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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 38372

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Prof. Dr. Jun Lu

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Auckland Bioengineering Institute, University of Auckland, Auckland 1142, New Zealand
Interests: diabetes; obesity; cancer; non-communicalbe diseases; marine natural compounds; fucoidan; seaweed; clams; food chemistry; pharmacology; drug metabolism; pharmacokinetics; pre-clinical pharmacology; natural compound extraction; polyamine metabolism; marine bioactives
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Special Issue Information

Dear Colleagues,

Life starts from the ocean. We look for inspiration from the sea in literature, design, engineering, food, and medicine. Marine organisms have provided many medicines in the past, and we are searching for more to enrich our biomedicine collection. Natural marine metabolites have long been providing us with biomedicines and/or nutraceuticals.

Biomedicines or potential candidates of biomedicines from marine organisms are a research target for many field specialists around the world. Some compounds have been successfully developed into drugs. For example, triterpenoids extracted from sea sponges have become an anticancer drug. Other marine bioactives are in clinical trials to be developed into medicines and/or nutraceuticals to be used in our daily life, including peptides, carbohydrates, and lipids. Biomedicines from the sea with various bioactivities have become a popular research field that is yielding interesting results every day. Hence, this Special Issue aims to gather the most relevant and new research articles in this field, including but not limited to chemical and biological extraction, identification, screening, and testing of marine compounds; preclinical and clinical investigation of compounds/products from the sea in medicine; and the development of those compounds/products into pharmaceuticals and/or nutraceuticals. We hope to capture the progress and development in this important field, through this Special Issue, which will also offer an opportunity for scientists who are working in this field to showcase their recent findings and attract the attention of their peers and the wider readership of this journal. With the open access model and a high impact factor (4.717), this will be an excellent platform for you to display your important research findings.

Prof. Dr. Jun Lu
Guest Editor

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Keywords

Marine
biomedicine
metabolite
natural compounds
nutraceutical
sea products
pharmaceutical
pharmacology
clinical trial
drug discovery
drug development

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Published Papers (12 papers)

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Research

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23 pages, 4021 KiB

Open AccessArticle

Novel Nematode-Killing Protein-1 (Nkp-1) from a Marine Epiphytic Bacterium Pseudoalteromonas tunicata

by Nor Hawani Salikin, Malak Dubois, Jadranka Nappi, Helene Lebhar, Christopher Marquis and Suhelen Egan

Biomedicines 2021, 9(11), 1586; https://doi.org/10.3390/biomedicines9111586 - 30 Oct 2021

Cited by 2 | Viewed by 2739

Abstract

Drug resistance among parasitic nematodes has resulted in an urgent need for the development of new therapies. However, the high re-discovery rate of anti-nematode compounds from terrestrial environments necessitates a new repository for future drug research. Marine epiphytes are hypothesised to produce nematicidal compounds as a defence against bacterivorous predators, thus representing a promising yet underexplored source for anti-nematode drug discovery. The marine epiphytic bacterium Pseudoalteromonas tunicata is known to produce several bioactive compounds. Screening heterologously expressed genomic libraries of P. tunicata against the nematode Caenorhabditis elegans, identified as an E. coli clone (HG8), shows fast-killing activity. Here we show that clone HG8 produces a novel nematode-killing protein-1 (Nkp-1) harbouring a predicted carbohydrate-binding domain with weak homology to known bacterial pore-forming toxins. We found bacteria expressing Nkp-1 were able to colonise the C. elegans intestine, with exposure to both live bacteria and protein extracts resulting in physical damage and necrosis, leading to nematode death within 24 h of exposure. Furthermore, this study revealed C. elegans dar (deformed anal region) and internal hatching may act as a nematode defence strategy against Nkp-1 toxicity. The characterisation of this novel protein and putative mode of action not only contributes to the development of novel anti-nematode applications in the future but reaffirms the potential of marine epiphytic bacteria as a new source of novel biomolecules. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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22 pages, 4556 KiB

