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Abstract

Marine organisms possess the capacity to produce a variety of unique and biologically potent natural products for treating human diseases, many of which are currently commercially available or are in advanced clinical trials. Here we provide a short review on progress in the field and discuss a case study of an EU-funded project, PharmaSea, which aims to discover novel products for the treatment of infections, inflammation and neurodegenerative diseases. Research in this sector is opening new doors for harnessing the potential of marine natural products with pharmaceutical properties.

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... The A549 (human alveolar carcinoma) lung cancer cell line is often used to investigate anticancer activity in vitro, enabling comparison between studies (Table 6). Significant inhibition of A549 proliferation has been shown using a recombinant tumor necrosis factor from the Pacific oyster (200 ng/mL) [247], crude methanol extracts of an intertidal snail Euchelus asper (40% inhibition at 10 µg/mL) [248], and lipid extract from a squid digestive gland (CC 50 260 µg/mL) [249] (Table 6). Liu et al. [250] tested extracts of Ampullarriidae, a family of freshwater snails used in TCM for epilepsy and stomach ache, reporting 31-57% inhibition of A549 between 20-200 µg/mL, and Zhang et al. [251] reports 73-96% inhibition using ethanol extracts of eight Chinese mollusc species, some of which are used in TCM [104]. ...
... In assays using a novel peptide (termed Mere15) from the Asiatic clam Meretrix meretrix (Veneridae), Wang et al. [252] found that A549 was more susceptible (IC 50 31.80 µg/mL) than other cancer (breast, colorectal, liver, pancreas; IC 50 43.5-57.4 µg/mL) and healthy (IC 50 123.1-149.5 µg/mL) cell lines ( Table 6). ...
... µg/mL) than other cancer (breast, colorectal, liver, pancreas; IC 50 43.5-57.4 µg/mL) and healthy (IC 50 123.1-149.5 µg/mL) cell lines ( Table 6). These results prompted the use of A549 in a mouse xenograft model, whereby 50 mg/kg Mere15 administered by subcutaneous injection inhibited tumor growth by 69%, an effect greater than (although statistically indifferent to) the control chemotherapeutic cyclophosphamide (53% inhibition at the same concentration) [252] (Table 7). ...
Article
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Respiratory diseases place an immense burden on global health and there is a compelling need for the discovery of new compounds for therapeutic development. Here, we identify research priorities by critically reviewing pre-clinical and clinical studies using extracts and compounds derived from molluscs, as well as traditional molluscan medicines, used in the treatment of respiratory diseases. We reviewed 97 biomedical articles demonstrating the anti-inflammatory, antimicrobial, anticancer, and immunomodulatory properties of >320 molluscan extracts/compounds with direct relevance to respiratory disease, in addition to others with promising bioactivities yet to be tested in the respiratory context. Of pertinent interest are compounds demonstrating biofilm inhibition/disruption and antiviral activity, as well as synergism with approved antimicrobial and chemotherapeutic agents. At least 100 traditional medicines, incorporating over 300 different mollusc species, have been used to treat respiratory-related illness in cultures worldwide for thousands of years. These medicines provide useful clues for the discovery of bioactive components that likely underpin their continued use. There is particular incentive for investigations into anti-inflammatory compounds, given the extensive application of molluscan traditional medicines for symptoms of inflammation, and shells, which are the principal molluscan product used in these preparations. Overall, there is a need to target research toward specific respiratory disease-related hypotheses, purify bioactive compounds and elucidate their chemical structures, and develop an evidence base for the integration of quality-controlled traditional medicines.
