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Special Issue "In Vitro and In Vivo Approaches in the Driving Seat of Marine Drugs Discovery"

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: 10 June 2019

Special Issue Editors

Guest Editor
Prof. Mei-Chin Lu

Graduate Institute of Marine Biology, National Dong Hwa University, Taiwan
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Interests: structural elucidation; marine secondary metabolites; marine natural products; biological activities; cytotoxic mechanism; in vitro and in vivo assays
Guest Editor
Prof. Mohamed El-Shazly

1. Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 115, Egypt
2. Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 114, Egypt
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Interests: molecular biology; cell biology; cancer research; food science; catalysis; chemical biology
Guest Editor
Dr. Kuei-Hung Lai

National Museum of Marine Biology & Aquarium, Pingtung 94450, Taiwan
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Interests: natural products chemistry; drug development; functional and healthy food development

Special Issue Information

Dear Colleagues,

Isaac Newton once said, “I don't know what I may seem to the world, but as to myself, I seem to have been only like a boy playing on the sea-shore and diverting myself in now and then finding a smoother pebble or a prettier shell than ordinary, whilst the great ocean of truth lay all undiscovered before me.” Despite three centuries of great scientific discoveries, the truth about oceans and their organisms remains elusive. Natural products, medicinal and synthetic chemists along with pharmacologists, biochemists, cell biologists and microbiologists united their forces to unleash hidden treasures of oceans and seas. New classes of secondary metabolites were discovered from marine organisms with an unprecedented spectrum of biological activities. Several compounds entered the drug pipeline and many others are in various stages of clinical trials. Scientists used all available biological assays to screen marine organism extracts and fractions to zoom in on the most important compounds.

This Special Issue of Marine Drugs entitled “In Vitro and In Vivo Approaches in the Driving Seat of Marine Drugs Discovery” focuses on presenting the most recent advances in biological assays applied for the discovery of marine secondary metabolites with potential biological activities. Full research papers, short notes and review articles reporting the applications of in vitro and in vivo assays to reveal biological activities of marine natural products, will be considered. Colleagues are invited to present their research on biochemical and cell line assays along with pharmacokinetics, pharmacodynamics and disease models. They are also encouraged to present the most recent discoveries in new targets and assays for accelerating the process of drug discovery.

Prof. Mei-Chin Lu
Dr. Kuei-Hung Lai
Prof. Mohamed El-Shazly
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Marine secondary metabolites
  • Biological activities
  • In vitro assays
  • In vivo assays
  • Drug discovery

Published Papers (6 papers)

