Marine Drugs

12 pages, 2155 KiB

Open AccessArticle

Identification and Characterization of Mycemycin Biosynthetic Gene Clusters in Streptomyces olivaceus FXJ8.012 and Streptomyces sp. FXJ1.235

by Fangying Song, Ning Liu, Minghao Liu, Yihua Chen and Ying Huang

Mar. Drugs 2018, 16(3), 98; https://doi.org/10.3390/md16030098 - 20 Mar 2018

Cited by 6 | Viewed by 5834

Abstract

Mycemycins A–E are new members of the dibenzoxazepinone (DBP) family, derived from the gntR gene-disrupted deep sea strain Streptomyces olivaceus FXJ8.012Δ1741 and the soil strain Streptomyces sp. FXJ1.235. In this paper, we report the identification of the gene clusters and pathways’ inference for [...] Read more.

Mycemycins A–E are new members of the dibenzoxazepinone (DBP) family, derived from the gntR gene-disrupted deep sea strain Streptomyces olivaceus FXJ8.012Δ1741 and the soil strain Streptomyces sp. FXJ1.235. In this paper, we report the identification of the gene clusters and pathways’ inference for mycemycin biosynthesis in the two strains. Bioinformatics analyses of the genome sequences of S. olivaceus FXJ8.012Δ1741 and S. sp. FXJ1.235 predicted two divergent mycemycin gene clusters, mym and mye, respectively. Heterologous expression of the key enzyme genes of mym and genetic manipulation of mye as well as a feeding study in S. sp. FXJ1.235 confirmed the gene clusters and led to the proposed biosynthetic pathways for mycemycins. To the best of our knowledge, this is the first report on DBP biosynthetic gene clusters and pathways. Full article

(This article belongs to the Special Issue Microbial Gene Clusters of Marine Origin)

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14 pages, 4731 KiB

Open AccessArticle

Function-Oriented Synthesis of Marine Phidianidine Derivatives as Potential PTP1B Inhibitors with Specific Selectivity

by Jin Liu, Yu Chen, Jing-Ya Li, Cheng Luo, Jia Li, Kai-Xian Chen, Xu-Wen Li and Yue-Wei Guo

Mar. Drugs 2018, 16(3), 97; https://doi.org/10.3390/md16030097 - 20 Mar 2018

Cited by 22 | Viewed by 5610

Abstract

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a [...] Read more.

Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure–activity relationship (SAR) and molecular docking analyses are also described. Full article

(This article belongs to the Special Issue From Bioactive Compounds to New Drugs: Commemorative Issue Dedicated to Professor Ernesto Fattorusso (1937-2012))

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15 pages, 2379 KiB

Open AccessArticle

GABA and GABA-Alanine from the Red Microalgae Rhodosorus marinus Exhibit a Significant Neuro-Soothing Activity through Inhibition of Neuro-Inflammation Mediators and Positive Regulation of TRPV1-Related Skin Sensitization

by Amandine Scandolera, Jane Hubert, Anne Humeau, Carole Lambert, Audrey De Bizemont, Chris Winkel, Abdelmajid Kaouas, Jean-Hugues Renault, Jean-Marc Nuzillard and Romain Reynaud

Mar. Drugs 2018, 16(3), 96; https://doi.org/10.3390/md16030096 - 17 Mar 2018

Cited by 18 | Viewed by 8425

Abstract

The aim of the present study was to investigate the neuro-soothing activity of a water-soluble hydrolysate obtained from the red microalgae Rhodosorus marinus Geitler (Stylonemataceae). Transcriptomic analysis performed on ≈100 genes related to skin biological functions firstly revealed that the crude Rhodosorus marinus [...] Read more.

The aim of the present study was to investigate the neuro-soothing activity of a water-soluble hydrolysate obtained from the red microalgae Rhodosorus marinus Geitler (Stylonemataceae). Transcriptomic analysis performed on ≈100 genes related to skin biological functions firstly revealed that the crude Rhodosorus marinus extract was able to significantly negatively modulate specific genes involved in pro-inflammation (interleukin 1α encoding gene, IL1A) and pain detection related to tissue inflammation (nerve growth factor NGF and its receptor NGFR). An in vitro model of normal human keratinocytes was then used to evaluate the ability of the Rhodosorus marinus extract to control the release of neuro-inflammation mediators under phorbol myristate acetate (PMA)-induced inflammatory conditions. The extract incorporated at 1% and 3% significantly inhibited the release of IL-1α and NGF secretion. These results were confirmed in a co-culture system of reconstructed human epithelium and normal human epidermal keratinocytes on which a cream formulated with the Rhodosorus marinus extract at 1% and 3% was topically applied after systemic induction of neuro-inflammation. Finally, an in vitro model of normal human astrocytes was developed for the evaluation of transient receptor potential vanilloid 1 (TRPV1) receptor modulation, mimicking pain sensing related to neuro-inflammation as observed in sensitive skins. Treatment with the Rhodosorus marinus extract at 1% and 3% significantly decreased PMA-mediated TRPV1 over-expression. In parallel with these biological experiments, the crude Rhodosorus marinus extract was fractionated by centrifugal partition chromatography (CPC) and chemically profiled by a recently developed ¹³C NMR-based dereplication method. The CPC-generated fractions as well as pure metabolites were tested again in vitro in an attempt to identify the biologically active constituents involved in the neuro-soothing activity of the Rhodosorus marinus extract. Two active molecules, namely, γ-aminobutyric acid (GABA) and its structural derivative GABA-alanine, demonstrated a strong capacity to positively regulate skin sensitization mechanisms related to the TRPV1 receptors under PMA-induced inflammatory conditions, therefore providing interesting perspectives for the treatment of sensitive skins, atopia, dermatitis, or psoriasis. Full article