... Over the years, bioactive MNPs from different oceans have found many pharmaceutical applications, as said above, ranging from antitumoral to antimicrobials. Some drug examples include the nucleosides isolated in the 1950s from a Caribbean sponge, later used as scaffolds for commercial antiviral drugs [Ara-A (Acyclovir R ) or Ara-C], the analgesic ω-conotoxin analog ziconotide (Prialt R ) from a Conus mollusc used for chronic pain, ecteinascidin 743 (Yondelis R ) from a tunicate for cancer chemotherapy (sarcoma), and eribulin mesylate (Halaven R ), a derivative of halichondrin B from the cold-water sponge Halichondria okadai as an anticancer drug (Gerwick and Moore, 2012;Jaspars et al., 2016;Giordano et al., 2018). Many MNPs are commonly used in food industry as stabilizers and food additives, like the carrageenans from red seaweeds (Carragelose R ), also employed in antiviral sprays, or carotenoids, used as food colorants, additives, and nutraceuticals (Jaspars et al., 2016). ...
... Some drug examples include the nucleosides isolated in the 1950s from a Caribbean sponge, later used as scaffolds for commercial antiviral drugs [Ara-A (Acyclovir R ) or Ara-C], the analgesic ω-conotoxin analog ziconotide (Prialt R ) from a Conus mollusc used for chronic pain, ecteinascidin 743 (Yondelis R ) from a tunicate for cancer chemotherapy (sarcoma), and eribulin mesylate (Halaven R ), a derivative of halichondrin B from the cold-water sponge Halichondria okadai as an anticancer drug (Gerwick and Moore, 2012;Jaspars et al., 2016;Giordano et al., 2018). Many MNPs are commonly used in food industry as stabilizers and food additives, like the carrageenans from red seaweeds (Carragelose R ), also employed in antiviral sprays, or carotenoids, used as food colorants, additives, and nutraceuticals (Jaspars et al., 2016). The use of new enzymes is also of great interest for many industrial processes, like the proteases, amylases, cellulases, carboxymethylcellulases, xylanases,. . ...
... The use of new enzymes is also of great interest for many industrial processes, like the proteases, amylases, cellulases, carboxymethylcellulases, xylanases,. . ., for their use in the production of pharmaceuticals, foods, beverages, confectionery, paper, textile and leather processing, and waste-water treatment (Jaspars et al., 2016;Giordano et al., 2018). Cosmetics, on the other hand, include MNPs used as sun protectors, face, skin, and hair care products, such as Abyssine R , Depollutine R , Grevilline R , RefirMAR R , Resilience R , SeaCode R , XCELL-30 R , and others (Martins et al., 2014;Reen et al., 2015). ...
Article
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Antarctic marine benthic invertebrates are an underexplored source of natural products for biodiscovery. Bioactive marine natural products from Antarctica are reviewed here for their potential use as drugs, considering the main examples in Porifera (15 species), Cnidaria (eight species), Mollusca (one species), Bryozoa (one species), Nemertea (one species), Echinodermata (six species), and Tunicata (five species). A wide variety of bioactivities are reported here, from antitumoral to antimicrobial activities, as well as against neurodegenerative diseases and others. If we aim to use their chemodiversity for human benefits we must maintain the biodiversity, solving the supply problem, speeding up the process, and decreasing research costs to fully exploit the benefits of biodiscovery in Antarctic Marine Natural Products in a near future in a sustainable way.
... The A549 (human alveolar carcinoma) lung cancer cell line is often used to investigate anticancer activity in vitro, enabling comparison between studies (Table 6). Significant inhibition of A549 proliferation has been shown using a recombinant tumor necrosis factor from the Pacific oyster (200 ng/mL) [247], crude methanol extracts of an intertidal snail Euchelus asper (40% inhibition at 10 µg/mL) [248], and lipid extract from a squid digestive gland (CC 50 260 µg/mL) [249] (Table 6). Liu et al. [250] tested extracts of Ampullarriidae, a family of freshwater snails used in TCM for epilepsy and stomach ache, reporting 31-57% inhibition of A549 between 20-200 µg/mL, and Zhang et al. [251] reports 73-96% inhibition using ethanol extracts of eight Chinese mollusc species, some of which are used in TCM [104]. ...