Open AccessArticle

Potential of Marine Terpenoids against SARS-CoV-2: An In Silico Drug Development Approach

by Alaka Sahoo, Shivkanya Fuloria, Shasank S. Swain, Sujogya K. Panda, Mahendran Sekar, Vetriselvan Subramaniyan, Maitreyee Panda, Ajaya K. Jena, Kathiresan V. Sathasivam and Neeraj Kumar Fuloria

Biomedicines 2021, 9(11), 1505; https://doi.org/10.3390/biomedicines9111505 - 20 Oct 2021

Cited by 28 | Viewed by 3327

Abstract

In an emergency, drug repurposing is the best alternative option against newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, several bioactive natural products have shown potential against SARS-CoV-2 in recent studies. The present study selected sixty-eight broad-spectrum antiviral marine terpenoids and performed molecular docking against two novel SARS-CoV-2 enzymes (main protease or M^pro or 3CL^pro) and RNA-dependent RNA polymerase (RdRp). In addition, the present study analysed the physiochemical-toxicity-pharmacokinetic profile, structural activity relationship, and phylogenetic tree with various computational tools to select the ‘lead’ candidate. The genomic diversity study with multiple sequence analyses and phylogenetic tree confirmed that the newly emerged SARS-CoV-2 strain was up to 96% structurally similar to existing CoV-strains. Furthermore, the anti-SARS-CoV-2 potency based on a protein−ligand docking score (kcal/mol) exposed that the marine terpenoid brevione F (−8.4) and stachyflin (−8.4) exhibited similar activity with the reference antiviral drugs lopinavir (−8.4) and darunavir (−7.5) against the target SARS−CoV−M^pro. Similarly, marine terpenoids such as xiamycin (−9.3), thyrsiferol (−9.2), liouvilloside B (−8.9), liouvilloside A (−8.8), and stachyflin (−8.7) exhibited comparatively higher docking scores than the referral drug remdesivir (−7.4), and favipiravir (−5.7) against the target SARS-CoV-2−RdRp. The above in silico investigations concluded that stachyflin is the most ‘lead’ candidate with the most potential against SARS-CoV-2. Previously, stachyflin also exhibited potential activity against HSV-1 and CoV-A59 within IC₅₀, 0.16–0.82 µM. Therefore, some additional pharmacological studies are needed to develop ‘stachyflin’ as a drug against SARS-CoV-2. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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15 pages, 4730 KiB

Open AccessArticle

Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin

by Hsien-Lin Chen, Yu-Chieh Su, Huang-Chi Chen, Jui-Hsin Su, Chang-Yi Wu, Shih-Wei Wang, In-Pin Lin, Chung-Yi Chen and Chien-Hsing Lee

Biomedicines 2021, 9(9), 1109; https://doi.org/10.3390/biomedicines9091109 - 29 Aug 2021

Cited by 5 | Viewed by 2943 | Correction

Abstract

Lymphatic metastasis is a biological procedure associated with the pathogenesis of several diseases, especially in tumor metastasis. Therefore, regulation of lymphangiogenesis has become a promising strategy for cancer therapy. In this study, we aimed to investigate the anti-lymphangiogenic effect of heteronemin (SP-1) isolated from the sponge Hyrtios sp. in vitro and in vivo. Human lymphatic endothelial cells (LECs) were utilized to evaluate the anti-lymphangiogenic effect of SP-1 in vitro. Molecular docking, western blotting, flow-cytometry, MTT and ELISA were performed to investigate the mechanism of action. For in vivo approaches, the transgenic (fli1:EGFP; gata1:DsRed) zebrafish and mouse ear sponges were used. Molecular docking studies showed that SP-1 is a potent vascular endothelial growth factor receptor 3 (VEGFR-3)-binding compound. Treatment of LEC with SP-1 reduced the phosphorylation of VEGFR-3. SP-1 suppressed the development of the thoracic duct in zebrafish and mouse lymphangiogenesis ear sponges in vivo. Mechanistically, SP-1 induced the cell cycle arrest of LECs in the G0/G1 phase and reduced the downstream of VEGFR-3, such as phosphorylated MEK/ERK and NF-κB. In addition, SP-1 inhibited LECs’ tubulogenesis and migration through the ARF-1 and MMP-9/VE-cadherin/vimentin. Overall, anti-lymphangiogenic properties of SP-1 occur by downregulating the VEGFR-3 cascade, ARF-1 and MMP-9/VE-cadherin/vimentin. Collectively, these results proposed that SP-1 might be a potential candidate for the treatment of lymphangiogenesis-associated diseases. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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17 pages, 4334 KiB