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13 pages, 2540 KiB

Open AccessFeature PaperArticle

Phocoenamicins B and C, New Antibacterial Spirotetronates Isolated from a Marine Micromonospora sp.

by Mercedes Pérez-Bonilla, Daniel Oves-Costales, Mercedes De la Cruz, Maria Kokkini, Jesús Martín, Francisca Vicente, Olga Genilloud and Fernando Reyes

Mar. Drugs 2018, 16(3), 95; https://doi.org/10.3390/md16030095 - 16 Mar 2018

Cited by 31 | Viewed by 6353

Abstract

Phocoenamicins B and C (1 and 2), together with the known spirotetronate phocoenamicin (3), were isolated from cultures of Micromonospora sp. The acetone extract from a culture of this strain, isolated from marine sediments collected in the Canary Islands, [...] Read more.

Phocoenamicins B and C (1 and 2), together with the known spirotetronate phocoenamicin (3), were isolated from cultures of Micromonospora sp. The acetone extract from a culture of this strain, isolated from marine sediments collected in the Canary Islands, displayed activity against methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis H37Ra and Mycobacterium bovis. Bioassay-guided fractionation of this extract using SP207ss column chromatography and preparative reversed-phased HPLC led to the isolation of the new compounds 1 and 2 belonging to the spirotetronate class of polyketides. Their structures were determined using a combination of HRMS, 1D and 2D NMR experiments and comparison with the spectra reported for phocoenamicin. Antibacterial activity tests of the pure compounds against these pathogens revealed minimal inhibitory concentration (MIC) values ranging from 4 to 64 µg/mL for MRSA, and 16 to 32 µg/mL for M. tuberculosis H37Ra, with no significant activity found against M. bovis and vancomycin-resistant Enterococcus faecium (VRE) at concentrations below 128 µg/mL, and weak activity detected against Bacillus subtilis grown on agar plates. Full article

(This article belongs to the Special Issue Isolation and Structure Elucidation of Marine Secondary Metabolites)

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12 pages, 1196 KiB

Open AccessArticle

Anti-BACE1 and Antimicrobial Activities of Steroidal Compounds Isolated from Marine Urechis unicinctus

by Yong-Zhe Zhu, Jing-Wen Liu, Xue Wang, In-Hong Jeong, Young-Joon Ahn and Chuan-Jie Zhang

Mar. Drugs 2018, 16(3), 94; https://doi.org/10.3390/md16030094 - 14 Mar 2018

Cited by 31 | Viewed by 6225

Abstract

The human β-site amyloid cleaving enzyme (BACE1) has been considered as an effective drug target for treatment of Alzheimer’s disease (AD). In this study, Urechis unicinctus (U. unicinctus), which is a Far East specialty food known as innkeeper worm, ethanol extract was [...] Read more.

The human β-site amyloid cleaving enzyme (BACE1) has been considered as an effective drug target for treatment of Alzheimer’s disease (AD). In this study, Urechis unicinctus (U. unicinctus), which is a Far East specialty food known as innkeeper worm, ethanol extract was studied by bioassay-directed fractionation and isolation to examine its potential β-site amyloid cleaving enzyme inhibitory and antimicrobial activity. The following compounds were characterized: hecogenin, cholest-4-en-3-one, cholesta-4,6-dien-3-ol, and hurgadacin. These compounds were identified by their mass spectrometry, ¹H, and ¹³C NMR spectral data, comparing those data with NIST/EPA/NIH Mass spectral database (NIST11) and published values. Hecogenin and cholest-4-en-3-one showed significant inhibitory activity against BACE1 with EC₅₀ values of 116.3 and 390.6 µM, respectively. Cholesta-4,6-dien-3-ol and hurgadacin showed broad spectrum antimicrobial activity, particularly strongly against Escherichia coli (E. coli), Salmonella enterica (S. enterica), Pasteurella multocida (P. multocida), and Physalospora piricola (P. piricola), with minimal inhibitory concentration (MIC) ranging from 0.46 to 0.94 mg/mL. This is the first report regarding those four known compounds that were isolated from U. unicinctus and their anti-BACE1 and antimicrobial activity, highlighting the fact that known natural compounds may be a critical source of new medicine leads. These findings provide scientific evidence for potential application of those bioactive compounds for the development of AD drugs and antimicrobial agents. Full article

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10 pages, 2045 KiB

Open AccessArticle

Anti-Inflammatory Polyoxygenated Steroids from the Soft Coral Lobophytum michaelae

by Chiung-Yao Huang, Wan-Ru Tseng, Atallah F. Ahmed, Pei-Lun Chiang, Chi-Jen Tai, Tsong-Long Hwang, Chang-Feng Dai and Jyh-Horng Sheu

Mar. Drugs 2018, 16(3), 93; https://doi.org/10.3390/md16030093 - 13 Mar 2018

Cited by 25 | Viewed by 5217

Abstract

Three new polyoxygenated steroids, michosterols A–C (1–3), and four known compounds (4–7) were isolated from the ethyl acetate (EtOAc) extract of the soft coral Lobophytum michaelae, collected off the coast of Taitung. The structures [...] Read more.