... In assays using a novel peptide (termed Mere15) from the Asiatic clam Meretrix meretrix (Veneridae), Wang et al. [252] found that A549 was more susceptible (IC 50 31.80 µg/mL) than other cancer (breast, colorectal, liver, pancreas; IC 50 43.5-57.4 µg/mL) and healthy (IC 50 123.1-149.5 µg/mL) cell lines ( Table 6). ...
... µg/mL) than other cancer (breast, colorectal, liver, pancreas; IC 50 43.5-57.4 µg/mL) and healthy (IC 50 123.1-149.5 µg/mL) cell lines ( Table 6). These results prompted the use of A549 in a mouse xenograft model, whereby 50 mg/kg Mere15 administered by subcutaneous injection inhibited tumor growth by 69%, an effect greater than (although statistically indifferent to) the control chemotherapeutic cyclophosphamide (53% inhibition at the same concentration) [252] (Table 7). ...
Thesis
Identification of bioactive compounds (specifically, hemolymph proteins and brominated indoles) from marine molluscs to: i) inhibit bacterial planktonic log phase growth and biofilm formation in vitro and; ii) attenuate virus-mediated cell death and inflammatory markers in human lung epithelial cell lines
... Prochloron is able to synthesize various cyanobactins, which exhibit strong bioactivity and have been intensively studied with respect to their structural chemistry, catalytic properties and pharmacological application [22][23][24][25][26]. Here we focus on patellamides, which were discovered in 1981 by researchers in search of bioactive molecules for medical applications. ...
... Moreover, patellamide D was shown to reverse multidrug resistance in the human leukemic cell line, presumably by competitively binding to p-gp and by blocking transport proteins involved in causing drug resistance [50]. There is continuous interest in naturally occurring cyclic peptides for potential medical applications and while many bioactivity screening studies are performed with extracts from collected ascidian specimens, synthetic derivatives have also been extensively used [26,35,36,40,[51][52][53][54][55]. ...
Article
Full-text available
Patellamides are highly bioactive compounds found along with other cyanobactins in the symbiosis between didemnid ascidians and the enigmatic cyanobacterium Prochloron. The biosynthetic pathway of patellamide synthesis is well understood, the relevant operons have been identified in the Prochloron genome and genes involved in patellamide synthesis are among the most highly transcribed cyanobacterial genes in hospite. However, a more detailed study of the in vivo dynamics of patellamides and their function in the ascidian-Prochloron symbiosis is complicated by the fact that Prochloron remains uncultivated despite numerous attempts since its discovery in 1975. A major challenge is to account for the highly dynamic microenvironmental conditions experienced by Prochloron in hospite, where light-dark cycles drive rapid shifts between hyperoxia and anoxia as well as pH variations from pH ~6 to ~10. Recently, work on patellamide analogues has pointed out a range of different catalytic functions of patellamide that could prove essential for the ascidian-Prochloron symbiosis and could be modulated by the strong microenvironmental dynamics. Here, we review fundamental properties of patellamides and their occurrence and dynamics in vitro and in vivo. We discuss possible functions of patellamides in the ascidian-Prochloron symbiosis and identify important knowledge gaps and needs for further experimental studies.
... The hardest challenge is turning these products into useful drugs due to the high costs of releasing a new medicine to market from discovery through a clinical phase to approval. Another major challenge is to reduce the time taken to approve these products for use, which is nowadays approximately 10 years [189]. In addition, the extraction, isolation, and characterization of molecules from marine sources are crucial steps of drug discovery. ...
... Even so, research on compounds of marine origin for the treatment of AD should continue in the search for new drugs with significant neuroprotective activity. A better understanding of the potential health benefits from marine organisms, the compounds they produce, and the environmental conditions affecting their production will allow for the better management and sustainable development of these valuable marine resources in the future [189]. ...
