Marine Drugs

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Open AccessArticle

New Steroids from the Soft Coral Nephthea chabrolii

by Shang-Kwei Wang, Shyh-Yueh Puu and Chang-Yih Duh

Mar. Drugs 2013, 11(2), 571-580; https://doi.org/10.3390/md11020571 - 22 Feb 2013

Cited by 20 | Viewed by 6702

A new cytotoxic 19-oxygenated steroid, nebrosteroid Q (1) and two new cytotoxic 19-norergosterols, nebrosteroids R and S (2 and 3) were isolated from the soft coral Nephthea chabrolii collected at San-Hsian-Tai. The structures of nebrosteroids Q–S (1– [...] Read more.

A new cytotoxic 19-oxygenated steroid, nebrosteroid Q (1) and two new cytotoxic 19-norergosterols, nebrosteroids R and S (2 and 3) were isolated from the soft coral Nephthea chabrolii collected at San-Hsian-Tai. The structures of nebrosteroids Q–S (1–3) were elucidated by spectral analysis, and their cytotoxicity against selected cancer cells as well as antiviral activity against human cytomegalovirus (HCMV) were measured in vitro. Full article

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Open AccessShort Note

Probing a Coral Genome for Components of the Photoprotective Scytonemin Biosynthetic Pathway and the 2-Aminoethylphosphonate Pathway

by Eiichi Shoguchi, Makiko Tanaka, Takeshi Takeuchi, Chuya Shinzato and Nori Satoh

Mar. Drugs 2013, 11(2), 559-570; https://doi.org/10.3390/md11020559 - 22 Feb 2013

Cited by 5 | Viewed by 8350

Abstract

Genome sequences of the reef-building coral, Acropora digitifera, have been decoded. Acropora inhabits an environment with intense ultraviolet exposure and hosts the photosynthetic endosymbiont, Symbiodinium. Acropora homologs of all four genes necessary for biosynthesis of the photoprotective cyanobacterial compound, shinorine, are [...] Read more.

Genome sequences of the reef-building coral, Acropora digitifera, have been decoded. Acropora inhabits an environment with intense ultraviolet exposure and hosts the photosynthetic endosymbiont, Symbiodinium. Acropora homologs of all four genes necessary for biosynthesis of the photoprotective cyanobacterial compound, shinorine, are present. Among metazoans, these genes are found only in anthozoans. To gain further evolutionary insights into biosynthesis of photoprotective compounds and associated coral proteins, we surveyed the Acropora genome for 18 clustered genes involved in cyanobacterial synthesis of the anti-UV compound, scytonemin, even though it had not previously been detected in corals. We identified candidates for only 6 of the 18 genes, including tyrP, scyA, and scyB. Therefore, it does not appear that Acropora digitifera can synthesize scytonemin independently. On the other hand, molecular phylogenetic analysis showed that one tyrosinase gene is an ortholog of vertebrate tyrosinase genes and that the coral homologs, scyA and scyB, are similar to bacterial metabolic genes, phosphonopyruvate (ppyr) decarboxylase and glutamate dehydrogenase (GDH), respectively. Further genomic searches for ppyr gene-related biosynthetic components indicate that the coral possesses a metabolic pathway similar to the bacterial 2-aminoethylphosphonate (AEP) biosynthetic pathway. The results suggest that de novo synthesis of carbon-phosphorus compounds is performed in corals. Full article

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

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Open AccessArticle

Isolation and Structural Elucidation of Chondrosterins F–H from the Marine Fungus Chondrostereum sp.

by Hou-Jin Li, Ting Chen, Ying-Lu Xie, Wen-Dan Chen, Xiao-Feng Zhu and Wen-Jian Lan

Mar. Drugs 2013, 11(2), 551-558; https://doi.org/10.3390/md11020551 - 22 Feb 2013

Cited by 33 | Viewed by 6874

Abstract

The marine fungus Chondrostereum sp. was collected from a soft coral of the species Sarcophyton tortuosum from the South China Sea. Three new compounds, chondrosterins F–H (1, 4 and 5), together with three known compounds, incarnal (2), arthrosporone [...] Read more.