Open AccessArticle

Effects of Sponge-Derived Alkaloids on Activities of the Bacterial α-D-Galactosidase and Human Cancer Cell α-N-Acetylgalactosaminidase

by Natalia Utkina, Galina Likhatskaya, Olesya Malyarenko, Svetlana Ermakova, Larisa Balabanova, Lubov Slepchenko and Irina Bakunina

Biomedicines 2021, 9(5), 510; https://doi.org/10.3390/biomedicines9050510 - 5 May 2021

Cited by 3 | Viewed by 2414

Abstract

During a search for glycosidase inhibitors among marine natural products, we applied an integrated in vitro and in silico approach to evaluate the potency of some aaptamines and makaluvamines isolated from marine sponges on the hydrolyzing activity of α-N-acetylgalactosaminidase (α-NaGalase) from human cancer cells and the recombinant α-D-galactosidase (α-PsGal) from a marine bacterium Pseudoalteromonas sp. KMM 701. These alkaloids showed no direct inhibitory effect on the cancer α-NaGalase; but isoaaptamine (2), 9-demethylaaptamine (3), damirone B (6), and makaluvamine H (7) reduced the expression of the enzyme in the human colorectal adenocarcinoma cell line DLD-1 at 5 μM. Isoaaptamine (2), 9-demethylaaptamine (3), makaluvamine G (6), and zyzzyanone A (7) are slow-binding irreversible inhibitors of the bacterial α-PsGal with the inactivation rate constants (k_inact) 0.12 min⁻¹, 0.092 min⁻¹, 0.079 min⁻¹, and 0.037 min⁻¹, as well as equilibrium inhibition constants (K_i) 2.70 µM, 300 µM, 411 µM, and 105 µM, respectively. Docking analysis revealed that these alkaloids bind in a pocket close to the catalytic amino acid residues Asp451 and Asp516 and form complexes, due to π-π interactions with the Trp308 residue and hydrogen bonds with the Lys449 residue. None of the studied alkaloids formed complexes with the active site of the human α-NaGalase. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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15 pages, 3522 KiB

Open AccessArticle

Ecklonia cava Extract and Its Derivative Dieckol Promote Vasodilation by Modulating Calcium Signaling and PI3K/AKT/eNOS Pathway in In Vitro and In Vivo Models

by Yu-An Lu, Jun-Geon Je, Jin Hwang, You-Jin Jeon and BoMi Ryu

Biomedicines 2021, 9(4), 438; https://doi.org/10.3390/biomedicines9040438 - 19 Apr 2021