Article
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Neurodegenerative diseases are sociosanitary challenges of today, as a result of increased average life expectancy, with Alzheimer’s disease being one of the most prevalent. This pathology is characterized by brain impairment linked to a neurodegenerative process culminating in cognitive decline and behavioral disorders. Though the etiology of this pathology is still unknown, it is usually associated with the appearance of senile plaques and neurofibrillary tangles. The most used prophylaxis relies on anticholinesterase drugs and NMDA receptor antagonists, whose main action is to relieve symptoms and not to treat or prevent the disease. Currently, the scientific community is gathering efforts to disclose new natural compounds effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been shown to be promising candidates, and some have been proven to exert a high neuroprotection effect, constituting a large reservoir of potential drugs and nutraceutical agents. The present article attempts to describe the processes of extraction and isolation of bioactive compounds derived from sponges, algae, marine bacteria, invertebrates, crustaceans, and tunicates as drug candidates against AD, with a focus on the success of pharmacological activity in the process of finding new and effective drug compounds.
... O uso medicinal de macroalgas na prevenção e cura de doenças, faz parte da cultura milenar dos países orientais. Historicamente as civilizações asiáticas têm usado as algas como medicamento fitoterápico desde 300 a.C. (Jaspars et al., 2016). Na Europa, na região do Mediterrâneo, os efeitos medicinais das algas são conhecidos desde a antiguidade. ...
... Os tratamentos de doenças que utilizam algas ou derivados de algas são muito diversos. Eles incluem tratamentos para câncer, problemas digestivos, hidropisia, eczema, problemas glandulares, bócio, gota, hipertireoidismo, infecção parasitária, doenças renais, entre outros (Jaspars et al., 2016). ...
... O uso medicinal de macroalgas na prevenção e cura de doenças, faz parte da cultura milenar dos países orientais. Historicamente as civilizações asiáticas têm usado as algas como medicamento fitoterápico desde 300 a.C. (Jaspars et al., 2016). Na Europa, na região do Mediterrâneo, os efeitos medicinais das algas são conhecidos desde a antiguidade. ...
... Os tratamentos de doenças que utilizam algas ou derivados de algas são muito diversos. Eles incluem tratamentos para câncer, problemas digestivos, hidropisia, eczema, problemas glandulares, bócio, gota, hipertireoidismo, infecção parasitária, doenças renais, entre outros (Jaspars et al., 2016). ...
Book
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This book aims to further contribute to the study of the practical and sustainable use of marine resources, balancing the demands for development with the those of critical environment protections. The objective of Volume 2 and it’s 18 chapters is to examine emerging topics related to the Bioecology, aquaculture and fishing. It will offer professors and students from various areas of discipline within the Sea Sciences in Brazil with the newest theoretical and scientific research to help us better contextualize the understanding of our seas and oceans.
... O uso medicinal de macroalgas na prevenção e cura de doenças, faz parte da cultura milenar dos países orientais. Historicamente as civilizações asiáticas têm usado as algas como medicamento fitoterápico desde 300 a.C. (Jaspars et al., 2016). Na Europa, na região do Mediterrâneo, os efeitos medicinais das algas são conhecidos desde a antiguidade. ...
... Os tratamentos de doenças que utilizam algas ou derivados de algas são muito diversos. Eles incluem tratamentos para câncer, problemas digestivos, hidropisia, eczema, problemas glandulares, bócio, gota, hipertireoidismo, infecção parasitária, doenças renais, entre outros (Jaspars et al., 2016). ...
... Significant academic national efforts in China, the USA, and Europe, coupled with private initiatives like Pharmamar in Spain have contributed to the collection of marine macro-and microorganisms from several regions around the world. The main objective was to discover new and high-value drugs from these organisms, with a special focus on anticancer agents [3][4][5]. Marine biodiscovery has focused largely on marine invertebrates, but this has recently shifted toward microorganisms that represent a much more diverse group, and thus opening new avenues for biotechnology and an efficient producer of bioactive metabolites [6]. ...
... For example, traditional medicine was integral to ancient societies and was used to treat various ailments and disease [17,18]. Interestingly, naturally inspired drugs remain important today and have greatly benefitted from advances in natural product chemistry and drug discovery, including from the marine environment [5]. ...
