-epi-type analogs of TTX that have been found in a natural source. Furthermore, we examined the composition of the TTX analogs in this newt and in the ovary of the puffer fish, Fugu poecilonotus, using LC/MS. The results indicate that TTX and 11-deoxyTTX were present in both sources. However, 6-epiTTX and 8-epi-type analogs were detected only in the newt, while 5,6,11-trideoxyTTX was a specific and major analog in the puffer fish. Such considerable differences among analog compositions might reflect differences in the biosynthesis or metabolism of TTX between these animals. http://www.mdpi.com/1660-3397/10/3/655 Thu, 22 Mar 2012 00:00:00 CET Marine Drugs 2012-03-22 10 3 Article 655 667 1660-3397 Isolation and Structural Determination of the First 8-epi-type Tetrodotoxin Analogs from the Newt, Cynops ensicauda popei, and Comparison of Tetrodotoxin Analogs Profiles of This Newt and the Puffer Fish, Fugu poecilonotus 2012-03-22 doi: 10.3390/md10030655 Yuta Kudo Takeshi Yasumoto Keiichi Konoki Yuko Cho Mari Yotsu-Yamashita http://www.mdpi.com/1660-3397/10/3/639 An anti-fibrotic compound produced by Streptomyces xiamenensis, found in mangrove sediments, was investigated for possible therapeutic effects against fibrosis. The compound, N-[[3,4-dihydro-3S-hydroxy-2S-methyl-2-(4¢R-methyl-3¢S-pentenyl)-2H-1-benzopyran-6-yl]carbonyl]-threonine (1), was isolated from crude extracts and its structure, including the absolute configuration was determined by extensive spectroscopic data analyses, Mosher’s method, Marfey’s reagent and quantum mechanical calculations. In terms of biological effects, this compound inhibits the proliferation of human lung fibroblasts (WI26), blocks adhesion of human acute monocytic leukemia cells (THP-1) to a monolayer of WI26 cells, and reduces the contractile capacity of WI26 cells in three-dimensional free-floating collagen gels. Altogether, these data indicate that we have identified a bioactive alkaloid (1) with multiple inhibitory biological effects on lung excessive fibrotic characteristics, that are likely involved in fibrosis, suggesting that this molecule might indeed have therapeutic potential against fibrosis. http://www.mdpi.com/1660-3397/10/3/639 Thu, 15 Mar 2012 00:00:00 CET Marine Drugs 2012-03-15 10 3 Article 639 654 1660-3397 Identification and Characterization of an Anti-Fibrotic Benzopyran Compound Isolated from Mangrove-Derived Streptomyces xiamenensis 2012-03-15 doi: 10.3390/md10030639 Min-Juan Xu Xiao-Jin Liu Yi-Lei Zhao Dong Liu Zhen-Hao Xu Xiao-Meng Lang Ping Ao Wen-Han Lin Song-Lin Yang Zhi-Gang Zhang Jun Xu http://www.mdpi.com/1660-3397/10/3/627 The marine fungus Chondrostereum sp. was collected from a soft coral Sarcophyton tortuosum from the South China Sea. This fungus was cultured in potato dextrose broth medium and the culture broth was extracted with EtOAc. Five new triquinane-type sesquiterpenoids, chondrosterins A–E (1–5), and the known sesquiterpenoid hirsutanol C (6), were isolated. The structures were elucidated mainly on the basis of NMR, MS, and X-ray single-crystal diffraction data. Chondrosterin A (1) showed significant cytotoxic activities against cancer lines A549, CNE2, and LoVo with IC50 values of 2.45, 4.95, and 5.47 μM, respectively. http://www.mdpi.com/1660-3397/10/3/627 Tue, 13 Mar 2012 00:00:00 CET Marine Drugs 2012-03-13 10 3 Article 627 638 1660-3397 Chondrosterins A–E, Triquinane-Type Sesquiterpenoids from Soft Coral-Associated Fungus Chondrostereum sp. 2012-03-13 doi: 10.3390/md10030627 Hou-Jin Li Ying-Lu Xie Zhong-Liang Xie Ying Chen Chi-Keung Lam Wen-Jian Lan http://www.mdpi.com/1660-3397/10/3/617 Three new cembranoids, sarcocrassocolides M–O (1–3), have been isolated from the soft coral Sarcophyton crassocaule. The structures of the metabolites were determined by extensive spectroscopic analysis. Compounds 1–3 were shown to exhibit moderate cytotoxicity toward a limited panel of cancer cell lines and display significant in vitro anti-inflammatory activity in LPS-stimulated RAW264.7 macrophage cells by inhibiting the expression of the iNOS protein. http://www.mdpi.com/1660-3397/10/3/617 Thu, 08 Mar 2012 00:00:00 CET Marine Drugs 2012-03-08 10 3 Article 617 626 1660-3397 Sarcocrassocolides M–O, Bioactive Cembranoids from the Dongsha Atoll Soft Coral Sarcophyton crassocaule 2012-03-08 doi: 10.3390/md10030617 Wan-Yu Lin Yi Lu Bo-Wei Chen Chiung-Yao Huang Jui-Hsin Su Zhi-Hong Wen Chang-Feng Dai Yao-Haur Kuo Jyh-Horng Sheu http://www.mdpi.com/1660-3397/10/3/604 The World Health Organization (WHO) estimates that 2.3 billion people will be overweight and 700 million obese in 2015. The reasons for this disastrous trend are attributed to the global tendency toward the reduced magnitude of exercise and physical activity and the increased dietary intake of fats, sugars and calories with reduced amount of vitamins and minerals. To prevent life-style-related diseases, like Metabolic Syndrome (MS), researchers’ attention is increasingly focusing on some of the so called “functional foods” which may be useful for their prevention and treatment. One of these functional ingredients is fucoxanthin (FX), a characteristic carotenoid present in edible brown seaweeds, such as Undaria pinnatifida (Wakame), Hijikia fusiformis (Hijiki), Laminaria japonica (Ma-Kombu) and Sargassum fulvellum. The increasing popularity of this molecule is certainly due to its anti-obesity effect, primarily detected by murine studies. These works revealed FX mediated induction of uncoupling protein-1 (UCP-1) in abdominal white adipose tissue (WAT) mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Beyond this important role, in recent studies FX has shown a great antioxidant activity, anti-cancer, anti-diabetic and anti-photoaging properties. The aim of this review is to highlight the main effects of FX on human health. http://www.mdpi.com/1660-3397/10/3/604 Wed, 07 Mar 2012 00:00:00 CET Marine Drugs 2012-03-07 10 3 Review 604 616 1660-3397 Fucoxantin: A Treasure from the Sea 2012-03-07 doi: 10.3390/md10030604 Nicolantonio D’Orazio Eugenio Gemello Maria Alessandra Gammone Massimo de Girolamo Cristiana Ficoneri Graziano Riccioni http://www.mdpi.com/1660-3397/10/3/598 To study the antimicrobial components from the endophytic fungus A1 of mangrove plant Scyphiphora hydrophyllacea Gaertn. F., a new fatty acid glucoside was isolated by column chromatography from the broth of A1, and its structure was identified as R-3-hydroxyundecanoic acid methylester-3-O-α-l-rhamnopyranoside (1) by spectroscopic methods including 1D and 2D NMR (HMQC, 1H-1H COSY and HMBC) and chemical methods. Antimicrobial assay showed compound 1 possessed modest inhibitory effect on Saphylococcus aureus and methicillin-resistant S. aureus (MRSA) using the filter paper disc agar diffusion method. http://www.mdpi.com/1660-3397/10/3/598 Tue, 06 Mar 2012 00:00:00 CET Marine Drugs 2012-03-06 10 3 Article 598 603 1660-3397 A Fatty Acid Glycoside from a Marine-Derived Fungus Isolated from Mangrove Plant Scyphiphora hydrophyllacea 2012-03-06 doi: 10.3390/md10030598 Yan-Bo Zeng Hui Wang Wen-Jian Zuo Bo Zheng Tao Yang Hao-Fu Dai Wen-Li Mei http://www.mdpi.com/1660-3397/10/3/583 Hemocytes mediate a series of immune reactions essential for bivalve survival in the environment, however, the impact of harmful algal species and their associated phycotoxins upon bivalve immune system is under debate. To better understand the possible toxic effects of these toxins, Crassostrea gigas hemocytes were exposed to brevetoxin (PbTx-2). Hemocyte viability, monitored through the neutral red retention and MTT reduction assays, and apoptosis (Hoechst staining) remained unchanged during 12 h of exposure to PbTx-2 in concentrations up to 1000 µg/L. Despite cell viability and apoptosis remained stable, hemocytes incubated for 4 h with 1000 µg/L of PbTx-2 revealed higher expression levels of Hsp70 (p < 0.01) and CYP356A1 ( p < 0.05) transcripts and a tendency to increase FABP expression, as evaluated by Real-Time quantitative PCR. The expression of other studied genes (BPI, IL-17, GSTO, EcSOD, Prx6, SOD and GPx) remained unchanged. The results suggest that the absence of cytotoxic effects of PbTx-2 in Crassostrea gigas hemocytes, even at high concentrations, allow early defense responses to be produced by activating protective mechanisms associated to detoxification (CYP356A1 and possibly FABP) and stress (Hsp70), but not to immune or to antioxidant (BPI, IL-17, EcSOD, Prx6, GPx and SOD) related genes. http://www.mdpi.com/1660-3397/10/3/583 Mon, 05 Mar 2012 00:00:00 CET Marine Drugs 2012-03-05 10 3 Article 583 597 1660-3397 Cellular and Transcriptional Responses of Crassostrea gigas Hemocytes Exposed in Vitro to Brevetoxin (PbTx-2) 2012-03-05 doi: 10.3390/md10030583 Danielle F. Mello Eliza S. de Oliveira Renato C. Vieira Erik Simoes Rafael Trevisan Alcir Luiz Dafre Margherita Anna Barracco http://www.mdpi.com/1660-3397/10/3/559 A new approach to activate silent gene clusters for dormant secondary metabolite production has been developed by introducing gentamicin-resistance to an originally inactive, marine-derived fungal strain Penicillium purpurogenum G59. Upon treatment of the G59 spores with a high concentration of gentamicin in aqueous DMSO, a total of 181 mutants were obtained by single colony isolation. In contrast to the strain G59, the EtOAc extracts of nine mutant cultures showed inhibitory effects on K562 cells, indicating that the nine mutants had acquired capability to produce antitumor metabolites. This was evidenced by TLC and HPLC analysis of EtOAc extracts of G59 and the nine mutants. Further isolation and characterization demonstrated that four antitumor secondary metabolites, janthinone (1), fructigenine A (2), aspterric acid methyl ester (3) and citrinin (4), were newly produced by mutant 5-1-4 compared to the parent strain G59, and which were also not found in the secondary metabolites of other Penicillium purpurogenum strains. However, Compounds 1–4 inhibited the proliferation of K562 cells with inhibition rates of 34.6% (1), 60.8% (2), 31.7% (3) and 67.1% (4) at 100 μg/mL, respectively. The present study demonstrated the effectiveness of a simple, yet practical approach to activate the production of dormant fungal secondary metabolites by introducing acquired resistance to aminoglycoside antibiotics, which could be applied to the studies for eliciting dormant metabolic potential