Three new polyoxygenated steroids, michosterols A–C (1–3), and four known compounds (4–7) were isolated from the ethyl acetate (EtOAc) extract of the soft coral Lobophytum michaelae, collected off the coast of Taitung. The structures of the new compounds were elucidated on the basis of spectroscopic analyses and comparison of the nuclear magnetic resonance (NMR) data with related steroids. The cytotoxicity of compounds 1–3 against the proliferation of a limited panel of cancer cell lines was assayed. Compound 1 was found to display moderate cytotoxicity against adenocarcinomic human alveolar basal epithelial (A549) cancer cells. It also exhibited potent anti-inflammatory activity by suppressing superoxide anion generation and elastase release in N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-stimulated human neutrophils. Furthermore, 3 could effectively inhibit elastase release, as well. Full article

(This article belongs to the Special Issue Natural Products from Coral Reef Organisms)

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10 pages, 679 KiB

Open AccessArticle

Cytotoxic Polyhydroxysteroidal Glycosides from Starfish Culcita novaeguineae

by Yunyang Lu, Hu Li, Minchang Wang, Yang Liu, Yingda Feng, Ke Liu and Haifeng Tang

Mar. Drugs 2018, 16(3), 92; https://doi.org/10.3390/md16030092 - 13 Mar 2018

Cited by 12 | Viewed by 4726

Abstract

Four new polyhydroxysteroidal glycosides—culcinosides A–D (1, 2, 4, and 7)—along with three known compounds—echinasteroside C (3), linckoside F (5), and linckoside L3 (6)—were isolated from the ethanol extract of starfish Culcita novaeguineae [...] Read more.

Four new polyhydroxysteroidal glycosides—culcinosides A–D (1, 2, 4, and 7)—along with three known compounds—echinasteroside C (3), linckoside F (5), and linckoside L3 (6)—were isolated from the ethanol extract of starfish Culcita novaeguineae collected from the Xisha Islands of the South China Sea. The structures of new compounds were elucidated through extensive spectroscopic studies and chemical evidence, especially two-dimensional (2D) NMR techniques. The cytotoxicity of the new compounds against human glioblastoma cell lines U87, U251, and SHG44 were evaluated. Full article

(This article belongs to the Special Issue Marine Glycosides)

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16 pages, 12125 KiB

Open AccessArticle

Biphasic Scaffolds from Marine Collagens for Regeneration of Osteochondral Defects

by Anne Bernhardt, Birgit Paul and Michael Gelinsky

Mar. Drugs 2018, 16(3), 91; https://doi.org/10.3390/md16030091 - 13 Mar 2018

Cited by 39 | Viewed by 5948

Abstract

Background: Collagens of marine origin are applied increasingly as alternatives to mammalian collagens in tissue engineering. The aim of the present study was to develop a biphasic scaffold from exclusively marine collagens supporting both osteogenic and chondrogenic differentiation and to find a suitable [...] Read more.

Background: Collagens of marine origin are applied increasingly as alternatives to mammalian collagens in tissue engineering. The aim of the present study was to develop a biphasic scaffold from exclusively marine collagens supporting both osteogenic and chondrogenic differentiation and to find a suitable setup for in vitro chondrogenic and osteogenic differentiation of human mesenchymal stroma cells (hMSC). Methods: Biphasic scaffolds from biomimetically mineralized salmon collagen and fibrillized jellyfish collagen were fabricated by joint freeze-drying and crosslinking. Different experiments were performed to analyze the influence of cell density and TGF-β on osteogenic differentiation of the cells in the scaffolds. Gene expression analysis and analysis of cartilage extracellular matrix components were performed and activity of alkaline phosphatase was determined. Furthermore, histological sections of differentiated cells in the biphasic scaffolds were analyzed. Results: Stable biphasic scaffolds from two different marine collagens were prepared. An in vitro setup for osteochondral differentiation was developed involving (1) different seeding densities in the phases; (2) additional application of alginate hydrogel in the chondral part; (3) pre-differentiation and sequential seeding of the scaffolds and (4) osteochondral medium. Spatially separated osteogenic and chondrogenic differentiation of hMSC was achieved in this setup, while osteochondral medium in combination with the biphasic scaffolds alone was not sufficient to reach this ambition. Conclusions: Biphasic, but monolithic scaffolds from exclusively marine collagens are suitable for the development of osteochondral constructs. Full article

(This article belongs to the Special Issue Collagen from Marine Biological Source and Medical Applications)

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9 pages, 1112 KiB

Open AccessCommunication

New Naphthoquinone Terpenoids from Marine Actinobacterium, Streptomyces sp. CNQ-509

by Jin-Soo Park and Hak Cheol Kwon

Mar. Drugs 2018, 16(3), 90; https://doi.org/10.3390/md16030090 - 12 Mar 2018

Cited by 19 | Viewed by 5849

Abstract

A member of the marine streptomycete clade MAR4, Streptomyces sp. CNQ-509, has genetic potential for the biosynthesis of hybrid isoprenoids and produces several meroterpenoids such as naphterpin, nitropyrrolin and marinophenazine. Our research on the strain CNQ-509 led to the isolation of two new [...] Read more.