The marine fungus Chondrostereum sp. was collected from a soft coral of the species Sarcophyton tortuosum from the South China Sea. Three new compounds, chondrosterins F–H (1, 4 and 5), together with three known compounds, incarnal (2), arthrosporone (3), and (2E)-decene-4,6,8-triyn-1-ol (6), were isolated. Their structures were elucidated primarily based on NMR and MS data. Incarnal (2) exhibited potent cytotoxic activity against various cancer cell lines. Full article

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

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Open AccessReview

Jellyfish Stings and Their Management: A Review

by Luca Cegolon, William C. Heymann, John H. Lange and Giuseppe Mastrangelo

Mar. Drugs 2013, 11(2), 523-550; https://doi.org/10.3390/md11020523 - 22 Feb 2013

Cited by 143 | Viewed by 25557

Abstract

Jellyfish (cnidarians) have a worldwide distribution. Despite most being harmless, some species may cause local and also systemic reactions. Treatment of jellyfish envenomation is directed at: alleviating the local effects of venom, preventing further nematocyst discharges and controlling systemic reactions, including shock. In [...] Read more.

Jellyfish (cnidarians) have a worldwide distribution. Despite most being harmless, some species may cause local and also systemic reactions. Treatment of jellyfish envenomation is directed at: alleviating the local effects of venom, preventing further nematocyst discharges and controlling systemic reactions, including shock. In severe cases, the most important step is stabilizing and maintaining vital functions. With some differences between species, there seems to be evidence and consensus on oral/topical analgesics, hot water and ice packs as effective painkillers and on 30 s application of domestic vinegar (4%–6% acetic acid) to prevent further discharge of unfired nematocysts remaining on the skin. Conversely, alcohol, methylated spirits and fresh water should be carefully avoided, since they could massively discharge nematocysts; pressure immobilization bandaging should also be avoided, as laboratory studies show that it stimulates additional venom discharge from nematocysts. Most treatment approaches are presently founded on relatively weak evidence; therefore, further research (especially randomized clinical trials) is strongly recommended. Dissemination of appropriate treatment modalities should be deployed to better inform and educate those at risk. Adequate signage should be placed at beaches to notify tourists of the jellyfish risk. Swimmers in risky areas should wear protective equipment. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

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Open AccessArticle

Xyloketal B Exhibits Its Antioxidant Activity through Induction of HO-1 in Vascular Endothelial Cells and Zebrafish

by Zhen-Xing Li, Jian-Wen Chen, Feng Yuan, Yun-Ying Huang, Li-Yan Zhao, Jie Li, Huan-Xing Su, Jie Liu, Ji-Yan Pang, Yong-Cheng Lin, Xi-Lin Lu, Zhong Pei, Guan-Lei Wang and Yong-Yuan Guan

Mar. Drugs 2013, 11(2), 504-522; https://doi.org/10.3390/md11020504 - 18 Feb 2013

Cited by 36 | Viewed by 6400

Abstract

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here [...] Read more.

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B. Full article

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

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Open AccessArticle

Sources of Secondary Metabolite Variation in Dysidea avara (Porifera: Demospongiae): The Importance of Having Good Neighbors

by Sonia De Caralt, Delphine Bry, Nataly Bontemps, Xavier Turon, Maria-Jesus Uriz and Bernard Banaigs

Mar. Drugs 2013, 11(2), 489-503; https://doi.org/10.3390/md11020489 - 18 Feb 2013

Cited by 33 | Viewed by 7834

Abstract

Several studies report temporal, geographical, and intra-individual variation in sponge metabolite yields. However, the internal and/or external factors that regulate the metabolite production remain poorly understood. Dysidea avara is a demosponge that produces sesquiterpenoids (avarol and derivatives) with interesting medical properties, which has [...] Read more.