of fungi to obtain cryptic secondary metabolites. http://www.mdpi.com/1660-3397/10/3/559 Fri, 02 Mar 2012 00:00:00 CET Marine Drugs 2012-03-02 10 3 Article 559 582 1660-3397 Activation of the Dormant Secondary Metabolite Production by Introducing Gentamicin-Resistance in a Marine-Derived Penicillium purpurogenum G59 2012-03-02 doi: 10.3390/md10030559 Yun-Jing Chai Cheng-Bin Cui Chang-Wei Li Chang-Jing Wu Cong-Kui Tian Wei Hua http://www.mdpi.com/1660-3397/10/3/551 Kiamycin (1), a new angucyclinone derivative possessing an 1,12-epoxybenz[a]anthracene ring system, was isolated from the marine Streptomyces sp. strain M268 along with the known compounds 8-O-methyltetrangomycin (3) and 8-O-methylrabelomycin (4). Their structures were elucidated by detailed spectroscopic analysis and comparison with literature data. The new angucyclinone derivative showed inhibitory activities against the human cell lines HL-60 (leukemia), A549 (lung adenocarcinoma), and BEL-7402 (hepatoma) with inhibition rates of 68.2%, 55.9%, and 31.7%, respectively, at 100 µM. It appears to have potential as an anticancer agent with selective activity. http://www.mdpi.com/1660-3397/10/3/551 Mon, 27 Feb 2012 00:00:00 CET Marine Drugs 2012-02-27 10 3 Article 551 558 1660-3397 Kiamycin, a Unique Cytotoxic Angucyclinone Derivative from a Marine Streptomyces sp. 2012-02-27 doi: 10.3390/md10030551 Zeping Xie Bing Liu Hongpeng Wang Shengxiang Yang Hongyu Zhang Yipeng Wang Naiyun Ji Song Qin Hartmut Laatsch http://www.mdpi.com/1660-3397/10/3/539 Five new oxygenated pimarane diterpenes, named scopararanes C–G (1–5) were isolated from the culture of a marine sediment-derived fungus Eutypella scoparia FS26 obtained from the South China Sea. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The absolute configurations of compounds 1–5, were determined by CD spectroscopic analysis and comparison with literature data. All isolated compounds (1–5) were evaluated for their cytotoxic activities against MCF-7, NCI-H460, and SF-268 tumor cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method. http://www.mdpi.com/1660-3397/10/3/539 Mon, 27 Feb 2012 00:00:00 CET Marine Drugs 2012-02-27 10 3 Article 539 550 1660-3397 Scopararanes C–G: New Oxygenated Pimarane Diterpenes from the Marine Sediment-Derived Fungus Eutypella scoparia FS26 2012-02-27 doi: 10.3390/md10030539 Li Sun Dongli Li Meihua Tao Yuchan Chen Feijun Dan Weimin Zhang http://www.mdpi.com/1660-3397/10/3/521 Marine environments are a rich source of significant bioactive compounds. The Hawaiian archipelago, located in the middle of the Pacific Ocean, hosts diverse microorganisms, including many endemic species. Thirty-eight microbial extracts from Hawaiian coastal waters were evaluated for their antiviral activity against four mammalian viruses including herpes simplex virus type one (HSV-1), vesicular stomatitis virus (VSV), vaccinia virus and poliovirus type one (poliovirus-1) using in vitro cell culture assay. Nine of the 38 microbial crude extracts showed antiviral potencies and three of these nine microbial extracts exhibited significant activity against the enveloped viruses. A secosteroid, 5α(H),17α(H),(20R)-beta-acetoxyergost-8(14)-ene was putatively identified and confirmed to be the active compound in these marine microbial extracts. These results warrant future in-depth tests on the isolation of these active elements in order to explore and validate their antiviral potential as important therapeutic remedies. http://www.mdpi.com/1660-3397/10/3/521 Fri, 24 Feb 2012 00:00:00 CET Marine Drugs 2012-02-24 10 3 Article 521 538 1660-3397 Antiviral Activities and Putative Identification of Compounds in Microbial Extracts from the Hawaiian Coastal Waters 2012-02-24 doi: 10.3390/md10030521 Jing Tong Hank Trapido-Rosenthal Jun Wang Youwei Wang Qing X. Li Yuanan Lu http://www.mdpi.com/1660-3397/10/2/509 Sharks are among the most threatened groups of marine species. Populations are declining globally to support the growing demand for shark fin soup. Sharks are known to bioaccumulate toxins that may pose health risks to consumers of shark products. The feeding habits of sharks are varied, including fish, mammals, crustaceans and plankton. The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) has been detected in species of free-living marine cyanobacteria and may bioaccumulate in the marine food web. In this study, we sampled fin clips from seven different species of sharks in South Florida to survey the occurrence of BMAA using HPLC-FD and Triple Quadrupole LC/MS/MS methods. BMAA was detected in the fins of all species examined with concentrations ranging from 144 to 1836 ng/mg wet weight. Since BMAA has been linked to neurodegenerative diseases, these results may have important relevance to human health. We suggest that consumption of shark fins may increase the risk for human exposure to the cyanobacterial neurotoxin BMAA. http://www.mdpi.com/1660-3397/10/2/509 Tue, 21 Feb 2012 00:00:00 CET Marine Drugs 2012-02-21 10 2 Article 509 520 1660-3397 Cyanobacterial Neurotoxin β-N-Methylamino-L-alanine (BMAA) in Shark Fins 2012-02-21 doi: 10.3390/md10020509 Kiyo Mondo Neil Hammerschlag Margaret Basile John Pablo Sandra A. Banack Deborah C. Mash http://www.mdpi.com/1660-3397/10/2/497 A new polyoxygenated sterol, sterolic acid (1), three new breviane spiroditerpenoids, breviones I–K (2–4), and the known breviones (5–8), were isolated from the crude extract of a Penicillium sp. obtained from a deep sea sediment sample that was collected at a depth of 5115 m. The structures of 1–4 were elucidated primarily by NMR experiments, and 1 was further confirmed by X-ray crystallography. The absolute configurations of 2 and 3 were deduced by comparison of their CD spectra with those of the model compounds. Compounds 2 and 5 showed significant cytotoxicity against MCF-7 cells, which is comparable to the positive control cisplatin. http://www.mdpi.com/1660-3397/10/2/497 Mon, 20 Feb 2012 00:00:00 CET Marine Drugs 2012-02-20 10 2 Article 497 508 1660-3397 A Sterol and Spiroditerpenoids from a Penicillium sp. Isolated from a Deep Sea Sediment Sample 2012-02-20 doi: 10.3390/md10020497 Yan Li Dezan Ye Zongze Shao Chengbin Cui Yongsheng Che http://www.mdpi.com/1660-3397/10/2/477 Dinoflagellates of the genus Ostreopsis are known to cause (often fatal) food poisoning in tropical coastal areas following the accumulation of palytoxin (PLTX) and/or its analogues (PLTX group) in crabs, sea urchins or fish. Ostreopsis spp. occurrence is presently increasing in the northern to north western Mediterranean Sea (Italy, Spain, Greece and France), probably in response to climate change. In France, Ostreopsis. cf. ovata has been associated with toxic events during summer 2006, at Morgiret, off the coast of Marseille, and a specific monitoring has been designed and implemented since 2007. Results from 2008 and 2009 showed that there is a real danger of human poisoning, as these demonstrated bioaccumulation of the PLTX group (PLTX and ovatoxin-a) in both filter-feeding bivalve molluscs (mussels) and herbivorous echinoderms (sea urchins). The total content accumulated in urchins reached 450 µg PLTX eq/kg total flesh (summer 2008). In mussels, the maximum was 230 µg eq PLTX/kg (summer 2009) compared with a maximum of 360 µg found in sea urchins during the same period at the same site. This publication brings together scientific knowledge obtained about the summer development of Ostreopsis spp. in France during 2007, 2008 and 2009. http://www.mdpi.com/1660-3397/10/2/477 Fri, 17 Feb 2012 00:00:00 CET Marine Drugs 2012-02-17 10 2 Article 477 496 1660-3397 Ovatoxin-a and Palytoxin Accumulation in Seafood in Relation to Ostreopsis cf. ovata Blooms on the French Mediterranean Coast 2012-02-17 doi: 10.3390/md10020477 Zouher Amzil Manoella Sibat Nicolas Chomerat Hubert Grossel Francoise Marco-Miralles Rodolphe Lemee Elisabeth Nezan Veronique Sechet http://www.mdpi.com/1660-3397/10/2/465 Geoditin A, an isomalabaricane triterpene isolated from marine sponge Geodia japonica, has been demonstrated to induce apoptosis in leukemia HL60 cells and human colon HT29 cancer cells through an oxidative stress, a process also interfering with normal melanogenesis in pigment cells. Treatment of murine melanoma B16 cells with geoditin A decreased expression of melanogenic proteins and cell melanogenesis which was aggravated with adenylate cyclase inhibitor SQ22536, indicating melanogenic inhibition was mediated through a cAMP-dependent signaling pathway. Immunofluorescence microscopy and glycosylation studies revealed abnormal glycosylation patterns of melanogenic proteins (tyrosinase and tyrosinase-related protein 1), and a co-localization of tyrosinase with calnexin (CNX) and lysosome-associated membrane protein 1 (LAMP-1), implicating a post-translational modification in the ER and a degradation of tyrosinase in the lysosome. Taken together, potent anti-melanogenic property and the relatively low cytotoxicity of geoditin A have demonstrated its therapeutic potential as a skin lightening agent. http://www.mdpi.com/1660-3397/10/2/465 Thu, 16 Feb 2012 00:00:00 CET Marine Drugs 2012-02-16 10 2 Article 465 476 1660-3397 Anti-Melanogenic Property of Geoditin A in Murine B16 Melanoma Cells 2012-02-16 doi: 10.3390/md10020465 Florence W. K. Cheung Jia Guo Yick-Hin Ling Chun-Tao Che Wing-Keung Liu http://www.mdpi.com/1660-3397/10/2/451 Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects. http://www.mdpi.com/1660-3397/10/2/451 Thu, 16 Feb 2012 00:00:00 CET Marine Drugs 2012-02-16 10 2 Article 451 464 1660-3397 Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents 2012-02-16 doi: 10.3390/md10020451 Tamara P. Kondratyuk Eun-Jung Park Rui Yu Richard B. van Breemen Ratnakar N. Asolkar Brian T. Murphy William Fenical John M. Pezzuto http://www.mdpi.com/1660-3397/10/2/439 One new sterol, crassarosterol A (1), and four new steroidal glycosides, crassarosterosides A–D (2–5) were isolated from the Formosan soft coral Sinularia crassa. The absolute configuration of 1 was determined using the Mosher’s method. The absolute configurations for the sugar moieties of 2–5 were determined by HPLC analysis on the o-tolylthiocarbamates derived from the liberated sugar after acid hydrolysis. Compounds 2 and 4 could significantly inhibit the expression of pro-inflammatory iNOS protein at 10 µM. In contrast, 1–3 were found to stimulate