A member of the marine streptomycete clade MAR4, Streptomyces sp. CNQ-509, has genetic potential for the biosynthesis of hybrid isoprenoids and produces several meroterpenoids such as naphterpin, nitropyrrolin and marinophenazine. Our research on the strain CNQ-509 led to the isolation of two new naphterpin derivatives (1 and 2) comprised of naphthoquinone and geranyl moieties along with the known terpenoid, debromomarinone. The two-dimensional structure of these compounds was determined through spectral data analysis using data from NMR, MS and UV spectroscopy. Furthermore, the full structures of 1 and 2 including absolute configurations were unequivocally established by a combination of NMR experiments and chemical modifications. Full article

(This article belongs to the Special Issue Natural Products from Marine Actinomycetes)

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14 pages, 1557 KiB

Open AccessArticle

Synthesis and Biological Evaluation of a New Structural Simplified Analogue of cADPR, a Calcium-Mobilizing Secondary Messenger Firstly Isolated from Sea Urchin Eggs

by Stefano D’Errico, Nicola Borbone, Bruno Catalanotti, Agnese Secondo, Tiziana Petrozziello, Ilaria Piccialli, Anna Pannaccione, Valeria Costantino, Luciano Mayol, Gennaro Piccialli and Giorgia Oliviero

Mar. Drugs 2018, 16(3), 89; https://doi.org/10.3390/md16030089 - 10 Mar 2018

Cited by 12 | Viewed by 4797

Abstract

Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca²⁺-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the “northern” ribose of cADPR was [...] Read more.

Herein, we reported on the synthesis of cpIPP, which is a new structurally-reduced analogue of cyclic ADP-ribose (cADPR), a potent Ca²⁺-releasing secondary messenger that was firstly isolated from sea urchin eggs extracts. To obtain cpIPP the “northern” ribose of cADPR was replaced by a pentyl chain and the pyrophosphate moiety by a phophono-phosphate anhydride. The effect of the presence of the new phosphono-phosphate bridge on the intracellular Ca²⁺ release induced by cpIPP was assessed in PC12 neuronal cells in comparison with the effect of the pyrophosphate bridge of the structurally related cyclic N1-butylinosine diphosphate analogue (cbIDP), which was previously synthesized in our laboratories, and with that of the linear precursor of cpIPP, which, unexpectedly, revealed to be the only one provided with Ca²⁺ release properties. Full article

(This article belongs to the Special Issue Marine Secondary Metabolite II, 2017)

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23 pages, 8588 KiB

Open AccessReview

Marine Spongin: Naturally Prefabricated 3D Scaffold-Based Biomaterial

by Teofil Jesionowski, Małgorzata Norman, Sonia Żółtowska-Aksamitowska, Iaroslav Petrenko, Yvonne Joseph and Hermann Ehrlich

Mar. Drugs 2018, 16(3), 88; https://doi.org/10.3390/md16030088 - 9 Mar 2018

Cited by 74 | Viewed by 12464

Abstract

The biosynthesis, chemistry, structural features and functionality of spongin as a halogenated scleroprotein of keratosan demosponges are still paradigms. This review has the principal goal of providing thorough and comprehensive coverage of spongin as a naturally prefabricated 3D biomaterial with multifaceted applications. The [...] Read more.

The biosynthesis, chemistry, structural features and functionality of spongin as a halogenated scleroprotein of keratosan demosponges are still paradigms. This review has the principal goal of providing thorough and comprehensive coverage of spongin as a naturally prefabricated 3D biomaterial with multifaceted applications. The history of spongin’s discovery and use in the form of commercial sponges, including their marine farming strategies, have been analyzed and are discussed here. Physicochemical and material properties of spongin-based scaffolds are also presented. The review also focuses on prospects and trends in applications of spongin for technology, materials science and biomedicine. Special attention is paid to applications in tissue engineering, adsorption of dyes and extreme biomimetics. Full article

(This article belongs to the Special Issue Marine Biomimetics)

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14 pages, 1717 KiB

Open AccessArticle

Fluostatins M–Q Featuring a 6-5-6-6 Ring Skeleton and High Oxidized A-Rings from Marine Streptomyces sp. PKU-MA00045

by Jing Jin, Xiaoyan Yang, Tan Liu, Hua Xiao, Guiyang Wang, Mengjie Zhou, Fawang Liu, Yingtao Zhang, Dong Liu, Minghua Chen, Wei Cheng, Donghui Yang and Ming Ma

Mar. Drugs 2018, 16(3), 87; https://doi.org/10.3390/md16030087 - 9 Mar 2018

Cited by 33 | Viewed by 6759

Abstract

Aromatic polyketides from marine actinomycetes have received increasing attention due to their unusual structures and potent bioactivities. Compared to their terrestrial counterparts, marine aromatic polyketides have been less discovered and their structural and biological diversities are far from being fully investigated. In this [...] Read more.

Aromatic polyketides from marine actinomycetes have received increasing attention due to their unusual structures and potent bioactivities. Compared to their terrestrial counterparts, marine aromatic polyketides have been less discovered and their structural and biological diversities are far from being fully investigated. In this study, we employed a PCR-based genome mining method to discover aromatic polyketides in our marine bacteria collection. Five new atypical angucyclinones, fluostatins M–Q (1–5) featuring a unique 6-5-6-6 ring skeleton, were discovered from one “positive” Streptomyces sp. PKU-MA00045. The structures of fluostatins M–Q (1–5) were elucidated based on comprehensive spectroscopic analyses and the crystallographic structure of fluostatin P (4), which contains the most oxidized A-ring, was solved by X-ray diffraction analysis with Cu Kα radiation. Compared to the published 16 fluostatin analogues, fluostatins M–Q (1–5) contained a different methoxy group attached at C-7 and hydroxy group attached at C-4, enriching the structural diversity of aromatic polyketides from marine actinomycetes. Genome sequencing of Streptomyces sp. PKU-MA00045 revealed the biosynthetic gene cluster of fluostatins M–Q (1–5), which contained different genes and gene organizations compared to known fluostatin gene clusters, facilitating the investigation of the biosynthesis of the unique 6-5-6-6 ring skeleton in all fluostatins. Full article