Several studies report temporal, geographical, and intra-individual variation in sponge metabolite yields. However, the internal and/or external factors that regulate the metabolite production remain poorly understood. Dysidea avara is a demosponge that produces sesquiterpenoids (avarol and derivatives) with interesting medical properties, which has prompted addressed studies to obtain enough amounts of these metabolites for research on drug discovery. Within this framework, specimens of Dysidea avara from a population of the Northwest Mediterranean were sampled and their secondary metabolites quantified to assess their variability and the possible relationship with external (seasonality, interactions with neighbors) and internal (reproductive stages) factors. The results show a variation of the amount of both avarol and its monoacetate derivative with time, with no clear relationship with seawater temperature. A trade-off with sponge reproduction was not found either. However, our results showed for the first time that sponges are able to increase production or accumulation of secondary metabolites in their peripheral zone depending on the nature of their neighbors. This finding could explain part of the high variability in the amount of secondary metabolites usually found in chemical ecology studies on sponges and opens new biotechnological approaches to enhance the metabolite yield in sponge cultures. Full article

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

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Open AccessArticle

Cloning, Characterization and Heterologous Expression of the Indolocarbazole Biosynthetic Gene Cluster from Marine-Derived Streptomyces sanyensis FMA

by Tong Li, Yuanyuan Du, Qiu Cui, Jingtao Zhang, Weiming Zhu, Kui Hong and Wenli Li

Mar. Drugs 2013, 11(2), 466-488; https://doi.org/10.3390/md11020466 - 06 Feb 2013

Cited by 31 | Viewed by 7020

Abstract

The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications. A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA. To elucidate the biosynthetic machinery associated with ICZs production [...] Read more.

The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications. A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA. To elucidate the biosynthetic machinery associated with ICZs production in S. sanyensis FMA, PCR using degenerate primers was carried out to clone the FAD-dependent monooxygenase gene fragment for ICZ ring formation, which was used as a probe to isolate the 34.6-kb DNA region containing the spc gene cluster. Sequence analysis revealed genes for ICZ ring formation (spcO, D, P, C), sugar unit formation (spcA, B, E, K, J, I), glycosylation (spcN, G), methylation (spcMA, MB), as well as regulation (spcR). Their involvement in ICZ biosynthesis was confirmed by gene inactivation and heterologous expression in Streptomyces coelicolor M1152. This work represents the first cloning and characterization of an ICZ gene cluster isolated from a marine-derived actinomycete strain and would be helpful for thoroughly understanding the biosynthetic mechanism of ICZ glycosides. Full article

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Open AccessArticle

New Casbane Diterpenoids from a South China Sea Soft Coral, Sinularia sp.

by Jian Yin, Min Zhao, Minshan Ma, Yuping Xu, Zheng Xiang, Yuepiao Cai, Jianyong Dong, Xinxiang Lei, Kexin Huang and Pengcheng Yan

Mar. Drugs 2013, 11(2), 455-465; https://doi.org/10.3390/md11020455 - 06 Feb 2013

Cited by 29 | Viewed by 5416

Abstract

Six new casbane diterpenoids, named as sinularcasbanes A–F (1–6), along with six known analogues 7–12, were isolated from a South China Sea soft coral, Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data [...] Read more.

Six new casbane diterpenoids, named as sinularcasbanes A–F (1–6), along with six known analogues 7–12, were isolated from a South China Sea soft coral, Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. All compounds were evaluated for their cytotoxicity against selected cancer cell lines and the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal macrophages. Full article

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Graphical abstract

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Open AccessArticle

Core Oligosaccharide of Plesiomonas shigelloides PCM 2231 (Serotype O17) Lipopolysaccharide — Structural and Serological Analysis

by Anna Maciejewska, Jolanta Lukasiewicz, Marta Kaszowska, Aleksandra Man-Kupisinska, Wojciech Jachymek and Czeslaw Lugowski

Mar. Drugs 2013, 11(2), 440-454; https://doi.org/10.3390/md11020440 - 06 Feb 2013

Cited by 10 | Viewed by 5231

Abstract

The herein presented complete structure of the core oligosaccharide of lipopolysaccharide (LPS) P. shigelloides Polish Collection of Microorganisms (PCM) 2231 (serotype O17) was investigated by ¹H, ¹³C NMR spectroscopy, mass spectrometry, chemical analyses and serological methods. The core oligosaccharide is composed [...] Read more.