the expression of COX-2 protein at this concentration. Steroids 1 and 4 also showed cytotoxicity toward the selected human liver cancer cells. http://www.mdpi.com/1660-3397/10/2/439 Thu, 16 Feb 2012 00:00:00 CET Marine Drugs 2012-02-16 10 2 Article 439 450 1660-3397 Steroids from the Soft Coral Sinularia crassa 2012-02-16 doi: 10.3390/md10020439 Chih-Hua Chao Kuei-Ju Chou Chiung-Yao Huang Zhi-Hong Wen Chi-Hsin Hsu Yang-Chang Wu Chang-Feng Dai Jyh-Horng Sheu http://www.mdpi.com/1660-3397/10/2/427 A new germacrane-type sesquiterpenoid, menelloide E (1), and a new cembrane-type diterpenoid, lobocrassin F (2), were isolated from the octocorals Menella sp. and Lobophytum crassum, respectively. The structures of terpenoids 1 and 2 were determined by spectroscopic and chemical methods and compound 2 was found to display a significant inhibitory effect on the release of elastase by human neutrophils. http://www.mdpi.com/1660-3397/10/2/427 Wed, 15 Feb 2012 00:00:00 CET Marine Drugs 2012-02-15 10 2 Article 427 438 1660-3397 Terpenoids from the Octocorals Menella sp. (Plexauridae) and Lobophytum crassum (Alcyonacea) 2012-02-15 doi: 10.3390/md10020427 Cheng-Hung Lee Chia-Ying Kao Shih-Yao Kao Chih-Han Chang Jui-Hsin Su Tsong-Long Hwang Yueh-Hsiung Kuo Zhi-Hong Wen Ping-Jyun Sung http://www.mdpi.com/1660-3397/10/2/417 Antihypertensive effect of long-term oral administration of jellyfish (Rhopilema esculentum) collagen peptides (JCP) on renovascular hypertension rats (RVHs) was evaluated. The systolic blood pressure and diastolic blood pressure of the RVHs were significantly reduced with administration of JCP (p < 0.05), compared with model control group. However, the arterial blood pressure of normal rats showed no significant changes during long-term oral treatment with high dose JCP (p > 0.05). Furthermore, effect of JCP on angiotensin II (Ang II) concentration of plasma had no significance (p > 0.05), but JCP significantly inhibited the Ang II concentration in RVHs’ kidney (p < 0.05). The kidney should be the target site of JCP. http://www.mdpi.com/1660-3397/10/2/417 Wed, 15 Feb 2012 00:00:00 CET Marine Drugs 2012-02-15 10 2 Communication 417 426 1660-3397 Antihypertensive Effect of Long-Term Oral Administration of Jellyfish (Rhopilema esculentum) Collagen Peptides on Renovascular Hypertension 2012-02-15 doi: 10.3390/md10020417 Yongliang Zhuang Liping Sun Yufeng Zhang Gaoxiang Liu http://www.mdpi.com/1660-3397/10/2/403 Marine algae are known to contain a wide variety of bioactive compounds, many of which have commercial applications in pharmaceutical, medical, cosmetic, nutraceutical, food and agricultural industries. Natural antioxidants, found in many algae, are important bioactive compounds that play an important role against various diseases and ageing processes through protection of cells from oxidative damage. In this respect, relatively little is known about the bioactivity of Hawaiian algae that could be a potential natural source of such antioxidants. The total antioxidant activity of organic extracts of 37 algal samples, comprising of 30 species of Hawaiian algae from 27 different genera was determined. The activity was determined by employing the FRAP (Ferric Reducing Antioxidant Power) assays. Of the algae tested, the extract of Turbinaria ornata was found to be the most active. Bioassay-guided fractionation of this extract led to the isolation of a variety of different carotenoids as the active principles. The major bioactive antioxidant compound was identified as the carotenoid fucoxanthin. These results show, for the first time, that numerous Hawaiian algae exhibit significant antioxidant activity, a property that could lead to their application in one of many useful healthcare or related products as well as in chemoprevention of a variety of diseases including cancer. http://www.mdpi.com/1660-3397/10/2/403 Wed, 15 Feb 2012 00:00:00 CET Marine Drugs 2012-02-15 10 2 Article 403 416 1660-3397 Antioxidant Activity of Hawaiian Marine Algae 2012-02-15 doi: 10.3390/md10020403 Dovi Kelman Ellen Kromkowski Posner Karla J. McDermid Nicole K. Tabandera Patrick R. Wright Anthony D. Wright http://www.mdpi.com/1660-3397/10/2/358 The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of the most relevant quinones/hydroquinones are described. http://www.mdpi.com/1660-3397/10/2/358 Tue, 14 Feb 2012 00:00:00 CET Marine Drugs 2012-02-14 10 2 Review 358 402 1660-3397 Synthetic Strategies to Terpene Quinones/Hydroquinones 2012-02-14 doi: 10.3390/md10020358 Marina Gordaliza http://www.mdpi.com/1660-3397/10/2/349 Two new tryptamine-derived alkaloids, named as leptoclinidamide (1) and (-)-leptoclinidamine B (2), were isolated from an Indonesian ascidian Leptoclinides dubius together with C2-α-D-mannosylpyranosyl-L-tryptophan (3). The structure of 1 was assigned on the basis of spectroscopic data for 1 and its N-acetyl derivative (4). Compound 1 was an amide of tryptamine with two β-alanine units. Although the planar structure of 2 is identical to that of the known compound (+)-leptoclinidamine B (5), compound 2 was determined to be the enantiomer of 5 based on amino acid analysis using HPLC methods. Compounds 1 to 4 were evaluated for cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells, but none of the compounds showed activity. http://www.mdpi.com/1660-3397/10/2/349 Fri, 10 Feb 2012 00:00:00 CET Marine Drugs 2012-02-10 10 2 Article 349 357 1660-3397 Two New Tryptamine Derivatives, Leptoclinidamide and (-)-Leptoclinidamine B, from an Indonesian Ascidian Leptoclinides dubius 2012-02-10 doi: 10.3390/md10020349 Hiroyuki Yamazaki Defny S. Wewengkang Teruaki Nishikawa Henki Rotinsulu Remy E. P. Mangindaan Michio Namikoshi http://www.mdpi.com/1660-3397/10/2/340 Three new eremophilane sesquiterpenes (1–3) were isolated from the mangrove endophytic fungus Xylaria sp. BL321 together with 07H239-A (4), a known analogue of the new compounds. The structures of these compounds were elucidated by analysis of their MS, 1D and 2D NMR spectroscopic data. Compound 4 showed activation activity on α-glucosidase at 0.15 μM (146%), and then, 4 gradually produced inhibitory activity on α-glucosidase with increasing concentration, and the IC50 value is 6.54 μM. http://www.mdpi.com/1660-3397/10/2/340 Mon, 06 Feb 2012 00:00:00 CET Marine Drugs 2012-02-06 10 2 Article 340 348 1660-3397 Four Eremophilane Sesquiterpenes from the Mangrove Endophytic Fungus Xylaria sp. BL321 2012-02-06 doi: 10.3390/md10020340 Yongxiang Song Jiajian Wang Hongbo Huang Lin Ma Jun Wang Yucheng Gu Lan Liu Yongcheng Lin http://www.mdpi.com/1660-3397/10/2/329 The toxin content in various life cycle stages of tank-cultivated bullseye puffer (Sphoeroides annulatus) were analyzed by mouse bioassay and ESI-MS spectrometry analysis. The presence of toxin content was determined in extracts of sperm, eggs, embryo, larvae, post-larvae, juvenile, pre-adult, and adult fish, as well as in food items used during the cultivation of the species. Our findings show that only the muscle of juveniles, the viscera of pre-adults, and muscle, liver, and gonad of adult specimens were slightly toxic ( < 1 mouse unit). Thus, cultivated S. annulatus, as occurs with other cultivated puffer fish species, does not represent a food safety risk to consumers. This is the first report of toxin analysis covering the complete life stages of a puffer fish under controlled conditions. http://www.mdpi.com/1660-3397/10/2/329 Fri, 03 Feb 2012 00:00:00 CET Marine Drugs 2012-02-03 10 2 Article 329 339 1660-3397 Toxicity of Cultured Bullseye Puffer Fish Sphoeroides annulatus 2012-02-03 doi: 10.3390/md10020329 Erick J. Nuñez-Vazquez Armando Garcia-Ortega Angel I. Campa-Cordova Isabel Abdo de la Parra Lilia Ibarra-Martinez Alejandra Heredia-Tapia Jose L. Ochoa http://www.mdpi.com/1660-3397/10/2/319 Four novel amicoumacins, namely lipoamicoumacins A–D (1–4), and one new bacilosarcin analog (5) were isolated from culture broth of a marine-derived bacterium Bacillus subtilis, together with six known amicoumacins. Their structures were elucidated on the basis of extensive spectroscopic (2D NNR, IR, CD and MS) analysis and in comparison with data in literature. http://www.mdpi.com/1660-3397/10/2/319 Fri, 03 Feb 2012 00:00:00 CET Marine Drugs 2012-02-03 10 2 Article 319 328 1660-3397 Five New Amicoumacins Isolated from a Marine-Derived Bacterium Bacillus subtilis 2012-02-03 doi: 10.3390/md10020319 Yongxin Li Ying Xu Lingli Liu Zhuang Han Pok Yui Lai Xiangrong Guo Xixiang Zhang Wenhan Lin Pei-Yuan Qian http://www.mdpi.com/1660-3397/10/2/306 Six new cembranolides, michaolides L–Q (1–6), and a known cembranolide, lobomichaolide (7) were isolated from the CH2Cl2 extract of the soft coral Lobophytum michaelae. Their structures were established by extensive spectral analysis. The anti-HCMV (human cytomegalovirus) activity of 1–7 and their cytotoxicity against selected cell lines were evaluated. http://www.mdpi.com/1660-3397/10/2/306 Tue, 31 Jan 2012 00:00:00 CET Marine Drugs 2012-01-31 10 2 Article 306 318 1660-3397 New Cytotoxic Cembranolides from the Soft Coral Lobophytum michaelae 2012-01-31 doi: 10.3390/md10020306 Shang-Kwei Wang Chang-Yih Duh http://www.mdpi.com/1660-3397/10/2/281 Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed. http://www.mdpi.com/1660-3397/10/2/281 Tue, 31 Jan 2012 00:00:00 CET Marine Drugs 2012-01-31 10 2 Review 281 305 1660-3397 Tetrodotoxin (TTX) as a Therapeutic Agent for Pain 2012-01-31 doi: 10.3390/md10020281 Francisco Rafael Nieto Enrique José Cobos Miguel Ángel Tejada Cristina Sánchez-Fernández Rafael González-Cano Cruz Miguel Cendán http://www.mdpi.com/1660-3397/10/2/258 Cone snail venoms are considered an untapped reservoir of extremely diverse peptides, named conopeptides, displaying a wide array of pharmacological activities. We report here for the first time, the presence of high molecular weight compounds that participate in the envenomation cocktail used by these marine snails. Using a combination of proteomic and transcriptomic approaches, we identified glycosyl hydrolase proteins, of the hyaluronidase type (Hyal), from the dissected and injectable venoms (“injectable venom” stands for the venom variety obtained by milking of the snails. This is in contrast to the “dissected venom”, which was obtained from dissected snails by extraction of the venom glands) of a fish-hunting cone snail, Conus consors (Pionoconus clade). The major Hyal