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Mar. Drugs, Volume 16, Issue 4 (April 2018)

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Cover Story (view full-size image) The current study elaborates on unique collagen fibers derived from Sarcophyton octocorals, their [...] Read more.
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Open AccessArticle Bioactive Compounds from Posidonia oceanica (L.) Delile Impair Malignant Cell Migration through Autophagy Modulation
Mar. Drugs 2018, 16(4), 137; https://doi.org/10.3390/md16040137
Received: 9 April 2018 / Revised: 18 April 2018 / Accepted: 19 April 2018 / Published: 21 April 2018
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Abstract
Posidonia oceanica (L.) Delile is a marine plant with interesting biological properties potentially ascribed to the synergistic combination of bioactive compounds. Our previously described extract, obtained from the leaves of P. oceanica, showed the ability to impair HT1080 cell migration by targeting
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Posidonia oceanica (L.) Delile is a marine plant with interesting biological properties potentially ascribed to the synergistic combination of bioactive compounds. Our previously described extract, obtained from the leaves of P. oceanica, showed the ability to impair HT1080 cell migration by targeting both expression and activity of gelatinases. Commonly, the lack of knowledge about the mechanism of action of phytocomplexes may be an obstacle regarding their therapeutic use and development. The aim of this study was to gain insight into the molecular signaling through which such bioactive compounds impact on malignant cell migration and gelatinolytic activity. The increase in autophagic vacuoles detected by confocal microscopy suggested an enhancement of autophagy in a time and dose dependent manner. This autophagy activation was further confirmed by monitoring pivotal markers of autophagy signaling as well as by evidencing an increase in IGF-1R accumulation on cell membranes. Taken together, our results confirm that the P. oceanica phytocomplex is a promising reservoir of potent and cell safe molecules able to defend against malignancies and other diseases in which gelatinases play a major role in progression. In conclusion, the attractive properties of this phytocomplex may be of industrial interest in regard to the development of novel health-promoting and pharmacological products for the treatment or prevention of several diseases. Full article
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Open AccessArticle Eurotiumins A–E, Five New Alkaloids from the Marine-Derived Fungus Eurotium sp. SCSIO F452
Mar. Drugs 2018, 16(4), 136; https://doi.org/10.3390/md16040136
Received: 25 March 2018 / Revised: 14 April 2018 / Accepted: 18 April 2018 / Published: 21 April 2018
Cited by 1 | PDF Full-text (2638 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Three new prenylated indole 2,5-diketopiperazine alkaloids (13) with nine known ones (513), one new indole alkaloid (4), and one new bis-benzyl pyrimidine derivative (14) were isolated and characterized from the marine-derived
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Three new prenylated indole 2,5-diketopiperazine alkaloids (13) with nine known ones (513), one new indole alkaloid (4), and one new bis-benzyl pyrimidine derivative (14) were isolated and characterized from the marine-derived fungus Eurotium sp. SCSIO F452. 1 and 2, occurring as a pair of diastereomers, both presented a hexahydropyrrolo[2,3-b]indole skeleton. Their chemical structures, including absolute configurations, were elucidated by 1D and 2D NMR, HRESIMS, quantum chemical calculations of electronic circular dichroism, and single crystal X-ray diffraction experiments. Most isolated compounds were screened for antioxidative potency. Compounds 3, 5, 6, 7, 9, 10, and 12 showed significant radical scavenging activities against DPPH with IC50 values of 13, 19, 4, 3, 24, 13, and 18 µM, respectively. Five new compounds were evaluated for cytotoxic activities. Full article
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Open AccessArticle The Protective Role of Sulfated Polysaccharides from Green Seaweed Udotea flabellum in Cells Exposed to Oxidative Damage
Mar. Drugs 2018, 16(4), 135; https://doi.org/10.3390/md16040135
Received: 16 March 2018 / Revised: 4 April 2018 / Accepted: 14 April 2018 / Published: 20 April 2018
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Abstract
Seaweed is a rich source of bioactive sulfated polysaccharides. We obtained six sulfated polysaccharide-rich fractions (UF-0.3, UF-0.5, UF-0.6, UF-0.7, UF-1.0, and UF-2.0) from the green seaweed Udotea flabellum (UF) by proteolytic digestion followed by sequential acetone precipitation. Biochemical analysis of these fractions showed