The herein presented complete structure of the core oligosaccharide of lipopolysaccharide (LPS) P. shigelloides Polish Collection of Microorganisms (PCM) 2231 (serotype O17) was investigated by ¹H, ¹³C NMR spectroscopy, mass spectrometry, chemical analyses and serological methods. The core oligosaccharide is composed of an undecasaccharide, which represents the second core type identified for P. shigelloides serotype O17 LPS. This structure is similar to that of the core oligosaccharide of P. shigelloides strains 302-73 (serotype O1) and 7-63 (serotype O17) and differs from these only by one sugar residue. Serological screening of 55 strains of P. shigelloides with the use of serum against identified core oligosaccharide conjugated with bovine serum albumin (BSA) indicated the presence of similar structures in the LPS core region of 28 O-serotypes. This observation suggests that the core oligosaccharide structure present in strain PCM 2231 could be the most common type among P. shigelloides lipopolysaccharides. Full article

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Open AccessCommunication

Novel One-Pot Green Synthesis of Indolizines Biocatalysed by Candida antarctica Lipases

by Rodica Mihaela Dinica, Bianca Furdui, Ioana Otilia Ghinea, Gabriela Bahrim, Simon Bonte and Martine Demeunynck

Mar. Drugs 2013, 11(2), 431-439; https://doi.org/10.3390/md11020431 - 06 Feb 2013

Cited by 22 | Viewed by 5758

Abstract

Marine microorganisms are of considerable interest as a promising source of enzymes with unsuspected potentials as catalysts for chemical synthesis. We describe here an efficient method for one-pot indolizine synthesis that has been developed using lipase A and lipase B from Candida antarctica [...] Read more.

Marine microorganisms are of considerable interest as a promising source of enzymes with unsuspected potentials as catalysts for chemical synthesis. We describe here an efficient method for one-pot indolizine synthesis that has been developed using lipase A and lipase B from Candida antarctica as biocatalysts. As showed by HPLC/MS analysis, the yield in indolizines was higher in the presence of the biocatalyst than in absence of enzyme. Lipase A, from Candida antarctica, showed high catalytic activity and selectivity for the cycloaddition reactions. When the reactions were performed under ultrasound irradiation, the Candida antarctica lipase catalyzed reactions yielded pure indolozines, in good yields and in very short time. Full article

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

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Open AccessArticle

Cytotoxic Effect of Clerosterol Isolated from Codium fragile on A2058 Human Melanoma Cells

by Areum Daseul Kim, Youngki Lee, Sang-Hyuck Kang, Gi Young Kim, Hye Sun Kim and Jin Won Hyun

Mar. Drugs 2013, 11(2), 418-430; https://doi.org/10.3390/md11020418 - 06 Feb 2013

Cited by 36 | Viewed by 6142

Abstract

The cytotoxic effects and mechanism of action of clerosterol, isolated from the marine alga Codium fragile, were investigated in A2058 human melanoma cells. Clerosterol inhibited the growth of A2058 cells with an IC₅₀ of 150 µM and induced apoptotic cell death, [...] Read more.

The cytotoxic effects and mechanism of action of clerosterol, isolated from the marine alga Codium fragile, were investigated in A2058 human melanoma cells. Clerosterol inhibited the growth of A2058 cells with an IC₅₀ of 150 µM and induced apoptotic cell death, as evidenced by DNA fragmentation, an increase in the number of sub-G₁ hypodiploid cells and the presence of apoptotic bodies. Clerosterol treatment caused the loss of mitochondrial membrane potential. Alterations in the expression of apoptosis-associated proteins in response to clerosterol treatment included upregulation of Bax, downregulation of Bcl-2 and activation of caspases 3 and 9. The pan-caspase inhibitor treatment attenuated the expression of the active form of caspases and cell death induced by clerosterol. The present results show that clerosterol exerts its cytotoxic effect in A2058 human melanoma cells by caspases-dependent apoptosis. Full article

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Open AccessArticle

Comparison of Physicochemical Characteristics and Anticoagulant Activities of Polysaccharides from Three Sea Cucumbers

by Lan Luo, Mingyi Wu, Li Xu, Wu Lian, Jingying Xiang, Feng Lu, Na Gao, Chuang Xiao, Shengmin Wang and Jinhua Zhao

Mar. Drugs 2013, 11(2), 399-417; https://doi.org/10.3390/md11020399 - 05 Feb 2013

Cited by 138 | Viewed by 12566

Abstract

In order to search for sulfated polysaccharides in different invertebrate connective tissues and to examine their biological activities, we have isolated three types of polysaccharides from the body wall of the three sea cucumbers Holothuria edulis, Apostichopus japonicas and Holothuria nobilis. [...] Read more.