Chapter
The term “marine biodiscovery” has been recently been adopted to describe the area of marine natural products dedicated to the search of new drugs. Several maritime countries such as Australia, New Zealand, South Korea, and Japan as well as some European countries have invested significantly in this area of research over the last 50 years. In the late 2000s, research in this field has received significant interest and support in Ireland for exploring new marine bioresources from the nutrient-rich waters of the Northeastern Atlantic Ocean. Despite undeniable success exemplified by the marketing of new drugs, especially in oncology, the integration of new technical but also environmental aspects should be considered. Indeed, global change, particularly in our oceans, such as climate change, biodiversity loss, and the emergence of microbial pathogens, not only affects the environment but ultimately contributes to social inequalities. In this contribution, new avenues and best practices are proposed, such as the development of biorepositories and shared data for the future of marine biodiscovery research. The extension of this type of scientific work will allow humanity to finally make the optimum use of marine bioresources.
... O uso medicinal de macroalgas na prevenção e cura de doenças, faz parte da cultura milenar dos países orientais. Historicamente as civilizações asiáticas têm usado as algas como medicamento fitoterápico desde 300 a.C. (Jaspars et al., 2016). Na Europa, na região do Mediterrâneo, os efeitos medicinais das algas são conhecidos desde a antiguidade. ...
... Os tratamentos de doenças que utilizam algas ou derivados de algas são muito diversos. Eles incluem tratamentos para câncer, problemas digestivos, hidropisia, eczema, problemas glandulares, bócio, gota, hipertireoidismo, infecção parasitária, doenças renais, entre outros (Jaspars et al., 2016). ...
Chapter
O subfilo Crustacea (do Latim “crusta” = carapaça dura) está entre os animais mais conhecidos e apreciados pela população em geral e representam o grupo mais abundante, com maior diversidade e maior distribuição nos oceanos. Vivendo amplamente em ambientes marinhos, dulcícolas e terrestres, os crustáceos representam um dos grupos mais bem-sucedidos nos processos de adaptação às condições desses ambientes. São encontrados desde o supralitoral até às maiores profundezas dos oceanos (11.000 m de profundidade). Atualmente, existem aproximadamente 52 mil espécies marinhas descritas de um total de cerca de 72 mil (incluindo formas fósseis) distribuídas em mais de 1.000 famílias, com uma estimativa que possa existir entre 5 a 10 vezes mais espécies para serem descobertas, especialmente nos ambientes de mar profundo. Representam, portanto, um grupo muito diverso e com grande plasticidade morfológica, podendo medir desde 10 μm (Tantulocarida) até 4 m de envergadura de patas. Sua amplitude morfológica supera a dos insetos, como destacou Martin e Davis (2001): “nenhum grupo de plantas ou de animais no planeta apresenta a amplitude de diversidade morfológica observada entre os crustáceos”.
... O uso medicinal de macroalgas na prevenção e cura de doenças, faz parte da cultura milenar dos países orientais. Historicamente as civilizações asiá cas têm usado as algas como medicamento toterápico desde 300 a.C. (Jaspars et al., 2016). Na Europa, na região do Mediterrâneo, os efeitos medicinais das algas são conhecidos desde a an guidade. ...
... Os tratamentos de doenças que u lizam algas ou derivados de algas são muito diversos. Eles incluem tratamentos para câncer, problemas diges vos, hidropisia, eczema, problemas glandulares, bócio, gota, hiper reoidismo, infecção parasitária, doenças renais, entre outros (Jaspars et al., 2016). ...
... PharmaSea was an FP7-funded European marine biodiscovery consortium, consisting of 24 partners (non-profit organizations, academia, and SME) from 13 countries, that, from 2012 to 2017, explored oceans in search of novel antibiotic, anti-inflammatory, and neuroactive compounds isolated from marine microorganisms [1][2][3]. The interest to develop drugs of marine origin derives from the fact that marine species can produce unique secondary metabolites in terms of chemistry and bioactivity, as these organisms have evolved to Bioactivity-guided purification ( Figure 1) led to the identification of TMC-120A and TMC-120B, as previously described [3], and halimide, reported in this paper. ...