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Seaweed is a rich source of bioactive sulfated polysaccharides. We obtained six sulfated polysaccharide-rich fractions (UF-0.3, UF-0.5, UF-0.6, UF-0.7, UF-1.0, and UF-2.0) from the green seaweed Udotea flabellum (UF) by proteolytic digestion followed by sequential acetone precipitation. Biochemical analysis of these fractions showed that they were enriched with sulfated galactans. The viability and proliferative capacity of 3T3 fibroblasts exposed to FeSO4 (2 µM), CuSO4 (1 µM) or ascorbate (2 mM) was not affected. However, these cells were exposed to oxidative stress in the presence of FeSO4 or CuSO4 and ascorbate, which caused the activation of caspase-3 and caspase-9, resulting in apoptosis of the cells. We also observed increased lipid peroxidation, evaluated by the detection of malondialdehyde and decreased glutathione and superoxide dismutase levels. Treating the cells with the ultrafiltrate fractions (UF) fractions protected the cells from the oxidative damage caused by the two salts and ascorbate. The most effective protection against the oxidative damage caused by iron was provided by UF-0.7 (1.0 mg/mL); on treatment with UF-0.7, cell viability was 55%. In the case of copper, cell viability on treatment with UF-0.7 was ~80%, but the most effective fraction in this model was UF-2.0, with cell viability of more than 90%. The fractions, mainly UF-0.7 and UF-2.0, showed low iron chelating activity, but high copper chelating activity and total antioxidant capacity (TAC). These results suggested that some of their protective mechanisms stem from these properties. Full article
(This article belongs to the Special Issue Development and Application of Herbal Medicine from Marine Origin)
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Open AccessArticle A Low Molecular Weight Protein from the Sea Anemone Anemonia viridis with an Anti-Angiogenic Activity
Mar. Drugs 2018, 16(4), 134; https://doi.org/10.3390/md16040134
Received: 16 March 2018 / Revised: 6 April 2018 / Accepted: 12 April 2018 / Published: 19 April 2018
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Abstract
Sea anemones are a remarkable source of active principles due to a decentralized venom system. New blood vessel growth or angiogenesis is a very promising target against cancer, but the few available antiangiogenic compounds have limited efficacy. In this study, a protein fraction,
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Sea anemones are a remarkable source of active principles due to a decentralized venom system. New blood vessel growth or angiogenesis is a very promising target against cancer, but the few available antiangiogenic compounds have limited efficacy. In this study, a protein fraction, purified from tentacles of Anemonia viridis, was able to limit endothelial cells proliferation and angiogenesis at low concentration (14 nM). Protein sequences were determined with Edman degradation and mass spectrometry in source decay and revealed homologies with Blood Depressing Substance (BDS) sea anemones. The presence of a two-turn alpha helix observed with circular dichroism and a trypsin activity inhibition suggested that the active principle could be a Kunitz-type inhibitor, which may interact with an integrin due to an Arginine Glycin Aspartate (RGD) motif. Molecular modeling showed that this RGD motif was well exposed to solvent. This active principle could improve antiangiogenic therapy from existing antiangiogenic compounds binding on the Vascular Endothelial Growth Factor (VEGF). Full article
(This article belongs to the collection Marine Compounds and Cancer) Printed Edition available
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Open AccessReview Recent Synthesis and Discovery of Brefeldin A Analogs
Mar. Drugs 2018, 16(4), 133; https://doi.org/10.3390/md16040133
Received: 13 March 2018 / Revised: 6 April 2018 / Accepted: 11 April 2018 / Published: 18 April 2018
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Abstract
The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing
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The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing activity of BFA in cancer cells highlights the possibility of further developing this natural product as an anticancer agent. Besides its biological importance, its structural features have also gathered tremendous interest from both medicinal and synthetic chemists. By a medicinal chemistry and total synthesis approach, numerous analogs from BFA have been developed to improve its inferior bioavailability and its antiproliferative ability. In this review, the recent medicinal chemistry efforts in relation to the production of BFA analogs are extensively presented. Full article
(This article belongs to the Special Issue Connection of Marine Natural Products and Cell Apoptosis)
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Open AccessArticle Pharmacokinetic and Tissue Distribution of Fucoidan from Fucus vesiculosus after Oral Administration to Rats
Mar. Drugs 2018, 16(4), 132; https://doi.org/10.3390/md16040132
Received: 21 March 2018 / Revised: 5 April 2018 / Accepted: 16 April 2018 / Published: 18 April 2018
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Abstract
Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated
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Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated polysaccharide found in Fucus (F.) vesiculosus. The pharmacokinetic profiling of active compounds is essential for drug development and approval. The aim of the study was to evaluate the pharmacokinetics and tissue distribution of fucoidan in rats after a single-dose oral administration. Fucoidan was isolated from F. vesiculosus. The method of measuring anti-activated factor X (anti-Xa) activity by amidolytic assay was used to analyze the plasma and tissue concentrations of fucoidan. The tissue distribution of fucoidan after intragastric administration to the rats was characterized, and it exhibited considerable heterogeneity. Fucoidan preferentially accumulates in the kidneys (AUC0–t = 10.74 µg·h/g; Cmax = 1.23 µg/g after 5 h), spleen (AUC0–t = 6.89 µg·h/g; Cmax = 0.78 µg/g after 3 h), and liver (AUC0–t = 3.26 µg·h/g; Cmax = 0.53 µg/g after 2 h) and shows a relatively long absorption time and extended circulation in the blood, with a mean residence time (MRT) = 6.79 h. The outcome of this study provides additional scientific data for traditional use of fucoidan-containing plants and offers tangible support for the continued development of new effective pharmaceuticals using fucoidan. Full article
(This article belongs to the Special Issue Marine Bioactive Natural Product Studies in Europe)
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Open AccessArticle Marine Longilenes, Oxasqualenoids with Ser-Thr Protein Phosphatase 2A Inhibition Activity
Mar. Drugs 2018, 16(4), 131; https://doi.org/10.3390/md16040131
Received: 27 March 2018 / Revised: 11 April 2018 / Accepted: 14 April 2018 / Published: 17 April 2018
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Abstract
The red seaweed Laurencia viridis is a rich source of oxygenated secondary metabolites that were derived from squalene. We report here the structures of three novel compounds, (+)-longilene peroxide (1), longilene (2), and (+)-prelongilene (3) that were
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The red seaweed Laurencia viridis is a rich source of oxygenated secondary metabolites that were derived from squalene. We report here the structures of three novel compounds, (+)-longilene peroxide (1), longilene (2), and (+)-prelongilene (3) that were isolated from this alga, in addition to other substances, 4 and 5, resulting from their acid-mediated degradation. The effect of compounds 1 and 3 against Ser-Thr protein phosphatase type 2A (PP2A) was evaluated, showing that (+)-longilene peroxide (1) inhibited PP2A (IC50 11.3 μM). In order to explain the interaction between PP2A and compounds 1 and 3, molecular docking simulations onto the PP2A enzyme-binding region were used. Full article
(This article belongs to the Special Issue Pre-Clinical Marine Drug Discovery)
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Open AccessArticle Antartin, a Cytotoxic Zizaane-Type Sesquiterpenoid from a Streptomyces sp. Isolated from an Antarctic Marine Sediment
Mar. Drugs 2018, 16(4), 130; https://doi.org/10.3390/md16040130
Received: 27 March 2018 / Revised: 10 April 2018 / Accepted: 11 April 2018 / Published: 16 April 2018
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Abstract
Antartin (1), a new zizaane-type sesquiterpene, was isolated from Streptomyces sp. SCO736. The chemical structure of 1 was assigned from the interpretation of 1D and 2D NMR in addition to mass spectrometric data. The relative stereochemistry of 1 was determined by
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Antartin (1), a new zizaane-type sesquiterpene, was isolated from Streptomyces sp. SCO736. The chemical structure of 1 was assigned from the interpretation of 1D and 2D NMR in addition to mass spectrometric data. The relative stereochemistry of 1 was determined by analysis of NOE data, while the absolute stereochemistry was decided based on a comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Antartin (1) showed cytotoxicity against A549, H1299, and U87 cancer cell lines by causing cell cycle arrest at the G1 phase. Full article
(This article belongs to the Special Issue Natural Products from Marine Actinomycetes)
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Open AccessArticle Biochemical Characterization and Degradation Pattern of a Unique pH-Stable PolyM-Specific Alginate Lyase from Newly Isolated Serratia marcescens NJ-07
Mar. Drugs 2018, 16(4), 129; https://doi.org/10.3390/md16040129
Received: 28 March 2018 / Revised: 11 April 2018 / Accepted: 12 April 2018 / Published: 15 April 2018
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Abstract
Enzymatic preparation of alginate oligosaccharides with versatile bioactivities by alginate lyases has attracted increasing attention due to its featured characteristics, such as wild condition and specific products. In this study, AlgNJ-07, a novel polyM-specific alginate lyase with high specific activity and pH stability,
[...] Read more.