Cited by 14 | Viewed by 3916

Abstract

Nitric oxide (NO), an endothelial-derived relaxing factor synthesized by endothelial nitric oxide synthase (eNOS) in endothelial cells, enhances vasodilation by modulating vascular tone. The calcium concentration critically influences eNOS activation in endothelial cells. Thus, modulation of calcium-dependent signaling pathways may be a potential therapeutic strategy to enhance vasodilation. Marine algae reportedly possess protective effects against cardiovascular disorders, including hypertension and vascular dysfunction; however, the underlying molecular signaling pathways remain elusive. In the present study, we extracted and isolated dieckol from Ecklonia cava and investigated calcium transit-enhanced vasodilation. Calcium modulation via the well-known M3 muscarinic acetylcholine receptor (AchM3R), which is linked to NO formation, was investigated and the vasodilatory effect of dieckol was verified. Our results indicated that dieckol effectively promoted NO generation via the PI3K/Akt/eNOS axis and calcium transients influenced by AchM3R. We also treated Tg(flk: EGFP) transgenic zebrafish with dieckol to assess its vasodilatory effect. Dieckol promoted vasodilation by enlarging the dorsal aorta diameter, thus regulating blood flow velocity. In conclusion, our findings suggest that dieckol modulates calcium transit through AchM3R, increases endothelial-dependent NO production, and efficiently enhances vasodilation. Thus, E. cava and its derivative, dieckol, can be considered as potential natural vasodilators. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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20 pages, 3489 KiB

Open AccessArticle

Isoproterenol-Induced Permeability Transition Pore-Related Dysfunction of Heart Mitochondria Is Attenuated by Astaxanthin

by Roman Krestinin, Yulia Baburina, Irina Odinokova, Alexey Kruglov, Irina Fadeeva, Alena Zvyagina, Linda Sotnikova and Olga Krestinina

Biomedicines 2020, 8(10), 437; https://doi.org/10.3390/biomedicines8100437 - 20 Oct 2020

Cited by 18 | Viewed by 3285

Abstract

Mitochondria are key organelles of the cell because their main function is the capture of energy-rich substrates from the cytoplasm and oxidative cleavage with the generation of carbon dioxide and water, processes that are coupled with the synthesis of ATP. Mitochondria are subject to oxidative stress through the formation of the mitochondrial permeability transition pore (mPTP). Various antioxidants are used to reduce damage caused by oxidative stress and to improve the protection of the antioxidant system. Astaxanthin (AST) is considered to be a dietary antioxidant, which is able to reduce oxidative stress and enhance the antioxidant defense system. In the present investigation, the effect of AST on the functional state of rat heart mitochondria impaired by isoproterenol (ISO) under mPTP functioning was examined. It was found that AST raised mitochondrial respiration, the Ca²⁺ retention capacity (CRC), and the rate of TPP⁺ influx in rat heart mitochondria (RHM) isolated from ISO-injected rats. However, the level of reactive oxygen species (ROS) production increased. In addition, the concentrations of cardiolipin (CL), Mn-SOD2, and the proteins regulating mPTP rose after the injection of ISO in RHM pretreated with AST. Based on the data obtained, we suggest that AST has a protective effect in rat heart mitochondria. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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Review

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13 pages, 1646 KiB

Open AccessReview

Oral Mucositis in Cancer and Potential Use of Omega-3 Free Fatty Acids in Its Management: A Review

by Roberta Cardim Lessa, Fabio de Abreu Alves, Erika Fortunati and Jun Lu

Biomedicines 2021, 9(11), 1531; https://doi.org/10.3390/biomedicines9111531 - 25 Oct 2021

Cited by 5 | Viewed by 2986

Abstract

Oral mucositis (OM) is a painful condition caused by chemotherapeutic or radiotherapeutic cancer treatments, occurring in patients with different tumour characteristics and locations. OM greatly impacts a patient’s quality of life and cancer recovery. Current OM management strategies are not providing sufficient prevention and treatment; new approaches to injury management are needed. Studies on the benefit of omega-3 free fatty acids (FFA) in human health have increased significantly in recent years. FFA properties have been studied extensively, including their potential therapeutic use in inflammatory conditions. However, omega-3 FFA’s use as a supplementary treatment for OM has not been clinically tested. Preliminary evidence suggests that utilising FFA to manage OM could be a useful strategy for lesion management, assisting with healthy oral mucosa recovery. This review will describe the incidence, risk factors, biology of OM and the current treatment strategies, leading to a discussion of the utility of omega-3 FFA as a novel therapeutic agent for OM. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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79 pages, 23687 KiB