isoform, Conohyal-Cn1, is expressed as a mixture of numerous glycosylated proteins in the 50 kDa molecular mass range, as observed in 2D gel and mass spectrometry analyses. Further proteomic analysis and venom duct mRNA sequencing allowed full sequence determination. Additionally, unambiguous segment location of at least three glycosylation sites could be determined, with glycans corresponding to multiple hexose (Hex) and N-acetylhexosamine (HexNAc) moieties. With respect to other known Hyals, Conohyal-Cn1 clearly belongs to the hydrolase-type of Hyals, with strictly conserved consensus catalytic donor and positioning residues. Potent biological activity of the native Conohyals could be confirmed in degrading hyaluronic acid. A similar Hyal sequence was also found in the venom duct transcriptome of C. adamsonii (Textilia clade), implying a possible widespread recruitment of this enzyme family in fish-hunting cone snail venoms. These results provide the first detailed Hyal sequence characterized from a cone snail venom, and to a larger extent in the Mollusca phylum, thus extending our knowledge on this protein family and its evolutionary selection in marine snail venoms. http://www.mdpi.com/1660-3397/10/2/258 Tue, 31 Jan 2012 00:00:00 CET Marine Drugs 2012-01-31 10 2 Article 258 280 1660-3397 Recruitment of Glycosyl Hydrolase Proteins in a Cone Snail Venomous Arsenal: Further Insights into Biomolecular Features of Conus Venoms 2012-01-31 doi: 10.3390/md10020258 Aude Violette Adrijana Leonardi David Piquemal Yves Terrat Daniel Biass Sébastien Dutertre Florian Noguier Frédéric Ducancel Reto Stöcklin Igor Križaj Philippe Favreau http://www.mdpi.com/1660-3397/10/1/242 Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1–10 μM) significantly attenuated rifampin (20 μM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions. http://www.mdpi.com/1660-3397/10/1/242 Mon, 23 Jan 2012 00:00:00 CET Marine Drugs 2012-01-23 10 1 Article 242 257 1660-3397 Fucoxanthin Attenuates Rifampin-Induced Cytochrome P450 3A4 (CYP3A4) and Multiple Drug Resistance 1 (MDR1) Gene Expression Through Pregnane X Receptor (PXR)-Mediated Pathways in Human Hepatoma HepG2 and Colon Adenocarcinoma LS174T Cells 2012-01-23 doi: 10.3390/md10010242 Cheng-Ling Liu Yun-Ping Lim Miao-Lin Hu http://www.mdpi.com/1660-3397/10/1/234 Four new bisabolane-type sesquiterpenoids, aspergiterpenoid A (1), (−)-sydonol (2), (−)-sydonic acid (3), and (−)-5-(hydroxymethyl)-2-(2′,6′,6′-trimethyltetrahydro-2H- pyran-2-yl)phenol (4) together with one known fungal metabolite (5) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Four of them (1–4) are optically active compounds. Their structures and absolute configurations were elucidated by using NMR spectroscopic techniques and mass spectrometric analysis, and by comparing their optical rotations with those related known analogues. Compounds 1–5 showed selective antibacterial activity against eight bacterial strains with the MIC (minimum inhibiting concentrations) values between 1.25 and 20.0 µM. The cytotoxic, antifouling, and acetylcholinesterase inhibitory activities of these compounds were also examined. http://www.mdpi.com/1660-3397/10/1/234 Thu, 19 Jan 2012 00:00:00 CET Marine Drugs 2012-01-19 10 1 Short Note 234 241 1660-3397 Antibacterial Bisabolane-Type Sesquiterpenoids from the Sponge-Derived Fungus Aspergillus sp. 2012-01-19 doi: 10.3390/md10010234 Dan Li Ying Xu Chang-Lun Shao Rui-Yun Yang Cai-Juan Zheng Yi-Yan Chen Xiu-Mei Fu Pei-Yuan Qian Zhi-Gang She Nicole J. de Voogd Chang-Yun Wang http://www.mdpi.com/1660-3397/10/1/223 The brominated pyrrole-imidazole Ageladine A was used for live imaging of the jellyfish (jellies) Nausithoe werneri, the sea anemone Metridium senile and the flatworm Macrostomum lignano. The fluorescence properties of Ageladine A allow for estimation of pH values in tissue and organs in living animals. The results showed that Nausithoe werneri had the most acidic areas in the tentacles and close to the mouth (pH 4–6.5), Metridium senile harbours aggregates of high acidity in the tentacles (pH 5) and in Macrostomum lignano, the rhabdoids, the gonads and areas close to the mouth were the most acidic with values down to pH 5. http://www.mdpi.com/1660-3397/10/1/223 Thu, 19 Jan 2012 00:00:00 CET Marine Drugs 2012-01-19 10 1 Article 223 233 1660-3397 The Alkaloid Ageladine A, Originally Isolated from Marine Sponges, Used for pH-Sensitive Imaging of Transparent Marine Animals 2012-01-19 doi: 10.3390/md10010223 Ulf Bickmeyer http://www.mdpi.com/1660-3397/10/1/209 A chemical investigation of an ethyl acetate extract of the Red Sea soft coral Sarcophyton glaucum has led to the isolation of two peroxide diterpenes, 11(S) hydroperoxylsarcoph-12(20)-ene (1), and 12(S)-hydroperoxylsarcoph-10-ene (2), as well as 8-epi-sarcophinone (3). In addition to these three new compounds, two known structures were identified including: ent-sarcophine (4) and sarcophine (5). Structures were elucidated by spectroscopic analysis, with the relative configuration of 1 and 2 confirmed by X-ray diffraction. Isolated compounds were found to be inhibitors of cytochrome P450 1A activity as well as inducers of glutathione S-transferases (GST), quinone reductase (QR), and epoxide hydrolase (mEH) establishing chemo-preventive and tumor anti-initiating activity for these characterized metabolites. http://www.mdpi.com/1660-3397/10/1/209 Wed, 18 Jan 2012 00:00:00 CET Marine Drugs 2012-01-18 10 1 Article 209 222 1660-3397 Bioactive Hydroperoxyl Cembranoids from the Red Sea Soft Coral Sarcophyton glaucum 2012-01-18 doi: 10.3390/md10010209 Mohamed-Elamir F. Hegazy Amira M. Gamal Eldeen Abdelaaty A. Shahat Fathy F. Abdel-Latif Tarik A. Mohamed Bruce R. Whittlesey Paul W. Paré http://www.mdpi.com/1660-3397/10/1/200 A new tetramic acid glycoside, aurantoside K, was isolated from a marine sponge belonging to the genus Melophlus. The structure of the compound was elucidated on the basis of spectroscopic analysis (1H NMR, 1H–1H COSY, HSQC, and HMBC, as well as high-resolution ESILCMS). Aurantoside K did not show any significant activity in antimalarial, antibacterial, or HCT-116 cytotoxicity assays, but exhibited a wide spectrum of antifungal activity against wild type Candida albicans, amphotericin-resistant C. albicans, Cryptococcus neoformans, Aspergillus niger, Penicillium sp., Rhizopus sporangia and Sordaria sp. http://www.mdpi.com/1660-3397/10/1/200 Wed, 18 Jan 2012 00:00:00 CET Marine Drugs 2012-01-18 10 1 Article 200 208 1660-3397 Aurantoside K, a New Antifungal Tetramic Acid Glycoside from a Fijian Marine Sponge of the Genus Melophlus 2012-01-18 doi: 10.3390/md10010200 Rohitesh Kumar Ramesh Subramani Klaus-D. Feussner William Aalbersberg http://www.mdpi.com/1660-3397/10/1/177 The demosponge Suberites domuncula has been described to contain high levels of a proteinaceous toxin, Suberitine, that displays haemolytic activityIn the present study this 7–8 kDa polypeptide has been isolated and was shown to exhibit also cytotoxic effects on cells of the same species. Addition of retinal, a recently identified metabolite of β-carotene that is abundantly present in S. domuncula was found to reduce both the haemolytic and the cell toxic activity of Suberitine at a molar ratio of 1:1. Spectroscopic analyses revealed that the interaction between β-carotene and Suberitine can be ascribed to a reversible energy transfer reaction. The enzyme that synthesises retinal in the sponge system is the β,β-carotene-15,15′-dioxygenase [carotene dioxygenase]. In order to clarify if this enzyme is the only β-carotene-metabolizing enzyme a further oxygenase had been identified and cloned, the (related) carotenoid oxygenase. In contrast to the dioxygenase, the carotenoid oxygenase could not degrade β-carotene or lycopene in Escherichia coli strains that produced these two carotenoids; therefore it had been termed related-carotenoid oxygenase. Exposure of primmorphs to light of different wavelengths from the visible spectrum resulted after 3 days in a strong upregulation of the dioxygenase in those 3D-cell aggregates that had been incubated with β-carotene. The strongest effect is seen with blue light at a maximum around 490 nm. It is concluded that the toxin Suberitine is non-covalently modified by retinal, the cleavage product from β-carotene via the enzyme carotene dioxygenase, a light inducible oxygenase. Hence, this study highlights that in S. domuncula the bioactive metabolite, retinal, has the property to detoxify its homologous toxin. http://www.mdpi.com/1660-3397/10/1/177 Wed, 18 Jan 2012 00:00:00 CET Marine Drugs 2012-01-18 10 1 Article 177 199 1660-3397 Differential Expression of the Demosponge (Suberites domuncula) Carotenoid Oxygenases in Response to Light: Protection Mechanism Against the Self-Produced Toxic Protein (Suberitine) 2012-01-18 doi: 10.3390/md10010177 Werner E. G. Müller Xiaohong Wang Michael Binder Johannes von Lintig Matthias Wiens Heinz C. Schröder http://www.mdpi.com/1660-3397/10/1/163 Tetrodotoxin (TTX) is a potent neurotoxin that has been identified in a range of phylogenetically unrelated marine and terrestrial organisms. Tetrodotoxin was recently detected in New Zealand in Pleurobranchaea maculata (the grey side-gilled sea slug). From June 2010 to June 2011 wild specimens were collected from 10 locations around New Zealand. At one site (Narrow Neck Beach, Auckland) up to 10 individuals were collected monthly for 6 months. Attempts were also made to rear P. maculata in captivity. Tetrodotoxin was detected in samples from eight of the ten sites. The highest average (368.7 mg kg−1) and maximum (1414.0 mg kg−1) concentrations were measured in samples from Illiomama Rock (Auckland). Of the toxic populations tested there was significant variability in TTX concentrations among individuals, with the highest difference (62 fold) measured at Illiomama Rock. Tetrodotoxin concentrations in samples from Narrow Neck Beach varied temporally, ranging from an average of 184 mg kg−1 in June 2010 to 17.5 mg kg−1 by December 2010. There was no correlation between TTX levels and mass. The highest levels correspond with the egg laying season (June–August) and this, in concert with the detection of high levels of TTX in eggs and early larval stages, suggests that TTX may have a defensive function in P. maculata. Only one larva was successfully reared to full maturation and no TTX was