Enzymatic preparation of alginate oligosaccharides with versatile bioactivities by alginate lyases has attracted increasing attention due to its featured characteristics, such as wild condition and specific products. In this study, AlgNJ-07, a novel polyM-specific alginate lyase with high specific activity and pH stability, has been purified from the newly isolated marine bacterium Serratia marcescens NJ-07. It has a molecular weight of approximately 25 kDa and exhibits the maximal activity of 2742.5 U/mg towards sodium alginate under 40 °C at pH 9.0. Additionally, AlgNJ-07 could retain more than 95% of its activity at pH range of 8.0–10.0, indicating it possesses excellent pH-stability. Moreover, it shows high activity and affinity towards polyM block and no activity to polyG block, which suggests that it is a strict polyM-specific alginate lyase. The degradation pattern of AlgNJ-07 has also been explored. The activity of AlgNJ-07 could be activated by NaCl with a low concentration (100–300 mM). It can be observed that AlgNJ-07 can recognize the trisaccharide as the minimal substrate and hydrolyze the trisaccharide into monosaccharide and disaccharide. The TLC and ESI-MS analysis indicate that it can hydrolyze substrates in a unique endolytic manner, producing not only oligosaccharides with Dp of 2–5 but also a large fraction of monosaccharide. Therefore, it may be a potent tool to produce alginate oligosaccharides with lower Dps (degree of polymerization). Full article
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Open AccessArticle Structural Characterization and Interaction with RCA120 of a Highly Sulfated Keratan Sulfate from Blue Shark (Prionace glauca) Cartilage
Mar. Drugs 2018, 16(4), 128; https://doi.org/10.3390/md16040128
Received: 22 March 2018 / Revised: 8 April 2018 / Accepted: 10 April 2018 / Published: 14 April 2018
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Abstract
As an important glycosaminoglycan, keratan sulfate (KS) mainly exists in corneal and cartilage, possessing various biological activities. In this study, we purified KS from blue shark (Prionace glauca) cartilage and prepared KS oligosaccharides (KSO) through keratanase II-catalyzed hydrolysis. The structures of
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As an important glycosaminoglycan, keratan sulfate (KS) mainly exists in corneal and cartilage, possessing various biological activities. In this study, we purified KS from blue shark (Prionace glauca) cartilage and prepared KS oligosaccharides (KSO) through keratanase II-catalyzed hydrolysis. The structures of KS and KSO were characterized using multi-dimensional nuclear magnetic resonance (NMR) spectra and liquid chromatography-mass spectrometry (LC-MS). Shark cartilage KS was highly sulfated and modified with ~2.69% N-acetylneuraminic acid (NeuAc) through α(2,3)-linked to galactose. Additionally, KS exhibited binding affinity to Ricinus communis agglutinin I (RCA120) in a concentration-dependent manner, a highly toxic lectin from beans of the castor plant. Furthermore, KSO from dp2 to dp8 bound to RCA120 in the increasing trend while the binding affinity of dp8 was superior to polysaccharide. These results define novel structural features for KS from Prionace glauca cartilage and demonstrate the potential application on ricin-antidote exploitation. Full article
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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Open AccessArticle Terpenoids from the Soft Coral Sinularia sp. Collected in Yongxing Island
Mar. Drugs 2018, 16(4), 127; https://doi.org/10.3390/md16040127
Received: 20 March 2018 / Revised: 8 April 2018 / Accepted: 10 April 2018 / Published: 13 April 2018
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Abstract
Three new sesquiterpenoids (sinuketal (1), sinulins A and B (2 and 3)) and two new cembranoids (sinulins C and D (4 and 5)), as well as eight known sesquiterpenoids (6–13) and eight known cembranoids (
[...] Read more.