Open AccessReview

Bioactive Compounds with Antiglioma Activity from Marine Species

by Rodion Khotimchenko, Igor Bryukhovetskiy, Maksim Khotimchenko and Yuri Khotimchenko

Biomedicines 2021, 9(8), 886; https://doi.org/10.3390/biomedicines9080886 - 25 Jul 2021

Cited by 5 | Viewed by 3276

Abstract

The search for new chemical compounds with antitumor pharmacological activity is a necessary process for creating more effective drugs for each specific malignancy type. This review presents the outcomes of screening studies of natural compounds with high anti-glioma activity. Despite significant advances in cancer therapy, there are still some tumors currently considered completely incurable including brain gliomas. This review covers the main problems of the glioma chemotherapy including drug resistance, side effects of common anti-glioma drugs, and genetic diversity of brain tumors. The main emphasis is made on the characterization of natural compounds isolated from marine organisms because taxonomic diversity of organisms in seawaters significantly exceeds that of terrestrial species. Thus, we should expect greater chemical diversity of marine compounds and greater likelihood of finding effective molecules with antiglioma activity. The review covers at least 15 classes of organic compounds with their chemical formulas provided as well as semi-inhibitory concentrations, mechanisms of action, and pharmacokinetic profiles. In conclusion, the analysis of the taxonomic diversity of marine species containing bioactives with antiglioma activity is performed noting cytotoxicity indicators and to the tumor cells in comparison with similar indicators of antitumor agents approved for clinical use as antiglioblastoma chemotherapeutics. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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25 pages, 753 KiB

Open AccessReview

Promising Activities of Marine Natural Products against Hematopoietic Malignancies

by Assunta Saide, Sara Damiano, Roberto Ciarcia and Chiara Lauritano

Biomedicines 2021, 9(6), 645; https://doi.org/10.3390/biomedicines9060645 - 5 Jun 2021

Cited by 6 | Viewed by 3304

Abstract

According to the WHO classification of tumors, more than 150 typologies of hematopoietic and lymphoid tumors exist, and most of them remain incurable diseases that require innovative approaches to improve therapeutic outcome and avoid side effects. Marine organisms represent a reservoir of novel bioactive metabolites, but they are still less studied compared to their terrestrial counterparts. This review is focused on marine natural products with anticancer activity against hematological tumors, highlighting recent advances and possible perspectives. Until now, there are five commercially available marine-derived compounds for the treatment of various hematopoietic cancers (e.g., leukemia and lymphoma), two molecules in clinical trials, and series of compounds and/or extracts from marine micro- and macroorganisms which have shown promising properties. In addition, the mechanisms of action of several active compounds and extracts are still unknown and require further study. The continuous upgrading of omics technologies has also allowed identifying enzymes with possible bioactivity (e.g., l-asparaginase is currently used for the treatment of leukemia) or the enzymes involved in the synthesis of bioactive secondary metabolites which can be the target of heterologous expression and genetic engineering. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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31 pages, 16691 KiB

Open AccessReview

Comprehensive Overview on the Chemistry and Biological Activities of Selected Alkaloid Producing Marine-Derived Fungi as a Valuable Reservoir of Drug Entities

by Fadia S. Youssef and Jesus Simal-Gandara

Biomedicines 2021, 9(5), 485; https://doi.org/10.3390/biomedicines9050485 - 28 Apr 2021