detected. http://www.mdpi.com/1660-3397/10/1/163 Tue, 17 Jan 2012 00:00:00 CET Marine Drugs 2012-01-17 10 1 Article 163 176 1660-3397 Tetrodotoxin Concentrations in Pleurobranchaea maculata: Temporal, Spatial and Individual Variability from New Zealand Populations 2012-01-17 doi: 10.3390/md10010163 Susanna A. Wood David I. Taylor Paul McNabb Jarrod Walker Janet Adamson Stephen Craig Cary http://www.mdpi.com/1660-3397/10/1/140 The Northern Adriatic Sea is the area of the Mediterranean Sea where eutrophication and episodes related to harmful algae have occurred most frequently since the 1970s. In this area, which is highly exploited for mollusk farming, the first occurrence of human intoxication due to shellfish consumption occurred in 1989, nearly 10 years later than other countries in Europe and worldwide that had faced similar problems. Until 1997, Adriatic mollusks had been found to be contaminated mostly by diarrhetic shellfish poisoning toxins (i.e., okadaic acid and dinophysistoxins) that, along with paralytic shellfish poisoning toxins (i.e., saxitoxins), constitute the most common marine biotoxins. Only once, in 1994, a toxic outbreak was related to the occurrence of paralytic shellfish poisoning toxins in the Adriatic coastal waters. Moreover, in the past 15 years, the Adriatic Sea has been characterized by the presence of toxic or potentially toxic algae, not highly widespread outside Europe, such as species producing yessotoxins (i.e., Protoceratium reticulatum, Gonyaulax spinifera and Lingulodinium polyedrum), recurrent blooms of the potentially ichthyotoxic species Fibrocapsa japonica and, recently, by blooms of palytoxin-like producing species of the Ostreopsis genus. This review is aimed at integrating monitoring data on toxin spectra and levels in mussels farmed along the coast of the Emilia-Romagna region with laboratory studies performed on the species involved in the production of those toxins; toxicity studies on toxic or potentially toxic species that have recently appeared in this area are also reviewed. Overall, reviewed data are related to: (i) the yessotoxins producing species P. reticulatum, G. spinifera and L. polyedrum, highlighting genetic and toxic characteristics; (ii) Adriatic strains of Alexandrium minutum, Alexandrium ostenfeldii and Prorocentrum lima whose toxic profiles are compared with those of strains of different geographic origins; (iii) F. japonica and Ostreopsis cf. ovata toxicity. Moreover, new data concerning domoic acid production by a Pseudo-nitzschia multistriata strain, toxicity investigations on a Prorocentrum cf. levis, and on presumably ichthyotoxic species, Heterosigma akashiwo and Chattonella cf. subsalsa, are also reported. http://www.mdpi.com/1660-3397/10/1/140 Tue, 17 Jan 2012 00:00:00 CET Marine Drugs 2012-01-17 10 1 Review 140 162 1660-3397 Toxin Levels and Profiles in Microalgae from the North-Western Adriatic Sea—15 Years of Studies on Cultured Species 2012-01-17 doi: 10.3390/md10010140 Rossella Pistocchi Franca Guerrini Laura Pezzolesi Manuela Riccardi Silvana Vanucci Patrizia Ciminiello Carmela Dell’Aversano Martino Forino Ernesto Fattorusso Luciana Tartaglione Anna Milandri Marinella Pompei Monica Cangini Silvia Pigozzi Elena Riccardi http://www.mdpi.com/1660-3397/10/1/131 Two new compounds, asperversin A (1) and 9ξ-O-2(2,3-dimethylbut-3-enyl)brevianamide Q (2), and nine known compounds, brevianamide K (3), brevianamide M (4), aversin (5), 6,8-di-O-methylnidurufin (6), 6,8-di-O-methylaverufin (7), 6-O-methylaverufin (8), 5α,8α-epidioxyergosta-6,22-dien-3β-ol (9), ergosta-7,22-diene-3β,5α,6β-triol (10), and 6β-methoxyergosta-7,22-diene-3β,5α-diol (11), were obtained from the culture of Aspergillus versicolor, an endophytic fungus isolated from the marine brown alga Sargassum thunbergii. The structures of these compounds were established by spectroscopic techniques. Compounds 4, 7 and 8 exhibited antibacterial activities against Escherichia coli and Staphyloccocus aureus, and 7 also showed lethality against brine shrimp (Artemia salina) with an LC50 value of 0.5 μg/mL. http://www.mdpi.com/1660-3397/10/1/131 Mon, 16 Jan 2012 00:00:00 CET Marine Drugs 2012-01-16 10 1 Article 131 139 1660-3397 Secondary Metabolites from an Algicolous Aspergillus versicolor Strain 2012-01-16 doi: 10.3390/md10010131 Feng-Ping Miao Xiao-Dong Li Xiang-Hong Liu Robert H. Cichewicz Nai-Yun Ji http://www.mdpi.com/1660-3397/10/1/119 We investigated the effects of polysaccharides from the brown seaweed Sargassum graminifolium (Turn.) (SGP) on calcium oxalate crystallization, and determined its antioxidant activities. To examine the effects of SGP on calcium oxalate crystallization, we monitored nucleation and aggregation of calcium oxalate monohydrate crystals, using trisodium citrate as a positive control. We assessed antioxidant activities of SGP by determining its reducing power, its ability to scavenge superoxide radicals, and its activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The nucleation inhibition ratio of trisodium citrate and SGP was 58.5 and 69.2%, respectively, and crystal aggregation was inhibited by 71.4 and 76.8%, respectively. Increasing concentrations of SGP resulted in increased scavenging of superoxide anions and DPPH radicals (IC50 = 1.9 and 0.6 mg/mL, respectively). These results suggest that SGP could be a candidate for treating urinary stones because of its ability to inhibit calcium oxalate crystallization and its antioxidant properties. http://www.mdpi.com/1660-3397/10/1/119 Mon, 16 Jan 2012 00:00:00 CET Marine Drugs 2012-01-16 10 1 Article 119 130 1660-3397 Antioxidant Properties of Polysaccharide from the Brown Seaweed Sargassum graminifolium (Turn.), and Its Effects on Calcium Oxalate Crystallization 2012-01-16 doi: 10.3390/md10010119 Chao-Yan Zhang Wen-Hui Wu Jue Wang Min-Bo Lan http://www.mdpi.com/1660-3397/10/1/116 Oxidative stress induced by reactive oxygen species plays an important role in the etiology of many diseases. Dietary phytochemical products, such as bioactive food components and marine carotenoids (asthaxantin, lutein, β-carotene, fucoxanthin), have shown an antioxidant effect in reducing oxidative markers stress. Scientific evidence supports the beneficial role of phytochemicals in the prevention of some chronic diseases. Many carotenoids with high antioxidant properties have shown a reduction in disease risk both in epidemiological studies and supplementation human trials. However, controlled clinical trials and dietary intervention studies using well-defined subjects population have not provided clear evidence of these substances in the prevention of diseases. The most important aspects of this special issue will cover the synthesis, biological activities, and clinical applications of marine carotenoids, with particular attention to recent evidence regarding anti-oxidant and anti-inflammatory properties in the prevention of cardiovascular disease. http://www.mdpi.com/1660-3397/10/1/116 Mon, 16 Jan 2012 00:00:00 CET Marine Drugs 2012-01-16 10 1 Editorial 116 118 1660-3397 Marine Carotenoids and Oxidative Stress 2012-01-16 doi: 10.3390/md10010116 Graziano Riccioni http://www.mdpi.com/1660-3397/10/1/106 A new fungal strain, displaying strong toxic activity against brine shrimp larvae, was isolated from a deep sea sediment sample collected at a depth of 1300 m. The strain, designated as F00120, was identified as a member of the genus Penicillium on the basis of morphology and ITS sequence analysis. One new sesquiterpene quinone, named penicilliumin A (1), along with two known compounds ergosterol (2) and ergosterol peroxide (3), were isolated and purified from the cultures of F00120 by silica gel column, Sephadex LH-20 column, and preparative thin layer chromatography. Their structures were elucidated by detailed nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analysis as well as comparison with literature data. The new compound penicilliumin A inhibited in vitro proliferation of mouse melanoma (B16), human melanoma (A375), and human cervical carcinoma (Hela) cell lines moderately. http://www.mdpi.com/1660-3397/10/1/106 Thu, 12 Jan 2012 00:00:00 CET Marine Drugs 2012-01-12 10 1 Article 106 115 1660-3397 A New Cytotoxic Sesquiterpene Quinone Produced by Penicillium sp. F00120 Isolated from a Deep Sea Sediment Sample 2012-01-12 doi: 10.3390/md10010106 Xiuping Lin Xuefeng Zhou Fazuo Wang Kaisheng Liu Bin Yang Xianwen Yang Yan Peng Juan Liu Zhe Ren Yonghong Liu http://www.mdpi.com/1660-3397/10/1/84 The effects of Tasco®, a product made from the brown seaweed (Ascophyllum nodosum) were tested for the ability to protect Caenorhabditis elegans against Pseudomonas aeruginosa infection. A water extract of Tasco® (TWE) reduced P. aeruginosa inflicted mortality in the nematode. The TWE, at a concentration of 300 µg/mL, offered the maximum protection and induced the expression of innate immune response genes viz.; zk6.7 (Lypases), lys-1 (Lysozyme), spp-1 (Saponin like protein), f28d1.3 (Thaumatin like protein), t20g5.7 (Matridin SK domain protein), abf-1 (Antibacterial protein) and f38a1.5 (Lectin family protein). Further, TWE treatment also affected a number of virulence components of the P. aeuroginosa and reduced its secreted virulence factors such as lipase, proteases and toxic metabolites; hydrogen cyanide and pyocyanin. Decreased virulence factors were associated with a significant reduction in expression of regulatory genes involved in quorum sensing, lasI, lasR, rhlI and rhlR. In conclusion, the TWE-treatment protected the C. elegans against P. aeruginosa infection by a combination of effects on the innate immunity of the worms and direct effects on the bacterial quorum sensing and virulence factors. http://www.mdpi.com/1660-3397/10/1/84 Wed, 11 Jan 2012 00:00:00 CET Marine Drugs 2012-01-11 10 1 Article 84 105 1660-3397 Tasco®: A Product of Ascophyllum nodosum Enhances Immune Response of Caenorhabditis elegans Against Pseudomonas aeruginosa Infection 2012-01-11 doi: 10.3390/md10010084 Saveetha Kandasamy Wajahatullah Khan Franklin Evans Alan T. Critchley Balakrishnan Prithiviraj http://www.mdpi.com/1660-3397/10/1/64 Anticancer properties of tyrindoleninone and 6-bromoisatin from Dicathais orbita were tested against physiologically normal primary human granulosa cells (HGC) and reproductive cancer cell lines. Tyrindoleninone reduced cancer cell viability with IC50 values of 39 µM (KGN; a