Three new sesquiterpenoids (sinuketal (1), sinulins A and B (2 and 3)) and two new cembranoids (sinulins C and D (4 and 5)), as well as eight known sesquiterpenoids (6–13) and eight known cembranoids (14–21), were isolated from the Xisha soft coral Sinularia sp. Their structures were elucidated by extensive spectroscopic analysis. Compound 1 possesses an unprecedented isopropyl-branched bicyclo [6.3.0] undecane carbon skeleton with unique endoperoxide moiety, and a plausible biosynthetic pathway of it was postulated. According to the reported biological properties of endoperoxide, the antimalarial, cytotoxic, antiviral, and target inhibitory activities of 1 were tested. Compound 1 showed mild in vitro antimalarial activity against Plasmodium falciparum 3D7, weak cytotoxic activities toward Jurkat, MDA-MB-231, and U2OS cell lines, inhibitory effects against influenza A viruses H1N1 and PR8, as well as mild target inhibitory activity against acetylcholinesterase. The other compounds were evaluated for cytotoxicities against HeLa, HCT-116, and A549 tumor cell lines and target inhibitory activities against protein tyrosine phosphatase 1B (PTP1B). Compound 20 exhibited cytotoxicities against HeLa and HCT-116, and compounds 5, 11, and 15 showed mild target inhibitory activities against PTP1B. Full article
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Open AccessArticle Astaxanthin Restrains Nitrative-Oxidative Peroxidation in Mitochondrial-Mimetic Liposomes: A Pre-Apoptosis Model
Mar. Drugs 2018, 16(4), 126; https://doi.org/10.3390/md16040126
Received: 22 February 2018 / Revised: 19 March 2018 / Accepted: 4 April 2018 / Published: 12 April 2018
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Abstract
Astaxanthin (ASTA) is a ketocarotenoid found in many marine organisms and that affords many benefits to human health. ASTA is particularly effective against radical-mediated lipid peroxidation, and recent findings hypothesize a “mitochondrial-targeted” action of ASTA in cells. Therefore, we examined the protective effects
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Astaxanthin (ASTA) is a ketocarotenoid found in many marine organisms and that affords many benefits to human health. ASTA is particularly effective against radical-mediated lipid peroxidation, and recent findings hypothesize a “mitochondrial-targeted” action of ASTA in cells. Therefore, we examined the protective effects of ASTA against lipid peroxidation in zwitterionic phosphatidylcholine liposomes (PCLs) and anionic phosphatidylcholine: phosphatidylglycerol liposomes (PCPGLs), at different pHs (6.2 to 8.0), which were challenged by oxidizing/nitrating conditions that mimic the regular and preapoptotic redox environment of active mitochondria. Pre-apoptotic conditions were created by oxidized/nitr(osyl)ated cytochrome c and resulted in the highest levels of lipoperoxidation in both PCL and PCPGLs (pH 7.4). ASTA was less protective at acidic conditions, especially in anionic PCPGLs. Our data demonstrated the ability of ASTA to hamper oxidative and nitrative events that lead to cytochrome c-peroxidase apoptosis and lipid peroxidation, although its efficiency changes with pH and lipid composition of membranes. Full article
(This article belongs to the Special Issue Connection of Marine Natural Products and Cell Apoptosis)
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Open AccessArticle Anticancer Activity of Anthopleura anjunae Oligopeptides in Prostate Cancer DU-145 Cells
Mar. Drugs 2018, 16(4), 125; https://doi.org/10.3390/md16040125
Received: 28 February 2018 / Revised: 29 March 2018 / Accepted: 4 April 2018 / Published: 12 April 2018
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Abstract
Anthopleura anjunae anti-tumor peptide (AAP-H) is a pentapeptide from the sea anemone Anthopleura anjunae with an amino acid sequence of Tyr-Val-Pro-Gly-Pro that is obtained by alkaline protease enzymatic hydrolysis extraction. In this study, we investigated the inhibitory effects of AAP-H on prostate cancer
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Anthopleura anjunae anti-tumor peptide (AAP-H) is a pentapeptide from the sea anemone Anthopleura anjunae with an amino acid sequence of Tyr-Val-Pro-Gly-Pro that is obtained by alkaline protease enzymatic hydrolysis extraction. In this study, we investigated the inhibitory effects of AAP-H on prostate cancer DU-145 cell proliferation using a methylthiazolyldiphenyl-tetrazolium bromide assay. Cell morphology was analyzed by hematoxylin-eosin staining, acridine orange/ethidium bromide fluorescence staining, Hoechst 33258 fluorescence staining, and scanning electron microscopy. The mitochondrial membrane potential was determined by flow cytometry following JC-1 staining. The cell apoptosis rate was measured by Annexin