In order to search for sulfated polysaccharides in different invertebrate connective tissues and to examine their biological activities, we have isolated three types of polysaccharides from the body wall of the three sea cucumbers Holothuria edulis, Apostichopus japonicas and Holothuria nobilis. The physicochemical properties and anticoagulant activities of these polysaccharides were examined and compared. The chemical composition analysis and nuclear magnetic resonance (NMR) analysis indicate that two types of polysaccharides, sulfated fucan and fucosylated chondroitin sulfate (FuCS), were found in all of the three species and in addition a neutral glycan was observed in H. edulis. The neutral α-glucan was firstly obtained from sea cucumber. The same type of polysaccharides from different species of sea cucumbers have similar physicochemical properties and anticoagulant activities, but those of different types of glycans are significantly different, possibly due to their different monosaccharide compositions, electric charges and average molecular weights. The FuCSs have stronger anticoagulant activities than the sulfated fucans, although the molecular sizes of the FuCSs are lower than those of the sulfated fucans, whereas the neutral glucan has no activity, as expected from the absence of sulfate. Thus, anticoagulant activities of the different type of polysaccharides are likely to relate to monosaccharide composition and sulfate content. Preliminary analysis suggests that the sulfation patterns of the FuCSs may result in the difference in anticoagulant activities. Our data could help elucidate the structure-activity relationship of the sea cucumber polysaccharides. Full article

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Open AccessArticle

Kocurin, the True Structure of PM181104, an Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Thiazolyl Peptide from the Marine-Derived Bacterium Kocuria palustris

by Jesús Martín, Thiciana Da S. Sousa, Gloria Crespo, Sara Palomo, Ignacio González, José R. Tormo, Mercedes De la Cruz, Matthew Anderson, Russell T. Hill, Francisca Vicente, Olga Genilloud and Fernando Reyes

Mar. Drugs 2013, 11(2), 387-398; https://doi.org/10.3390/md11020387 - 04 Feb 2013

Cited by 71 | Viewed by 11100

Abstract

A new thiazolyl peptide, kocurin (1), was isolated from culture broths of a marine-derived Kocuria palustris. Its structural elucidation was accomplished using a combination of spectroscopic and chemical methods, including HRMS, extensive 1D and 2D NMR analysis, MS/MS fragmentation, and [...] Read more.

A new thiazolyl peptide, kocurin (1), was isolated from culture broths of a marine-derived Kocuria palustris. Its structural elucidation was accomplished using a combination of spectroscopic and chemical methods, including HRMS, extensive 1D and 2D NMR analysis, MS/MS fragmentation, and chemical degradation and Marfey’s analysis of the resulting amino acid residues. The structure herein reported corrects that previously assigned to PM181104 (3). Kocurin displayed activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC values in the submicromolar range. Full article

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Open AccessArticle

Identification of Three Genes Encoding for the Late Acyltransferases of Lipid A in Cronobacter sakazakii

by Liping Cai, Yanyan Li, Guanjun Tao, Wen Guo, Chan Zhang and Xiaoyuan Wang

Mar. Drugs 2013, 11(2), 377-386; https://doi.org/10.3390/md11020377 - 31 Jan 2013

Cited by 14 | Viewed by 6731

Abstract

Lipid A, the hydrophobic anchor of lipopolysaccharide, is an essential component in the outer membrane of most Gram-negative bacteria. Food-borne pathogen Cronobacter sakazakii synthesizes two lipid A species, differing by the length of the secondary acyl chain. In this work, we identified three [...] Read more.

Lipid A, the hydrophobic anchor of lipopolysaccharide, is an essential component in the outer membrane of most Gram-negative bacteria. Food-borne pathogen Cronobacter sakazakii synthesizes two lipid A species, differing by the length of the secondary acyl chain. In this work, we identified three genes ESA02293, ESA02951 and ESA01386 encoding for the late acyltransferases of lipid A biosynthesis pathway in C. sakazakii. Based on the sequence alignment, proteins YP_001438378.1 encoded by ESA02293, YP_001439016.1 encoded by ESA02951, and YP_001437482.1 encoded by ESA01386 are homologous to E. coli LpxL, LpxP and LpxM, respectively. Functions of the three acyltransferases were confirmed by overexpressing the genes in E. coli, isolating lipid As and analyzing their structures using an ESI/MS. C. sakazakii LpxL and LpxM transfer a C14:0 secondary acyl chain to the 2′- and 3′-position of lipid A, respectively. C. sakazakii LpxP can transfer either a C16:1 or a C14:0 secondary acyl chains to the 2′-position of lipid A. Full article