Cited by 13 | Viewed by 3994

Abstract

Marine-associated fungal strains act as a valuable reservoir of bioactive diverse secondary metabolites including alkaloids which are highly popular by their biological activities. This review highlighted the chemistry and biology of alkaloids isolated from twenty-six fungal genera associated with marine organisms and marine sea sediments. The selected fungi are from different marine sources without focusing on mangroves. The studied fungal genera comprises Acrostalagmus, Arthrinium, Chaetomium, Cladosporium, Coniothyrium, Curvularia, Dichotomomyces, Eurotium, Eutypella, Exophiala, Fusarium, Hypocrea, Microsphaeropsis, Microsporum, Neosartorya, Nigrospora, Paecilomyces, Penicillium, Pleosporales, Pseudallescheria, Scedosporium, Scopulariopsis, Stagonosporopsis, Thielavia, Westerdykella, and Xylariaceae. Around 347 alkaloid metabolites were isolated and identified via chromatographic and spectroscopic techniques comprising 1D and 2D NMR (one and two dimensional nuclear magnetic resonance) which were further confirmed using HR-MS (high resolution mass spectrometry) and Mosher reactions for additional ascertaining of the stereochemistry. About 150 alkaloids showed considerable effect with respect to the tested activities. Most of the reported bioactive alkaloids showed considerable biological activities mainly cytotoxic followed by antibacterial, antifungal, antiviral, antioxidant; however, a few showed anti-inflammatory and antifouling activities. However, the rest of the compounds showed weak or no activity toward the tested biological activities and required further investigations for additional biological activities. Thus, alkaloids isolated from marine-associated fungi can afford an endless source of new drug entities that could serve as leads for drug discovery combating many human ailments. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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17 pages, 5739 KiB

Open AccessReview

Combined Proteotranscriptomic-Based Strategy to Discover Novel Antimicrobial Peptides from Cone Snails

by Anicet Ebou, Dominique Koua, Audrey Addablah, Solange Kakou-Ngazoa and Sébastien Dutertre

Biomedicines 2021, 9(4), 344; https://doi.org/10.3390/biomedicines9040344 - 29 Mar 2021

Cited by 10 | Viewed by 4161

Abstract

Despite their impressive diversity and already broad therapeutic applications, cone snail venoms have received less attention as a natural source in the investigation of antimicrobial peptides than other venomous animals such as scorpions, spiders, or snakes. Cone snails are among the largest genera (Conus sp.) of marine invertebrates, with more than seven hundred species described to date. These predatory mollusks use their sophisticated venom apparatus to capture prey or defend themselves. In-depth studies of these venoms have unraveled many biologically active peptides with pharmacological properties of interest in the field of pain management, the treatment of epilepsy, neurodegenerative diseases, and cardiac ischemia. Considering sequencing efficiency and affordability, cone snail venom gland transcriptome analyses could allow the discovery of new, promising antimicrobial peptides. We first present here the need for novel compounds like antimicrobial peptides as a viable alternative to conventional antibiotics. Secondly, we review the current knowledge on cone snails as a source of antimicrobial peptides. Then, we present the current state of the art in analytical methods applied to crude or milked venom followed by how antibacterial activity assay can be implemented for fostering cone snail antimicrobial peptides studies. We also propose a new innovative profile Hidden Markov model-based approach to annotate full venom gland transcriptomes and speed up the discovery of potentially active peptides from cone snails. Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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6 pages, 2733 KiB

Open AccessCorrection

Correction: Chen et al. Heteronemin Suppresses Lymphangiogenesis Through ARF-1 and MMP-9/VE-Cadherin/Vimentin. Biomedicines 2021, 9, 1109

by Hsien-Lin Chen, Yu-Chieh Su, Huang-Chi Chen, Jui-Hsin Su, Chang-Yi Wu, Shih-Wei Wang, In-Pin Lin, Chung-Yi Chen and Chien-Hsing Lee

Biomedicines 2024, 12(11), 2609; https://doi.org/10.3390/biomedicines12112609 - 15 Nov 2024

Viewed by 211

Abstract

Error in Affiliation [...] Full article

(This article belongs to the Special Issue Biomedicine from the Sea)

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