tumour-derived granulosa cell line), 39 μM (JAr), and 156 μM (OVCAR-3), compared to 3516 μM in HGC. Apoptosis in HGC’s occurred after 4 h at 391 µM tyrindoleninone compared to 20 µM in KGN cells. Differences in apoptosis between HGC and KGN cells were confirmed by TUNEL, with 66 and 31% apoptotic nuclei at 4 h in KGN and HGC, respectively. These marine compounds therefore have potential for development as treatments for female reproductive cancers. http://www.mdpi.com/1660-3397/10/1/64 Tue, 10 Jan 2012 00:00:00 CET Marine Drugs 2012-01-10 10 1 Article 64 83 1660-3397 Marine Compounds Selectively Induce Apoptosis in Female Reproductive Cancer Cells but Not in Primary-Derived Human Reproductive Granulosa Cells 2012-01-10 doi: 10.3390/md10010064 Vicki Edwards Kirsten Benkendorff Fiona Young http://www.mdpi.com/1660-3397/10/1/51 Two new sulfoxide-containing metabolites, aplisulfamines A (1) and B (2), have been isolated from an Aplidium sp. collected in the Bay of Naples. Their planar structure and geometry of a double bond were readily determined by using standard methods, mainly NMR spectroscopy. An original approach was used to assign the absolute configuration at the three contiguous chiral centers present in the structures of both aplisulfamines, two at carbon and one at sulfur. This involved Electronic Circular Dichroism (ECD) studies, J-based configuration analysis and Density Functional Theory (DFT) calculations and represents an interesting integration of modern techniques in stereoanalysis, which could contribute to the enhancement of theoretical protocols recently applied to solve stereochemical aspects in structure elucidation. http://www.mdpi.com/1660-3397/10/1/51 Wed, 04 Jan 2012 00:00:00 CET Marine Drugs 2012-01-04 10 1 Article 51 63 1660-3397 Aplisulfamines, New Sulfoxide-Containing Metabolites from an Aplidium Tunicate: Absolute Stereochemistry at Chiral Sulfur and Carbon Atoms Assigned Through an Original Combination of Spectroscopic and Computational Methods 2012-01-04 doi: 10.3390/md10010051 Anna Aiello Ernesto Fattorusso Concetta Imperatore Paolo Luciano Marialuisa Menna Rocco Vitalone http://www.mdpi.com/1660-3397/10/1/35 Discovery and development of new antitumor agents from abundant marine fish are attracting an increasing interest. In the present study, we extracted and purified a novel antitumor protein Syngnathusin from the whole body of Syngnathus acus L., a precious marine fish traditionally used for tumors. Syngnathusin was comprised of 16 kinds of amino acids, mainly acidic amino acids. Its molecular weight was 67.3 kDa and its isoelectric point was 4.57. The N-terminal amino acid sequence of Syngnathusin was determined to be Lys-Arg-Asp-Leu-Gly-Phe-Val-Asp-Glu-Ile-Ser-Ala-His-Tyr and showed no significant homology with the known proteins. Syngnathusin could significantly inhibit the growth of A549 and CCRF-CEM cells. However, the obvious proliferation inhibition against human non-tumor cell lines was not observed. Flow cytometry, morphologic assessment and comet assay revealed that Syngnathusin could induce apoptosis in A549 and CCRF-CEM cells and strongly cooperated with MTX. Syngnathusin could inhibit the growth of S180 tumor transplanted in mice. Syngnathusin may be developed as a novel, selective and effective antineoplastic agent. http://www.mdpi.com/1660-3397/10/1/35 Fri, 30 Dec 2011 00:00:00 CET Marine Drugs 2011-12-30 10 1 Article 35 50 1660-3397 Purification, Characterization and Antitumor Activities of a New Protein from Syngnathus acus, an Officinal Marine Fish 2011-12-30 doi: 10.3390/md10010035 Mengyue Wang Yuxiao Nie Ying Peng Fen He Jingyu Yang Chunfu Wu Xiaobo Li http://www.mdpi.com/1660-3397/10/1/20 Due to the increased consumption of marine collagen peptides preparation (MCP) as ingredients in functional foods and pharmaceuticals, it was necessary to carry out safety requirements in the form of an oral chronic toxicity assessment. In order to define the oral chronic toxicity of MCP, a 24-month feeding study of MCP was carried out. Sprague-Dawley (S-D) rats at the age of four-week of both sexes were treated with MCP at the diet concentrations of 0%, 2.25%, 4.5%, 9% and 18% (wt/wt). The actual food intake and bodyweight of the individual animals were recorded periodically until sacrifice. Blood and urine samples were collected for serum chemistry evaluations and urinalysis. Throughout the experimental period, there was no toxicologically significant difference between the vehicle and MCP-treated animals with respect to the survival rate, body weight, food consumption, urinalysis, clinical biochemistry parameter and relative organ weight in either sex. Moreover, incidences of non-neoplastic lesions in MCP-treated groups did not significantly increase compared with the control group. Under the present experimental conditions, no higher risk of chronic toxic effects was observed in MCP-treated rats at the diet concentrations of 2.25%, 4.5%, 9% and 18% (wt/wt) than in the rats fed with basal rodent diet. http://www.mdpi.com/1660-3397/10/1/20 Wed, 28 Dec 2011 00:00:00 CET Marine Drugs 2011-12-28 10 1 Article 20 34 1660-3397 A Chronic Oral Toxicity Study of Marine Collagen Peptides Preparation from Chum Salmon (Oncorhynchus keta) Skin Using Sprague-Dawley Rat 2011-12-28 doi: 10.3390/md10010020 Jiang Liang Xin-Rong Pei Zhao-Feng Zhang Nan Wang Jun-Bo Wang Yong Li http://www.mdpi.com/1660-3397/10/1/1 Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B16F10 cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B16F10 tumor cells. http://www.mdpi.com/1660-3397/10/1/1 Thu, 22 Dec 2011 00:00:00 CET Marine Drugs 2011-12-22 10 1 Article 1 19 1660-3397 Sarcophine-Diol, a Skin Cancer Chemopreventive Agent, Inhibits Proliferation and Stimulates Apoptosis in Mouse Melanoma B16F10 Cell Line 2011-12-22 doi: 10.3390/md10010001 Pawel T. Szymanski Bhimanna Kuppast Safwat A. Ahmed Sherief Khalifa Hesham Fahmy http://www.mdpi.com/1660-3397/9/12/2809 The chemical investigation of an Indonesian specimen of Theonella swinhoei afforded four aurantosides, one of which, aurantoside J (5), is a new compound. The structure of this metabolite, exhibiting the unprecedented N-α-glycosidic linkage between the pentose and the tetramate units, has been determined through detailed spectroscopic analysis. The four obtained aurantosides have been tested against five fungal strains (four Candida and one Fusarium) responsible of invasive infections in immuno-compromised patients. The non-cytotoxic aurantoside I (4) was the single compound to show an excellent potency against all the tested strains, thus providing valuable insights about the antifungal potential of this class of compounds and the structure-activity relationships. http://www.mdpi.com/1660-3397/9/12/2809 Tue, 20 Dec 2011 00:00:00 CET Marine Drugs 2011-12-20 9 12 Article 2809 2817 1660-3397 Aurantoside J: a New Tetramic Acid Glycoside from Theonella swinhoei. Insights into the Antifungal Potential of Aurantosides 2011-12-20 doi: 10.3390/md9122809 Rihab F. Angawi Giorgio Bavestrello Barbara Calcinai Henny Adeleida Dien Giovanna Donnarumma Maria Antonietta Tufano Iole Paoletti Elena Grimaldi Giuseppina Chianese Ernesto Fattorusso Orazio Taglialatela-Scafati http://www.mdpi.com/1660-3397/9/12/2793 Nonalcoholic steatohepatitis (NASH) is a disease closely associated with obesity and diabetes. A prevalence of type 2 diabetes and a high body mass index in cryptogenic cirrhosis may imply that obesity leads to cirrhosis. Here, we examined the effects of an extract of Ecklonia cava, a brown algae, on the activation of high glucose-induced hepatic stellate cells (HSCs), key players in hepatic fibrosis. Isolated HSCs were incubated with or without a high glucose concentration. Ecklonia cava extract (ECE) was added to the culture simultaneously with the high glucose. Treatment with high glucose stimulated expression of type I collagen and α-smooth muscle actin, which are markers of activation in HSCs, in a dose-dependent manner. The activation of high glucose-treated HSCs was suppressed by the ECE. An increase in the formation of intracellular reactive oxygen species (ROS) and a decrease in intracellular glutathione levels were observed soon after treatment with high glucose, and these changes were suppressed by the simultaneous addition of ECE. High glucose levels stimulated the secretion of bioactive transforming growth factor-β (TGF-β) from the cells, and the stimulation was also suppressed by treating the HSCs with ECE. These results suggest that the suppression of high glucose-induced HSC activation by ECE is mediated through the inhibition of ROS and/or GSH and the downregulation of TGF-β secretion. ECE is useful for preventing the development of diabetic liver fibrosis. http://www.mdpi.com/1660-3397/9/12/2793 Tue, 20 Dec 2011 00:00:00 CET Marine Drugs 2011-12-20 9 12 Article 2793 2808 1660-3397 Inhibitory Effects of Ecklonia cava Extract on High Glucose-Induced Hepatic Stellate Cell Activation 2011-12-20 doi: 10.3390/md9122793 Kumiko Yokogawa Isao Matsui-Yuasa Akiko Tamura Masaki Terada Akiko Kojima-Yuasa http://www.mdpi.com/1660-3397/9/12/2773 The structures, names, bioactivities, and references of 81 new secondary metabolites obtained from gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from sea whip gorgonian corals Junceella fragilis and Junceella juncea, collected from the tropical and subtropical Indo-Pacific Ocean. http://www.mdpi.com/1660-3397/9/12/2773 Mon, 19 Dec 2011 00:00:00 CET Marine Drugs 2011-12-19 9 12 Review 2773 2792 1660-3397 Natural Product Chemistry of Gorgonian Corals of Genus Junceella—Part II 2011-12-19 doi: 10.3390/md9122773 Yang-Chang Wu Jui-Hsin Su Tai-Ting Chou Yin-Pin Cheng Ching-Feng Weng Chia-Hung Lee Lee-Shing Fang Wei-Hsien Wang Jan-Jung Li Mei-Chin Lu Jimmy Kuo Jyh-Horng Sheu Ping-Jyun Sung http://www.mdpi.com/1660-3397/9/12/2729 Cyanobacteria are photosynthetic prokaryotes with wide geographic distribution that can produce secondary metabolites named cyanotoxins. These toxins can be classified into three main types according to their mechanism of action in vertebrates: hepatotoxins, dermatotoxins and neurotoxins. Many studies on the effects of cyanobacteria and their toxins over a wide range of aquatic organisms, including invertebrates and vertebrates, have reported acute effects (e.g., reduction in survivorship, feeding inhibition, paralysis), chronic effects (e.g., reduction in growth and fecundity), biochemical alterations (e.g., activity of phosphatases, GST, AChE, proteases), and behavioral alterations. Research has also focused on the potential for bioaccumulation and transferring of these toxins through the food chain. Although the herbivorous zooplankton is hypothesized as the main target of cyanotoxins, there is not unquestionable evidence of the deleterious effects of cyanobacteria and their toxins on these organisms. Also, the low toxin burden in secondary consumers points towards biodilution of microcystins in the food web as the predominant process. In this broad review we discuss important issues on bioaccumulation and the effects of cyanotoxins, with emphasis on microcystins, as well as drawbacks and future needs in this field of research. http://www.mdpi.com/1660-3397/9/12/2729 Fri, 16 Dec 2011 00:00:00 CET Marine Drugs 2011-12-16 9 12 Review 2729 2772 1660-3397 Cyanotoxins: Bioaccumulation and Effects on Aquatic Animals 2011-12-16 doi: 10.3390/md9122729 Aloysio da S. Ferrão-Filho Betina Kozlowsky-Suzuki http://www.mdpi.com/1660-3397/9/12/2717 Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia. http://www.mdpi.com/1660-3397/9/12/2717 Thu, 15 Dec 2011 00:00:00 CET Marine Drugs 2011-12-15 9 12 Article 2717 2728 1660-3397 Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia 2011-12-15 doi: 10.3390/md9122717 Charles B. Berde Umeshkumar Athiraman Barak Yahalom David Zurakowski Gabriel Corfas Christina Bognet http://www.mdpi.com/1660-3397/9/12/2705 Chemical investigation of the Dongsha Atoll soft coral Lobophytum crassum has afforded four new cembranoids, crassumols A–C (1–3) and 13-acetoxysarcophytoxide (4). The structures of these isolated compounds were elucidated by extensive NMR and HRESIMS experiments. The cytotoxicity and anti-HCMV (Human cytomegalovirus) activities of 1–4 were evaluated in vitro. Compound 4 exhibited cytotoxicity against A-549 (human lung carcinoma) cell line with an ED50 of 3.6 μg/mL. http://www.mdpi.com/1660-3397/9/12/2705 Thu, 15 Dec 2011 00:00:00 CET Marine Drugs 2011-12-15 9 12 Article 2705 2716 1660-3397 Cembranoids from the Dongsha Atoll Soft Coral Lobophytum crassum 2011-12-15 doi: 10.3390/md9122705 Shih-Tseng Lin Shang-Kwei Wang Chang-Yih Duh http://www.mdpi.com/1660-3397/9/12/2683 Carotid bodies (CBs) are secondary sensory receptors in which the sensing elements, chemoreceptor cells, are activated by decreases in arterial PO2 (hypoxic hypoxia). Upon activation, chemoreceptor cells (also known as Type I and glomus cells) increase their rate of release of neurotransmitters that drive the sensory activity in the carotid sinus nerve (CSN) which ends in the brain stem where reflex responses are coordinated. When challenged with hypoxic hypoxia, the physiopathologically most relevant stimulus to the CBs, they are activated and initiate ventilatory and cardiocirculatory reflexes. Reflex increase in minute volume ventilation promotes CO2 removal from alveoli and a decrease in alveolar PCO2 ensues. Reduced alveolar PCO2 makes possible alveolar and arterial PO2 to increase minimizing the intensity of hypoxia. The ventilatory effect, in conjunction the cardiocirculatory components of the CB chemoreflex, tend to maintain an adequate supply of oxygen to the tissues. The CB has been the focus of attention since the discovery of its nature as a sensory organ by de Castro (1928) and the discovery of its function as the origin of ventilatory reflexes by Heymans group (1930). A great deal of effort has been focused on the study of the mechanisms involved in O2 detection. This review is devoted to this topic, mechanisms of oxygen sensing. Starting from a summary of the main theories evolving through the years, we will emphasize the nature and significance of the findings obtained with veratridine and tetrodotoxin (TTX) in the genesis of current models of O2-sensing. http://www.mdpi.com/1660-3397/9/12/2683 Thu, 15 Dec 2011 00:00:00 CET Marine Drugs 2011-12-15 9 12 Review 2683 2704 1660-3397 Tetrodotoxin as a Tool to Elucidate Sensory Transduction Mechanisms: The Case for the Arterial Chemoreceptors of the Carotid Body 2011-12-15 doi: 10.3390/md9122683 Asuncion Rocher Ana Isabel Caceres Ana Obeso Constancio Gonzalez http://www.mdpi.com/1660-3397/9/12/2643 Lithistid sponges are known to produce a diverse array of compounds ranging from polyketides, cyclic and linear peptides, alkaloids, pigments, lipids, and sterols. A majority of these structurally complex compounds have very potent and interesting biological activities. It has been a decade since a thorough review has been published that summarizes the literature on the natural products reported from this amazing sponge order. This review provides an update on the current taxonomic classification of the Lithistida, describes structures and biological activities of 131 new natural products, and discusses highlights from the total syntheses of 16 compounds from marine sponges of the Order Lithistida providing a compilation of the literature since the last review published in 2002. http://www.mdpi.com/1660-3397/9/12/2643 Thu, 15 Dec 2011 00:00:00 CET Marine Drugs 2011-12-15 9 12 Review 2643 2682 1660-3397 Natural Products from the Lithistida: A Review of the Literature since 2000 2011-12-15 doi: 10.3390/md9122643 Priscilla L. Winder Shirley A. Pomponi Amy E. Wright http://www.mdpi.com/1660-3397/9/12/2622 Active compounds from natural products have been widely studied. The anti-tumor effects of 13-acetoxysarcocrassolide isolated from Formosan soft coral Sarcophyton crassocaule on bladder cancer cells were examined in this study. An MTT assay showed that 13-acetoxysarcocrassolide was cytotoxic to bladder female transitional cancer (BFTC) cells. We determined that the BFTC cells underwent cell death through apoptosis by flow cytometry. Due to the highly-migratory nature of the BFTC cells, the ability of 13-acetoxysarcocrassolide to stop their migration was assessed by a wound healing assay. To determine which proteins were affected in the BFTC cells upon treatment, a comparative proteomic analysis was performed. By LC-MS/MS analysis, we identified that 19 proteins were up-regulated and eight were down-regulated. Seven of the proteins were confirmed by western blotting analysis. This study reveals clues to the potential mechanism of the cytotoxic effects of 13-acetoxysarcocrassolide on BFTC cells. Moreover, it suggests that PPT1 and hnRNP F could be new biomarkers for bladder cancer. The results of this study are also helpful for the diagnosis, progression monitoring and therapeutic strategies of transitional cell tumors. http://www.mdpi.com/1660-3397/9/12/2622 Tue, 13 Dec 2011 00:00:00 CET Marine Drugs 2011-12-13 9 12 Article 2622 2642 1660-3397 An Investigation into the Cytotoxic Effects of 13-Acetoxysarcocrassolide from the Soft Coral Sarcophyton crassocaule on Bladder Cancer Cells 2011-12-13 doi: 10.3390/md9122622 Ching-Chyuan Su Jui-Hsin Su Jen-Jie Lin Cheng-Chi Chen Wen-Ing Hwang Han Hsiang Huang Yu-Jen Wu http://www.mdpi.com/1660-3397/9/12/2605 Fucose-containing sulfated polysaccharides (FCSPs) extracted from seaweeds, especially brown macro-algae, are known to possess essential bioactive properties, notably growth inhibitory effects on tumor cells. In this work, we conducted a series of in vitro studies to examine the influence of FCSPs products from Sargassum henslowianum C. Agardh (FSAR) and Fucus vesiculosus (FVES), respectively, on proliferation of melanoma B16 cells and to investigate the underlying apoptosis promoting mechanisms. Cell viability analysis showed that both FCSPs products, i.e., FSAR and FVES, decreased the proliferation of the melanoma cells in a dose-response fashion, with FSAR being more potent at lower dosages, and FVES being relatively more anti-proliferative than FSAR at higher dosages. Flow cytometric analysis by Annexin V staining of the melanoma cells exposed to the FCSPs products confirmed that both FSAR and FVES induced apoptosis. The FCSPs-induced apoptosis was evidenced by loss of plasma membrane asymmetry and translocation of the cell membrane phospholipids and was accompanied by the activation of caspase-3. The FCSPs bioactivity is proposed to be attributable to distinct structural features of the FCSPs, particularly the presence of sulfated galactofucans (notably in S. henslowianum) and sulfated fucans (notably in F. vesiculosus). This study thus indicates that unfractionated FCSPs may exert bioactive effects on skin cancer cells via induction of apoptosis through cascades of reactions that involve activation of caspase-3. http://www.mdpi.com/1660-3397/9/12/2605 Tue, 13 Dec 2011 00:00:00 CET Marine Drugs 2011-12-13 9 12 Article 2605 2621 1660-3397 Fucose-Containing Sulfated Polysaccharides from Brown Seaweeds Inhibit Proliferation of Melanoma Cells and Induce Apoptosis by Activation of Caspase-3 in Vitro 2011-12-13 doi: 10.3390/md9122605 Marcel Tutor Ale Hiroko Maruyama Hidekazu Tamauchi Jørn D. Mikkelsen Anne S. Meyer http://www.mdpi.com/1660-3397/9/12/2572 This review’s main objective is to discuss some physico-chemical features of polysaccharides as intrinsic determinants for the supramolecular structures that can efficiently provide encapsulation of drugs and other biological entities. Thus, the general characteristics of some basic polysaccharides are outlined in terms of their conformational, dynamic and thermodynamic properties. The analysis of some polysaccharide gelling properties is also provided, including the peculiarity of the charged polysaccharides. Then, the way the basic physical chemistry of polymer self-assembly is made in practice through the laboratory methods is highlighted. A description of the several literature procedures used to influence molecular interactions into the macroscopic goal of the encapsulation is given with an attempt at classification. Finally, a practical case study of specific interest, the use of marine polysaccharide matrices for encapsulation of vaccines in aquaculture, is reported. http://www.mdpi.com/1660-3397/9/12/2572 Thu, 08 Dec 2011 00:00:00 CET Marine Drugs 2011-12-08 9 12 Review 2572 2604 1660-3397 Marine Polysaccharides in Microencapsulation and Application to Aquaculture: “From Sea to Sea” 2011-12-08 doi: 10.3390/md9122572 Massimiliano Borgogna Barbara Bellich Attilio Cesàro http://www.mdpi.com/1660-3397/9/12/2553 Fish consumption is a potential