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Research

Open AccessArticle Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression
Mar. Drugs 2018, 16(6), 212; https://doi.org/10.3390/md16060212
Received: 22 May 2018 / Revised: 14 June 2018 / Accepted: 15 June 2018 / Published: 17 June 2018
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Abstract
Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine
[...] Read more.
Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-κB (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia. Full article
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Open AccessArticle Heteronemin, a Marine Sesterterpenoid-Type Metabolite, Induces Apoptosis in Prostate LNcap Cells via Oxidative and ER Stress Combined with the Inhibition of Topoisomerase II and Hsp90
Mar. Drugs 2018, 16(6), 204; https://doi.org/10.3390/md16060204
Received: 14 May 2018 / Revised: 31 May 2018 / Accepted: 9 June 2018 / Published: 10 June 2018
PDF Full-text (6480 KB) | HTML Full-text | XML Full-text
Abstract
Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in
[...] Read more.
Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent. Full article
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Open AccessArticle 7-Acetylsinumaximol B Induces Apoptosis and Autophagy in Human Gastric Carcinoma Cells through Mitochondria Dysfunction and Activation of the PERK/eIF2α/ATF4/CHOP Signaling Pathway
Mar. Drugs 2018, 16(4), 104; https://doi.org/10.3390/md16040104
Received: 16 January 2018 / Revised: 18 March 2018 / Accepted: 22 March 2018 / Published: 26 March 2018
Cited by 1 | PDF Full-text (22515 KB) | HTML Full-text | XML Full-text
Abstract
The 7-Acetylsinumaximol B (7-AB), a bioactive cembranoid, was originally discovered from aquaculture soft coral Sinularia sandensis. The current study investigated the anti-proliferative property of 7-AB towards the NCI-N87 human gastric cancer cell line. An MTT cell proliferative assay was applied to evaluate
[...] Read more.
The 7-Acetylsinumaximol B (7-AB), a bioactive cembranoid, was originally discovered from aquaculture soft coral Sinularia sandensis. The current study investigated the anti-proliferative property of 7-AB towards the NCI-N87 human gastric cancer cell line. An MTT cell proliferative assay was applied to evaluate cell survival, and immunofluorescence staining and western blotting were employed to analyze the effects of 7-AB on autophagy and apoptosis. Our results showed that 7-AB exerted a concentration-dependent anti-proliferative effect on NCI-N87 cells, and fluorescence staining indicated that the effect was due to the apoptosis induced by 7-AB. In addition, the 7-AB-induced anti-proliferation towards NCI-N87 cells was associated with the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (such as caspase-3/-9, Bax and Bad), and inhibition of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1). The 7-AB treatment also triggered endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/ATF4/CHOP apoptotic pathway. Furthermore, 7-AB initiated autophagy in NCI-N87 cells and induced the expression of autophagy-related proteins, including Atg3, Atg5, Atg7, Atg12, LC3-I, and LC3-II. Taken together, our findings suggested that 7-AB has the potential to be further developed as a useful anti-cancer or adjuvant agent for the treatment of human gastric cancer. Full article
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Open AccessArticle Isoaaptamine Induces T-47D Cells Apoptosis and Autophagy via Oxidative Stress
Mar. Drugs 2018, 16(1), 18; https://doi.org/10.3390/md16010018
Received: 6 December 2017 / Revised: 22 December 2017 / Accepted: 4 January 2018 / Published: 9 January 2018
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Abstract
Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was
[...] Read more.
Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer. Full article
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Open AccessArticle Lobocrassin B Induces Apoptosis of Human Lung Cancer and Inhibits Tumor Xenograft Growth
Mar. Drugs 2017, 15(12), 378; https://doi.org/10.3390/md15120378
Received: 19 September 2017 / Revised: 15 November 2017 / Accepted: 28 November 2017 / Published: 4 December 2017
Cited by 2 | PDF Full-text (3990 KB) | HTML Full-text | XML Full-text
Abstract
Lobocrassin B, a natural cembrane-type compound isolated from the soft coral Lobophytum crassum, has been shown to have significant biological effects, including anticancer activity. As the most common cause of cancer mortality worldwide, lung cancer remains a major concern threatening human health.
[...] Read more.
Lobocrassin B, a natural cembrane-type compound isolated from the soft coral Lobophytum crassum, has been shown to have significant biological effects, including anticancer activity. As the most common cause of cancer mortality worldwide, lung cancer remains a major concern threatening human health. In the current study, we conducted in vitro experiments to demonstrate the inhibiting effect of Lobocrassin B on CL1-5 and H520 human lung cancer cells growth and to explore the underlying mechanisms, as well as in nude mice bearing CL1-5 tumor xenografts. Lobocrassin B exerted cytotoxic effects on lung cancer cells, as shown by decreasing cell viability, and inducing apoptosis, oxidative stress and mitochondrial dysfunction. In addition, the increased level of Bax, cleaved caspase-3, -9 and -8, and the suppression of Bcl-2 were observed in the Lobocrassin B treated cells. Moreover, in vivo assays verified the significance of these results, revealing that Lobocrassin B inhibited CL1-5 tumor xenograft growth and that inhibitory effects were accompanied by a marked increase in tumor cell apoptosis. In conclusion, the results suggested that Lobocrassin B could be a potential anticancer compound for its propensity to inhibit growth and induce apoptosis in human lung cancer cells. Full article
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Open AccessArticle Anti-Inflammatory Cembranoids from the Soft Coral Lobophytum crassum
Mar. Drugs 2017, 15(10), 327; https://doi.org/10.3390/md15100327
Received: 26 September 2017 / Revised: 19 October 2017 / Accepted: 20 October 2017 / Published: 23 October 2017
Cited by 3 | PDF Full-text (2014 KB) | HTML Full-text | XML Full-text
Abstract
Abstract: Cembrane-type diterpenoids are among the most frequently encountered natural products from the soft corals of the genus Lobophytum. In the course of our investigation to identify anti-inflammatory constituents from a wild-type soft coral Lobophytum crassum, two new cembranoids, lobophyolide
[...] Read more.
Abstract: Cembrane-type diterpenoids are among the most frequently encountered natural products from the soft corals of the genus Lobophytum. In the course of our investigation to identify anti-inflammatory constituents from a wild-type soft coral Lobophytum crassum, two new cembranoids, lobophyolide A (1) and B (2), along with five known compounds (37), were isolated. The structures of these natural products were identified using NMR and MS spectroscopic analyses. Compound 1 was found to possess the first identified α-epoxylactone group among all cembrane-type diterpenoids. The in vitro anti-inflammatory effect of compounds 1–5 was evaluated. The results showed that compounds 1–5 not only reduced IL-12 release, but also attenuated NO production in LPS-activated dendritic cells. Our data indicated that the isolated series of cembrane-type diterpenoids demonstrated interesting structural features and anti-inflammatory activity which could be further developed into therapeutic entities. Full article
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