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Open AccessArticle

Construction of Monophosphoryl Lipid A Producing Escherichia coli Mutants and Comparison of Immuno-Stimulatory Activities of Their Lipopolysaccharides

by Yaning Han, Ye Li, Jiuzhou Chen, Yanzhen Tan, Feng Guan and Xiaoyuan Wang

Mar. Drugs 2013, 11(2), 363-376; https://doi.org/10.3390/md11020363 - 31 Jan 2013

Cited by 39 | Viewed by 10037

Abstract

The lipid A moiety of Escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine phosphorylated at the 1- and 4′-positions. It can be recognized by the TLR4/MD-2 complex of mammalian immune cells, leading to release of proinflammatory cytokines. The toxicity of lipid A [...] Read more.

The lipid A moiety of Escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine phosphorylated at the 1- and 4′-positions. It can be recognized by the TLR4/MD-2 complex of mammalian immune cells, leading to release of proinflammatory cytokines. The toxicity of lipid A depends on its structure. In this study, two E. coli mutants, HW001 and HW002, were constructed by deleting or integrating key genes related to lipid A biosynthesis in the chromosome of E. coli W3110. HW001 was constructed by deleting lacI and replacing lacZ with the Francisella novicida lpxE gene in the chromosome and only synthesizes monophosphoryl lipid A. HW002 was constructed by deleting lpxM in HW001 and synthesizes only the pentaacylated monophosphoryl lipid A. The structures of lipid A made in HW001 and HW002 were confirmed by thin layer chromatography and electrospray ionization mass spectrometry. HW001 and HW002 grew as well as the wild-type W3110. LPS purified from HW001 or HW002 was used to stimulate murine macrophage RAW264.7 cells, and less TNF-α were released. This study provides a feasible way to produce interesting lipid A species in E. coli. Full article

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Open AccessArticle

HPN, a Synthetic Analogue of Bromophenol from Red Alga Rhodomela confervoides: Synthesis and Anti-Diabetic Effects in C57BL/KsJ-db/db Mice

by Dayong Shi, Shuju Guo, Bo Jiang, Chao Guo, Tao Wang, Luyong Zhang and Jingya Li

Mar. Drugs 2013, 11(2), 350-362; https://doi.org/10.3390/md11020350 - 30 Jan 2013

Cited by 43 | Viewed by 9275

Abstract

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC₅₀ = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against [...] Read more.

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC₅₀ = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC₅₀ 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague–Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes. Full article

(This article belongs to the Special Issue Marine Algae)

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Open AccessArticle

Iodinin (1,6-Dihydroxyphenazine 5,10-Dioxide) from Streptosporangium sp. Induces Apoptosis Selectively in Myeloid Leukemia Cell Lines and Patient Cells

by Lene E. Myhren, Gyrid Nygaard, Gro Gausdal, Håvard Sletta, Knut Teigen, Kristin F. Degnes, Kolbjørn Zahlsen, Anders Brunsvik, Øystein Bruserud, Stein Ove Døskeland, Frode Selheim and Lars Herfindal

Mar. Drugs 2013, 11(2), 332-349; https://doi.org/10.3390/md11020332 - 30 Jan 2013

Cited by 25 | Viewed by 8864

Abstract

Despite recent improvement in therapy, acute myeloid leukemia (AML) is still associated with high lethality. In the presented study, we analyzed the bioactive compound iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from a marine actinomycetes bacterium for the ability to induce cell death in a range of [...] Read more.