route of human exposure to the hepatotoxic microcystins, especially in lakes and reservoirs that routinely experience significant toxic Microcystis blooms. Understanding the rates of uptake and elimination for microcystins as well as the transfer efficiency into tissues of consumers are important for determining the potential for microcystins to be transferred up the food web and for predicting potential human health impacts. The main objective of this work was to conduct laboratory experiments to investigate the kinetics of toxin accumulation in fish tissue. An oral route of exposure was employed in this study, in which juvenile yellow perch (Perca flavescens) were given a single oral dose of 5 or 20 μg of microcystin-LR (MC-LR) via food and accumulation in the muscle, liver, and tank water were measured over 24 h. Peak concentrations of the water soluble fraction of microcystin were generally observed 8–10 h after dosing in the liver and after 12–16 h in the muscle, with a rapid decline in both tissues by 24 h. Up to 99% of the total recoverable (i.e., unbound) microcystin was measured in the tank water by 16 h after exposure. The relatively rapid uptake and elimination of the unbound fraction of microcystin in the liver and muscle of juvenile yellow perch within 24 h of exposure indicates that fish consumption may not be a major route of human exposure to microcystin, particularly in the Great Lakes. http://www.mdpi.com/1660-3397/9/12/2553 Thu, 08 Dec 2011 00:00:00 CET Marine Drugs 2011-12-08 9 12 Article 2553 2571 1660-3397 A Kinetic Study of Accumulation and Elimination of Microcystin-LR in Yellow Perch (Perca Flavescens) Tissue and Implications for Human Fish Consumption 2011-12-08 doi: 10.3390/md9122553 Julianne Dyble Duane Gossiaux Peter Landrum Donna R. Kashian Steven Pothoven http://www.mdpi.com/1660-3397/9/12/2537 During a global research expedition, more than five hundred marine bacterial strains capable of inhibiting the growth of pathogenic bacteria were collected. The purpose of the present study was to determine if these marine bacteria are also a source of compounds that interfere with the agr quorum sensing system that controls virulence gene expression in Staphylococcus aureus. Using a gene reporter fusion bioassay, we recorded agr interference as enhanced expression of spa, encoding Protein A, concomitantly with reduced expression of hla, encoding α-hemolysin, and rnaIII encoding RNAIII, the effector molecule of agr. A marine Photobacterium produced compounds interfering with agr in S. aureus strain 8325-4, and bioassay-guided fractionation of crude extracts led to the isolation of two novel cyclodepsipeptides, designated solonamide A and B. Northern blot analysis confirmed the agr interfering activity of pure solonamides in both S. aureus strain 8325-4 and the highly virulent, community-acquired strain USA300 (CA-MRSA). To our knowledge, this is the first report of inhibitors of the agr system by a marine bacterium. http://www.mdpi.com/1660-3397/9/12/2537 Wed, 07 Dec 2011 00:00:00 CET Marine Drugs 2011-12-07 9 12 Article 2537 2552 1660-3397 Inhibition of Virulence Gene Expression in Staphylococcus aureus by Novel Depsipeptides from a Marine Photobacterium 2011-12-07 doi: 10.3390/md9122537 Maria Mansson Anita Nielsen Louise Kjærulff Charlotte H. Gotfredsen Matthias Wietz Hanne Ingmer Lone Gram Thomas O. Larsen http://www.mdpi.com/1660-3397/9/12/2526 Three new cembranoids, culobophylins A–C (1–3), along with two known compounds (4 and 5) were isolated from the cultured soft coral Lobophytum crassum. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. Among these metabolites, 2 is rarely found in cembranoids possessing an isopropyl moiety with an epoxide group. Compound 1 exhibited significant cytotoxic activity against HL60 and DLD-1 cancer cell lines. http://www.mdpi.com/1660-3397/9/12/2526 Wed, 07 Dec 2011 00:00:00 CET Marine Drugs 2011-12-07 9 12 Article 2526 2536 1660-3397 Tetrahydrofuran Cembranoids from the Cultured Soft Coral Lobophytum crassum 2011-12-07 doi: 10.3390/md9122526 Nai-Lun Lee Jui-Hsin Su http://www.mdpi.com/1660-3397/9/12/2514 Plants interact with the environment by sensing “non-self” molecules called elicitors derived from pathogens or other sources. These molecules bind to specific receptors located in the plasma membrane and trigger defense responses leading to protection against pathogens. In particular, it has been shown that cell wall and storage polysaccharides from green, brown and red seaweeds (marine macroalgae) corresponding to ulvans, alginates, fucans, laminarin and carrageenans can trigger defense responses in plants enhancing protection against pathogens. In addition, oligosaccharides obtained by depolymerization of seaweed polysaccharides also induce protection against viral, fungal and bacterial infections in plants. In particular, most seaweed polysaccharides and derived oligosaccharides trigger an initial oxidative burst at local level and the activation of salicylic (SA), jasmonic acid (JA) and/or ethylene signaling pathways at systemic level. The activation of these signaling pathways leads to an increased expression of genes encoding: (i) Pathogenesis-Related (PR) proteins with antifungal and antibacterial activities; (ii) defense enzymes such as pheylalanine ammonia lyase (PAL) and lipoxygenase (LOX) which determine accumulation of phenylpropanoid compounds (PPCs) and oxylipins with antiviral, antifugal and antibacterial activities and iii) enzymes involved in synthesis of terpenes, terpenoids and/or alkaloids having antimicrobial activities. Thus, seaweed polysaccharides and their derived oligosaccharides induced the accumulation of proteins and compounds with antimicrobial activities that determine, at least in part, the enhanced protection against pathogens in plants. http://www.mdpi.com/1660-3397/9/12/2514 Tue, 29 Nov 2011 00:00:00 CET Marine Drugs 2011-11-29 9 12 Review 2514 2525 1660-3397 Seaweed Polysaccharides and Derived Oligosaccharides Stimulate Defense Responses and Protection Against Pathogens in Plants 2011-11-29 doi: 10.3390/md9122514 Jeannette Vera Jorge Castro Alberto Gonzalez Alejandra Moenne http://www.mdpi.com/1660-3397/9/12/2499 Understanding the scale at which natural products vary the most is critical because it sheds light on the type of factors that regulate their production. The sponge Aplysina aerophoba is a common Mediterranean sponge inhabiting shallow waters in the Mediterranean and its area of influence in Atlantic Ocean. This species contains large concentrations of brominated alkaloids (BAs) that play a number of ecological roles in nature. Our research investigates the ecological variation in BAs of A. aerophoba from a scale of hundred of meters to thousand kilometers. We used a nested design to sample sponges from two geographically distinct regions (Canary Islands and Mediterranean, over 2500 km), with two zones within each region (less than 50 km), two locations within each zone (less than 5 km), and two sites within each location (less than 500 m). We used high-performance liquid chromatography to quantify multiple BAs and a spectrophotometer to quantify chlorophyll a (Chl a). Our results show a striking degree of variation in both natural products and Chl a content. Significant variation in Chl a content occurred at the largest and smallest geographic scales. The variation patterns of BAs also occurred at the largest and smallest scales, but varied depending on which BA was analyzed. Concentrations of Chl a and isofistularin-3 were negatively correlated, suggesting that symbionts may impact the concentration of some of these compounds. Our results underline the complex control of the production of secondary metabolites, with factors acting at both small and large geographic scales affecting the production of multiple secondary metabolites. http://www.mdpi.com/1660-3397/9/12/2499 Mon, 28 Nov 2011 00:00:00 CET Marine Drugs 2011-11-28 9 12 Article 2499 2513 1660-3397 Relevant Spatial Scales of Chemical Variation in Aplysina aerophoba 2011-11-28 doi: 10.3390/md9122499 Oriol Sacristan-Soriano Bernard Banaigs Mikel A. Becerro http://www.mdpi.com/1660-3397/9/12/2488 Chitosan is prepared by the deacetylation of chitin, the second-most abundant biopolymer in nature, and has applicability in the removal of dyes, heavy metals and radioactive waste for pollution control. In weight-reduction remedies, chitosan is used to form hydrogels with lipids and to depress the intestinal absorption of lipids. In this study, an experimental method was implemented to simulate the effect of chitosan on the adsorption of humic acid in the gastrointestinal tract. The adsorption capacity of chitosan was measured by its adsorption isotherm and analyzed using the Langmuir equation. The results showed that 3.3 grams of humic acid was absorbed by 1 gram of chitosan. The adsorption capacity of chitosan was much greater than that of chitin, diethylaminoethyl-cellulose or activated charcoal. Cellulose and carboxymethyl-cellulose, a cellulose derivative with a negative charge, could not adsorb humic acid in the gastrointestinal tract. This result suggests that chitosan entraps humic acid because of its positive charge. http://www.mdpi.com/1660-3397/9/12/2488 Mon, 28 Nov 2011 00:00:00 CET Marine Drugs 2011-11-28 9 12 Article 2488 2498 1660-3397 Chitosan, the Marine Functional Food, Is a Potent Adsorbent of Humic Acid 2011-11-28 doi: 10.3390/md9122488 Jeen-Kuan Chen Chao-Hsien Yeh Lian-Chen Wang Tzong-Horng Liou Chia-Rui Shen Chao-Lin Liu http://www.mdpi.com/1660-3397/9/11/2479 Five zoanthoxanthin alkaloids (1–5) and four sesquiterpenes (6–9) were isolated from the South China Sea gorgonian Echinogorgia pseudossapo. Their structures were determined on the bases of extensive spectroscopic analyses, including 1D and 2D NMR data. Among them, pseudozoanthoxanthins III and IV (1–2), 8-hydroxy-6β-methoxy-14-oxooplop-6,12-olide (6) and 3β-methoxyguaian-10(14)-en-2β-ol (7) were new, 1 and 3 showed mild anti-HSV-1 activity, and 7 showed significant antilarval activity towards Balanus amphitrite larvae. http://www.mdpi.com/1660-3397/9/11/2479 Thu, 24 Nov 2011 00:00:00 CET Marine Drugs 2011-11-24 9 11 Article 2479 2487 1660-3397 Alkaloids and Sesquiterpenes from the South China Sea Gorgonian Echinogorgia pseudossapo 2011-11-24 doi: 10.3390/md9112479 Cheng-Hai Gao Yi-Fei Wang Shen Li Pei-Yuan Qian Shu-Hua Qi