(This article belongs to the Special Issue Natural Products from Marine Actinomycetes)

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13 pages, 1968 KiB

Open AccessArticle

Purification and Characterization of a Novel Alginate Lyase from the Marine Bacterium Bacillus sp. Alg07

by Peng Chen, Yueming Zhu, Yan Men, Yan Zeng and Yuanxia Sun

Mar. Drugs 2018, 16(3), 86; https://doi.org/10.3390/md16030086 - 9 Mar 2018

Cited by 58 | Viewed by 8475

Abstract

Alginate oligosaccharides with different bioactivities can be prepared through the specific degradation of alginate by alginate lyases. Therefore, alginate lyases that can be used to degrade alginate under mild conditions have recently attracted public attention. Although various types of alginate lyases have been [...] Read more.

Alginate oligosaccharides with different bioactivities can be prepared through the specific degradation of alginate by alginate lyases. Therefore, alginate lyases that can be used to degrade alginate under mild conditions have recently attracted public attention. Although various types of alginate lyases have been discovered and characterized, few can be used in industrial production. In this study, AlgA, a novel alginate lyase with high specific activity, was purified from the marine bacterium Bacillus sp. Alg07. AlgA had a molecular weight of approximately 60 kDa, an optimal temperature of 40 °C, and an optimal pH of 7.5. The activity of AlgA was dependent on sodium chloride and could be considerably enhanced by Mg²⁺ or Ca²⁺. Under optimal conditions, the activity of AlgA reached up to 8306.7 U/mg, which is the highest activity recorded for alginate lyases. Moreover, the enzyme was stable over a broad pH range (5.0–10.0), and its activity negligibly changed after 24 h of incubation at 40 °C. AlgA exhibited high activity and affinity toward poly-β-d-mannuronate (polyM). These characteristics suggested that AlgA is an endolytic polyM-specific alginate lyase (EC 4.2.2.3). The products of alginate and polyM degradation by AlgA were purified and identified through fast protein liquid chromatography and electrospray ionization mass spectrometry, which revealed that AlgA mainly produced disaccharides, trisaccharides, and tetrasaccharide from alginate and disaccharides and trisaccharides from polyM. Therefore, the novel lysate AlgA has potential applications in the production of mannuronic oligosaccharides and poly-α-l-guluronate blocks from alginate. Full article

(This article belongs to the Special Issue Marine Enzymes: Sources, Biochemistry and Bioprocesses for Marine Biotechnology)

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18 pages, 10029 KiB

Open AccessArticle

Marine Bacterial Polysaccharide EPS11 Inhibits Cancer Cell Growth via Blocking Cell Adhesion and Stimulating Anoikis

by Ruobing Cao, Weihua Jin, Yeqi Shan, Ju Wang, Ge Liu, Shan Kuang and Chaomin Sun

Mar. Drugs 2018, 16(3), 85; https://doi.org/10.3390/md16030085 - 8 Mar 2018

Cited by 21 | Viewed by 5555

Abstract

Tumor cells that acquire metastatic potential have developed resistance to anoikis, a cell death process, after detachment from their primary site to the second organ. In this study, we investigated the molecular mechanisms of a novel marine bacterial polysaccharide EPS11 which exerts its [...] Read more.

Tumor cells that acquire metastatic potential have developed resistance to anoikis, a cell death process, after detachment from their primary site to the second organ. In this study, we investigated the molecular mechanisms of a novel marine bacterial polysaccharide EPS11 which exerts its cytotoxic effects through affecting cancer cell adhesion and anoikis. Firstly, we found that EPS11 could significantly affect cell proliferation and block cell adhesion in A549 cells. We further demonstrated that the expression of several cell adhesion associated proteins is downregulated and the filiform structures of cancer cells are destroyed after EPS11 treatment. Interestingly, the destruction of filiform structures in A549 cells by EPS11 is in a dose-dependent manner, and the inhibitory tendency is very consistent with that observed in the cell adhesion assay, which confirms that filiform structures play important roles in modulating cell adhesion. Moreover, we showed that EPS11 induces apoptosis of A549 cells through stimulating βIII-tubulin associated anoikis: (i) EPS11 inhibits the expression of βIII-tubulin in both transcription and translation levels; and (ii) EPS11 treatment dramatically decreases the phosphorylation of protein kinase B (PKB or AKT), a critical downstream effector of βIII-tubulin. Importantly, EPS11 evidently inhibits the growth of A549-derived tumor xenografts in vivo. Thus, our results suggest that EPS11 may be a potential candidate for human non-small cell lung carcinoma treatment via blocking filiform structure mediated adhesion and stimulating βIII-tubulin associated anoikis. Full article

(This article belongs to the Special Issue Connection of Marine Natural Products and Cell Apoptosis)

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13 pages, 1089 KiB

Open AccessArticle

New Crambescidin-Type Alkaloids from the Indonesian Marine Sponge Clathria bulbotoxa

by Kasmiati Kasmiati, Yukio Yoshioka, Tetsuji Okamoto and Makoto Ojika

Mar. Drugs 2018, 16(3), 84; https://doi.org/10.3390/md16030084 - 8 Mar 2018

Cited by 16 | Viewed by 5585

Abstract

A crude methanolic extract of the Indonesian sponge Clathria bulbotoxa showed a potent cytotoxic activity against the human epidermoid carcinoma A431 cells. An investigation of the active components led to the isolation of three new compounds named crambescidins 345 (1), 361 [...] Read more.