Despite recent improvement in therapy, acute myeloid leukemia (AML) is still associated with high lethality. In the presented study, we analyzed the bioactive compound iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from a marine actinomycetes bacterium for the ability to induce cell death in a range of cell types. Iodinin showed selective toxicity to AML and acute promyelocytic (APL) leukemia cells, with EC50 values for cell death up to 40 times lower for leukemia cells when compared with normal cells. Iodinin also successfully induced cell death in patient-derived leukemia cells or cell lines with features associated with poor prognostic such as FLT3 internal tandem duplications or mutated/deficient p53. The cell death had typical apoptotic morphology, and activation of apoptotic signaling proteins like caspase-3. Molecular modeling suggested that iodinin could intercalate between bases in the DNA in a way similar to the anti-cancer drug daunorubicin (DNR), causing DNA-strand breaks. Iodinin induced apoptosis in several therapy-resistant AML-patient blasts, but to a low degree in peripheral blood leukocytes, and in contrast to DNR, not in rat cardiomyoblasts. The low activity towards normal cell types that are usually affected by anti-leukemia therapy suggests that iodinin and related compounds represent promising structures in the development of anti-cancer therapy. Full article

(This article belongs to the Special Issue Marine Antibiotics)

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Open AccessArticle

Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway

by Cuiting Lv, Wenxia Sun, Haofen Sun, Shanjian Wei, Ruohua Chen, Bingui Wang and Caiguo Huang

Mar. Drugs 2013, 11(2), 316-331; https://doi.org/10.3390/md11020316 - 29 Jan 2013

Cited by 27 | Viewed by 11016

Abstract

Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A [...] Read more.

Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC₅₀) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies. Full article

(This article belongs to the Special Issue Marine Algae)

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Open AccessArticle

In Vitro Acylation of Okadaic Acid in the Presence of Various Bivalves’ Extracts

by Keiichi Konoki, Tatsuya Onoda, Ryuichi Watanabe, Yuko Cho, Shinnosuke Kaga, Toshiyuki Suzuki and Mari Yotsu-Yamashita

Mar. Drugs 2013, 11(2), 300-315; https://doi.org/10.3390/md11020300 - 29 Jan 2013

Cited by 32 | Viewed by 6820

Abstract

The dinoflagellate Dinophysis spp. is responsible for diarrhetic shellfish poisoning (DSP). In the bivalves exposed to the toxic bloom of the dinoflagellate, dinophysistoxin 3 (DTX3), the 7-OH acylated form of either okadaic acid (OA) or DTX1, is produced. We demonstrated in vitro acylation [...] Read more.

The dinoflagellate Dinophysis spp. is responsible for diarrhetic shellfish poisoning (DSP). In the bivalves exposed to the toxic bloom of the dinoflagellate, dinophysistoxin 3 (DTX3), the 7-OH acylated form of either okadaic acid (OA) or DTX1, is produced. We demonstrated in vitro acylation of OA with palmitoyl CoA in the presence of protein extract from the digestive gland, but not other tissues of the bivalve Mizuhopecten yessoensis. The yield of 7-O-palmitoyl OA reached its maximum within 2 h, was the highest at 37 °C followed by 28 °C, 16 °C and 4 °C and was the highest at pH 8 in comparison with the yields at pH 6 and pH 4. The transformation also proceeded when the protein extract was prepared from the bivalves Corbicula japonica and Crassostrea gigas. The OA binding protein OABP2 identified in the sponge Halichondria okadai was not detected in the bivalve M. yessoensis, the bivalve Mytilus galloprovincialis and the ascidian Halocynthia roretzi, though they are known to accumulate diarrhetic shellfish poisoning toxins. Since DTX3 does not bind to protein phosphatases 1 and 2A, the physiological target for OA and DTXs in mammalian cells, the acylation of DSP toxins would be related to a detoxification mechanism for the bivalve species. Full article

(This article belongs to the Special Issue Okadaic Acid and Dinophysis Toxins)

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Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues

by Hugo K. H. Fong and Brent R. Copp

Mar. Drugs 2013, 11(2), 274-299; https://doi.org/10.3390/md11020274 - 28 Jan 2013

Cited by 16 | Viewed by 6680

Abstract

A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2-mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines. Overall it was found [...] Read more.

A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2-mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines. Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (K_app 5.33 × 10⁶ and 3.64 × 10⁶ M⁻¹, respectively). In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro. Sub-panel selectivity towards non-small cell lung, melanoma and renal cancer cell lines were observed for a number of the analogues. Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI₅₀ 0.4 μM and 0.32 μM, respectively) with clogP ~4.0–4.5. Full article

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Mar. Drugs, Volume 11, Issue 2 (February 2013) – 20 articles , Pages 274-580

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