V-fluorescein isothiocyanate and propidium iodide staining followed by flow cytometric analysis, and the expression of apoptosis-associated proteins was assayed by Western blotting. The results demonstrated that AAP-H induced significant reductions in the number of viable cells and increased cell death in both a dose-dependent and time-dependent manner, with an IC50 of approximately 9.605 mM, 7.910 mM, and 2.298 mM at 24 h, 48 h, and 72 h, respectively. The morphologic characteristics of apoptotic cells were observed after treatment with AAP-H. The mitochondrial membrane potential was markedly decreased, and apoptosis increased after AAP-H treatment. Pro-apoptotic proteins, such as Bax, cytochrome-C, caspase-3, and caspase-9 were increased, but Bcl-2 was decreased. These findings suggest that AAP-H has moderate inhibitory effects on prostate cancer DU-145 cells, and the mechanism might involve the mitochondria-mediated apoptotic pathway. Therefore, AAP-H is a candidate anti-prostate cancer drug or health-care food. Full article
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Open AccessArticle The Structure of the Lipid A from the Halophilic Bacterium Spiribacter salinus M19-40T
Mar. Drugs 2018, 16(4), 124; https://doi.org/10.3390/md16040124
Received: 17 March 2018 / Revised: 4 April 2018 / Accepted: 8 April 2018 / Published: 11 April 2018
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Abstract
The study of the adaptation mechanisms that allow microorganisms to live and proliferate in an extreme habitat is a growing research field. Directly exposed to the external environment, lipopolysaccharides (LPS) from Gram-negative bacteria are of great appeal as they can present particular structural
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The study of the adaptation mechanisms that allow microorganisms to live and proliferate in an extreme habitat is a growing research field. Directly exposed to the external environment, lipopolysaccharides (LPS) from Gram-negative bacteria are of great appeal as they can present particular structural features that may aid the understanding of the adaptation processes. Moreover, through being involved in modulating the mammalian immune system response in a structure-dependent fashion, the elucidation of the LPS structure can also be seen as a fundamental step from a biomedical point of view. In this paper, the lipid A structure of the LPS from Spiribacter salinus M19-40T, a halophilic gamma-proteobacteria, was characterized through chemical analyses and matrix-assisted laser desorption ionization (MALDI) mass spectrometry. This revealed a mixture of mono- and bisphosphorylated penta- to tri-acylated species with the uncommon 2 + 3 symmetry and bearing an unusual 3-oxotetradecaonic acid. Full article
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Open AccessArticle Holotoxin A1 Induces Apoptosis by Activating Acid Sphingomyelinase and Neutral Sphingomyelinase in K562 and Human Primary Leukemia Cells
Mar. Drugs 2018, 16(4), 123; https://doi.org/10.3390/md16040123
Received: 22 February 2018 / Revised: 29 March 2018 / Accepted: 4 April 2018 / Published: 10 April 2018
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Abstract
Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A1 is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C2, the 25(26)-dihydro derivative of holotoxin A1,
[...] Read more.
Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A1 is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C2, the 25(26)-dihydro derivative of holotoxin A1, induced apoptosis in human leukemia cells by activating ceramide synthase 6. Thus, we hypothesized that holotoxin A1, which is structurally similar to cladoloside C2, might induce apoptosis in human leukemia cells through the same molecular mechanism. In this paper, we compared holotoxin A1 and cladoloside C2 for killing potency and mechanism of action. We found that holotoxin A1 induced apoptosis more potently than cladoloside C2. Moreover, holotoxin A1 induced apoptosis in K562 cells by activating caspase-8 and caspase-3, but not by activating caspase-9. During holotoxin A1-induced apoptosis, acid sphingomyelinase (SMase) and neutral SMase were activated in both K562 cells and human primary leukemia cells. Specifically inhibiting acid SMase and neutral SMаse with chemical inhibitors or siRNAs significantly inhibited holotoxin A1–induced apoptosis. These results indicated that holotoxin A1 might induce apoptosis by activating acid SMase and neutral SMase. In conclusion, holotoxin A1 represents a potential anticancer agent for treating leukemia. Moreover, the aglycone structure of marine triterpene glycosides might affect the mechanism involved in inducing apoptosis. Full article
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