A crude methanolic extract of the Indonesian sponge Clathria bulbotoxa showed a potent cytotoxic activity against the human epidermoid carcinoma A431 cells. An investigation of the active components led to the isolation of three new compounds named crambescidins 345 (1), 361 (2), and 373 (3), together with the known related metabolites crambescidins 359 (4), 657 (5), and 800 (6). The structures of the compounds were determined by spectroscopic analysis. These compounds 1–4 that possess a simple pentacyclic guanidine core exhibited moderate cytotoxicity against the A431 cells with the IC₅₀ values of 7.0, 2.5, 0.94, and 3.1 μM, respectively, while the known compounds 5 and 6 that possess a long aliphatic side chain were found to be significantly cytotoxic. On the other hand, in an anti-oomycete activity test against the fungus-like plant pathogen Phytophthora capsici, 1–4 showed a higher activity than that of 5 and 6, suggesting that the long aliphatic side chain plays a significant role for cytotoxicity, but is not effective or suppressive for anti-oomycete activity. Full article

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12 pages, 963 KiB

Open AccessArticle

Conversion of Squid Pens to Chitosanases and Proteases via Paenibacillus sp. TKU042

by Chien Thang Doan, Thi Ngoc Tran, Van Bon Nguyen, Anh Dzung Nguyen and San-Lang Wang

Mar. Drugs 2018, 16(3), 83; https://doi.org/10.3390/md16030083 - 8 Mar 2018

Cited by 28 | Viewed by 5651

Abstract

Chitosanases and proteases have received much attention due to their wide range of applications. Four kinds of chitinous materials, squid pens, shrimp heads, demineralized shrimp shells and demineralized crab shells, were used as the sole carbon and nitrogen (C/N) source to produce chitosanases, [...] Read more.

Chitosanases and proteases have received much attention due to their wide range of applications. Four kinds of chitinous materials, squid pens, shrimp heads, demineralized shrimp shells and demineralized crab shells, were used as the sole carbon and nitrogen (C/N) source to produce chitosanases, proteases and α-glucosidase inhibitors (αGI) by four different strains of Paenibacillus. Chitosanase productivity was highest in the culture supernatants using squid pens as the sole C/N source. The maximum chitosanase activity of fermented squid pens (0.759 U/mL) was compared to that of fermented shrimp heads (0.397 U/mL), demineralized shrimp shells (0.201 U/mL) and demineralized crab shells (0.216 U/mL). A squid pen concentration of 0.5% was suitable for chitosanase, protease and αGI production via Paenibacillus sp. TKU042. Multi-purification, including ethanol precipitation and column chromatography of Macro-Prep High S as well as Macro-Prep DEAE (diethylaminoethyl), led to the isolation of Paenibacillus sp. TKU042 chitosanase and protease with molecular weights of 70 and 35 kDa, respectively. For comparison, 16 chitinolytic bacteria, including strains of Paenibacillus, were investigated for the production of chitinase, exochitinase, chitosanase, protease and αGI using two kinds of chitinous sources. Full article

(This article belongs to the Special Issue Bioconversion of Marine Resources)

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16 pages, 4920 KiB

Open AccessArticle

Oligo-Porphyran Ameliorates Neurobehavioral Deficits in Parkinsonian Mice by Regulating the PI3K/Akt/Bcl-2 Pathway

by Yingjuan Liu, Lihua Geng, Jingjing Zhang, Jing Wang, Qi Zhang, Delin Duan and Quanbin Zhang

Mar. Drugs 2018, 16(3), 82; https://doi.org/10.3390/md16030082 - 6 Mar 2018

Cited by 31 | Viewed by 6393

Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra, produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo-porphyran (OP) could be beneficial in an experimental model of PD in mice. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected (20 mg/kg body weight) for seven days to simulate PD, followed by OP administration. We found that the behavioral deficits in spontaneous motor activity, latency to descend in a pole test, and suspension in a traction test were ameliorated, and excessive dopamine (DA) metabolism was suppressed after OP treatment. Additionally, we found that OP protected dopaminergic neurons by preventing MPTP-induced decreases in dopaminergic transporter and tyrosine hydroxylase protein levels. We speculated whether OP regulates a signaling pathway that affects the behavioral changes seen in PD mice. In this study, the PI3K/Akt/Bcl-2 pathway was detected. Our results demonstrate that OP increased the phosphorylation of PI3K/Akt/GSK-3β and inhibited the activation of caspase-3 and poly (ADP-ribose) polymerase, with changes in the Bax/Bcl-2 ratio. These results showed that OP might promote DA neuron survival in vivo by regulating the PI3K/Akt/Bcl-2 pathway, thereby ameliorating the neurobehavioral deficits in a PD mouse model and suggesting OP as a neuroprotective treatment for PD. Full article

(This article belongs to the Special Issue Marine Compounds in Neurodegenerative Diseases)

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11 pages, 910 KiB

Open AccessArticle

Preliminary Results on the Evaluation of the Occurrence of Tetrodotoxin Associated to Marine Vibrio spp. in Bivalves from the Galician Rias (Northwest of Spain)

by Jose Manuel Leão, Antonio Lozano-Leon, Jorge Giráldez, Óscar Vilariño and Ana Gago-Martínez

Mar. Drugs 2018, 16(3), 81; https://doi.org/10.3390/md16030081 - 6 Mar 2018

Cited by 54 | Viewed by 5795

Abstract

Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to [...] Read more.

Tetrodotoxins (TTX) are a potent group of natural neurotoxins putatively produced by symbiotic microorganisms and affecting the aquatic environment. These neurotoxins have been recently found in some species of bivalves and gastropods along the European Coasts (Greece, UK, and The Netherlands) linked to the presence of high concentrations of Vibrio, in particular Vibrio parahaemolyticus. This study is focused on the evaluation of the presence of Vibrio species and TTX in bivalves (mussels, oysters, cockles, clams, scallops, and razor clams) from Galician Rias (northwest of Spain). The detection and isolation of the major Vibrio spp. and other enterobacterial populations have been carried out with the aim of screening for the presence of the pathways genes, poliketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) possibly involved in the biosynthesis of these toxins. Samples containing Vibrio spp. were analyzed by biochemical (API20E-galery) and genetic tests (PCR-RT). These samples were then screened for TTX toxicity by a neuroblastoma cell-based assay (N2a) and the presence of TTX was further confirmed by LC-MS/MS. TTX was detected in two infaunal samples. This is the first confirmation of the presence of TTX in bivalve molluscs from the Galician Rias. Full article

(This article belongs to the Special Issue Tetrodotoxin)

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13 pages, 2665 KiB

Open AccessArticle

Molecular Characterization of a Novel N-Acetylneuraminate Lyase from a Deep-Sea Symbiotic Mycoplasma

by Shao-lu Wang, Yun-liang Li, Zhuang Han, Xi Chen, Qi-jia Chen, Yong Wang and Li-sheng He

Mar. Drugs 2018, 16(3), 80; https://doi.org/10.3390/md16030080 - 5 Mar 2018

Cited by 9 | Viewed by 4953

Abstract

N-acetylneuraminic acid (Neu5Ac) based novel pharmaceutical agents and diagnostic reagents are highly required in medical fields. However, N-acetylneuraminate lyase（NAL）for Neu5Ac synthesis is not applicable for industry due to its low catalytic efficiency. In this study, we biochemically characterized a deep-sea NAL [...] Read more.

N-acetylneuraminic acid (Neu5Ac) based novel pharmaceutical agents and diagnostic reagents are highly required in medical fields. However, N-acetylneuraminate lyase（NAL）for Neu5Ac synthesis is not applicable for industry due to its low catalytic efficiency. In this study, we biochemically characterized a deep-sea NAL enzyme (abbreviated form: MyNal) from a symbiotic Mycoplasma inhabiting the stomach of a deep-sea isopod, Bathynomus jamesi. Enzyme kinetic studies of MyNal showed that it exhibited a very low K_m for both cleavage and synthesis activities compared to previously described NALs. Though it favors the cleavage process, MyNal out-competes the known NALs with respect to the efficiency of Neu5Ac synthesis and exhibits the highest k_cat/K_m values. High expression levels of recombinant MyNal could be achieved (9.56 mol L⁻¹ culture) with a stable activity in a wide pH (5.0–9.0) and temperature (40–60 °C) range. All these features indicated that the deep-sea NAL has potential in the industrial production of Neu5Ac. Furthermore, we found that the amino acid 189 of MyNal (equivalent to Phe190 in Escherichia coli NAL), located in the sugar-binding domain, GX189DE, was also involved in conferring its enzymatic features. Therefore, the results of this study improved our understanding of the NALs from different environments and provided a model for protein engineering of NAL for biosynthesis of Neu5Ac. Full article

(This article belongs to the Special Issue Marine Natural Products from Symbiotic Ecosystems)

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21 pages, 4914 KiB

Open AccessReview

Collagens of Poriferan Origin

by Hermann Ehrlich, Marcin Wysokowski, Sonia Żółtowska-Aksamitowska, Iaroslav Petrenko and Teofil Jesionowski

Mar. Drugs 2018, 16(3), 79; https://doi.org/10.3390/md16030079 - 3 Mar 2018

Cited by 75 | Viewed by 9627

Abstract

The biosynthesis, structural diversity, and functionality of collagens of sponge origin are still paradigms and causes of scientific controversy. This review has the ambitious goal of providing thorough and comprehensive coverage of poriferan collagens as a multifaceted topic with intriguing hypotheses and numerous [...] Read more.

The biosynthesis, structural diversity, and functionality of collagens of sponge origin are still paradigms and causes of scientific controversy. This review has the ambitious goal of providing thorough and comprehensive coverage of poriferan collagens as a multifaceted topic with intriguing hypotheses and numerous challenging open questions. The structural diversity, chemistry, and biochemistry of collagens in sponges are analyzed and discussed here. Special attention is paid to spongins, collagen IV-related proteins, fibrillar collagens from demosponges, and collagens from glass sponge skeletal structures. The review also focuses on prospects and trends in applications of sponge collagens for technology, materials science and biomedicine. Full article

(This article belongs to the Special Issue Collagen from Marine Biological Source and Medical Applications)

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14 pages, 739 KiB

Open AccessArticle

Microginins from a Microcystis sp. Bloom Material Collected from the Kishon Reservoir, Israel

by Anat Lodin-Friedman and Shmuel Carmeli

Mar. Drugs 2018, 16(3), 78; https://doi.org/10.3390/md16030078 - 2 Mar 2018

Cited by 22 | Viewed by 4874

Abstract

During blooms, cyanobacteria produce diverse modified peptides. Among these are the microginins, which inhibit zinc-containing metalloproteases. Ten microginins, microginins KR767 (1), KR801(2), KR835 (3), KR785 (4), KR604 (5), KR638 (6), KR781 [...] Read more.

During blooms, cyanobacteria produce diverse modified peptides. Among these are the microginins, which inhibit zinc-containing metalloproteases. Ten microginins, microginins KR767 (1), KR801(2), KR835 (3), KR785 (4), KR604 (5), KR638 (6), KR781 (7), KR815 (8), FR3 (9), and FR4 (10), were isolated from the extract of a bloom material of Microcystis sp. (IL-405) collected from the Kishon Reservoir, Israel in the fall of 2009. The structures of the pure compounds were elucidated using 1D and 2D NMR techniques and high-resolution mass spectrometry. The absolute configuration of the chiral centers of the amino acids were determined by Marfey’s and advance Marfey’s methods and by comparison of ¹H and ¹³C NMR chemical shifts of the Ahda derivatives with those of known microginins. These microginins differ in sequence and absolute configuration of the chiral centers of the Ahda moieties and by N-methylation of the Ahda amine group and extent of chlorination of the Ahda terminal methyl group. The compounds were evaluated for inhibition of the zinc metalloprotease, aminopeptidase M, and exhibited low- to sub-nanomolar half maximal inhibitory concentration (IC₅₀) values. Full article

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20 pages, 4926 KiB

Open AccessArticle

ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A

by Xuemei Wan, Jeffrey D. Serrill, Ian R. Humphreys, Michelle Tan, Kerry L. McPhail, Ian G. Ganley and Jane E. Ishmael

Mar. Drugs 2018, 16(3), 77; https://doi.org/10.3390/md16030077 - 1 Mar 2018

Cited by 22 | Viewed by 6097

Abstract

Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces [...] Read more.

Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5^−/− cells relative to ATG5^+/+ cells. Time-dependent changes in annexin V staining, membrane integrity, metabolic capacity and caspase activation indicated that MEFs with a functional autophagy pathway are more sensitive to coibamide A. This pattern could be distinguished from autophagy modulators that induce acute ER stress (thapsigargin, tunicamycin), ATP depletion (oligomycin A) or mTORC1 inhibition (rapamycin), but was shared with the Sec61 inhibitor apratoxin A. Coibamide- or apratoxin-induced cell stress was further distinguished from the action of thapsigargin by a pattern of early LC3-II accumulation in the absence of CHOP or BiP expression. Time-dependent changes in ATG5-ATG12, PARP1 and caspase-3 expression patterns were consistent with the conversion of ATG5 to a pro-death signal in response to both compounds. Full article

(This article belongs to the Special Issue Marine Compounds as Modulators of Autophagy and Lysosomal Activity)

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15 pages, 1484 KiB

Open AccessArticle

Comparative Analysis of Culture Conditions for the Optimization of Carotenoid Production in Several Strains of the Picoeukaryote Ostreococcus

by Jean-Baptiste Guyon, Valérie Vergé, Philippe Schatt, Jean-Claude Lozano, Marion Liennard and François-Yves Bouget

Mar. Drugs 2018, 16(3), 76; https://doi.org/10.3390/md16030076 - 28 Feb 2018

Cited by 7 | Viewed by 4755

Abstract

Microalgae are promising sources for the sustainable production of compounds of interest for biotechnologies. Compared to higher plants, microalgae have a faster growth rate and can be grown in industrial photobioreactors. The microalgae biomass contains specific metabolites of high added value for biotechnology [...] Read more.

Microalgae are promising sources for the sustainable production of compounds of interest for biotechnologies. Compared to higher plants, microalgae have a faster growth rate and can be grown in industrial photobioreactors. The microalgae biomass contains specific metabolites of high added value for biotechnology such as lipids, polysaccharides or carotenoid pigments. Studying carotenogenesis is important for deciphering the mechanisms of adaptation to stress tolerance as well as for biotechnological production. In recent years, the picoeukaryote Ostreococcus tauri has emerged as a model organism thanks to the development of powerful genetic tools. Several strains of Ostreococcus isolated from different environments have been characterized with respect to light response or iron requirement. We have compared the carotenoid contents and growth rates of strains of Ostreococcus (OTTH595, RCC802 and RCC809) under a wide range of light, salinity and temperature conditions. Carotenoid profiles and productivities varied in a strain-specific and stress-dependent manner. Our results also illustrate that phylogenetically related microalgal strains originating from different ecological niches present specific interests for the production of specific molecules under controlled culture conditions. Full article

(This article belongs to the Special Issue Marine Microalgae)

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13 pages, 3491 KiB

Open AccessArticle

Briaviolides K–N, New Briarane-Type Diterpenoids from Cultured Octocoral Briareum violaceum

by Jing-Hao Xu, Kuei-Hung Lai, Yin-Di Su, Yu-Chia Chang, Bo-Rong Peng, Anders Backlund, Zhi-Hong Wen and Ping-Jyun Sung

Mar. Drugs 2018, 16(3), 75; https://doi.org/10.3390/md16030075 - 27 Feb 2018

Cited by 17 | Viewed by 4472

Abstract

Four new briarane diterpenoids, briaviolides K–N (1–4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1–4 were identified. This study employed an in vitro model of lipopolysaccharide [...] Read more.

Four new briarane diterpenoids, briaviolides K–N (1–4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1–4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages. Full article

(This article belongs to the Special Issue Natural Products from Coral Reef Organisms)

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Mar. Drugs, Volume 16, Issue 3 (March 2018) – 24 articles

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