... The use of zebrafish embryos and larvae, a small vertebrate animal model, allows medium-throughput in vivo assessment of bioactivities using only microgram quantities [62]. This is a key advantage for (marine) natural product discovery and research, where material is often scarce [62,63] and was, therefore, used by PharmaSea for neuroactive drug discovery [1][2][3]. Other examples of zebrafish-based screening for active marine natural products can be found in [64,65]. ...
Article
Full-text available
PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin’s antiseizure action.
... Notwithstanding these difficulties, there is a general consensus that, in the near future, the marine environment will still be the most important source of novel bioactive compounds. In the last decades, there has been a 'renaissance' in marine drug discovery due to technological developments and the use of marine microbial genomics to provide biosynthetic pathways [337]. The technological advancements may help in exploring the great animal biodiversity in the sea, as most of the research on MNPs is concentrated on less than 1% of the invertebrate species, especially those living in shallow waters. ...
... The technological advancements may help in exploring the great animal biodiversity in the sea, as most of the research on MNPs is concentrated on less than 1% of the invertebrate species, especially those living in shallow waters. The accessibility of deep waters, up to 200 m in depth, via remotely operated vehicles, is expanding the range of collection of new species that can be of interest for the discovery of new MNPs [337]. In addition, up to now the bulk of investigation was carried out along the well-studied coasts of Europe and North America, whereas the remaining coastal environments of the planet are still scantily known. ...
Article
Full-text available
Aquatic invertebrates are a major source of biomaterials and bioactive natural products that can find applications as pharmaceutics, nutraceutics, cosmetics, antibiotics, antifouling products and biomaterials. Symbiotic microorganisms are often the real producers of many secondary metabolites initially isolated from marine invertebrates; however, a certain number of them are actually synthesized by the macro-organisms. In this review, we analysed the literature of the years 2010-2019 on natural products (bioactive molecules and biomaterials) from the main phyla of marine invertebrates explored so far, including sponges, cnidarians, molluscs, echinoderms and ascidians, and present relevant examples of natural products of interest to public and private stakeholders. We also describe omics tools that have been more relevant in identifying and understanding mechanisms and processes underlying the biosynthesis of secondary metabolites in marine invertebrates. Since there is increasing attention on finding new solutions for a sustainable large-scale supply of bioactive compounds, we propose that a possible improvement in the biodiscovery pipeline might also come from the study and utilization of aquatic invertebrate stem cells.
... Microalgae are a huge renewable and eco-friendly source of natural compounds, including vitamins, carbohydrates, pigments, sterols and lipids, presenting several bioactivities for biotechnological applications in the pharmaceutical, nutraceutical and cosmeceutical sectors [1][2][3], such as antiviral [4], antimicrobial [5], anti-inflammatory [4], immunomodulatory [6] and anticancer activities [5]. Microalgae are found in both marine and terrestrial habitats due to their ability to adapt and survive in very different environments. ...
Article
Full-text available
Haptophytes are important primary producers in the oceans, and among the phylum Haptophyta, the flagellate Isochrysis galbana has been found to be rich in high-value compounds, such as lipids, carotenoids and highly branched polysaccharides. In the present work, I. galbana was cultured and collected at both stationary and exponential growth phases. A transcriptomic approach was used to analyze the possible activation of metabolic pathways responsible for bioactive compound synthesis at the gene level. Differential expression analysis of samples collected at the exponential versus stationary growth phase allowed the identification of genes involved in the glycerophospholipid metabolic process, the sterol biosynthetic process, ADP-ribose diphosphatase activity and others. I. galbana raw extracts and fractions were tested on specific human cancer cells for possible antiproliferative activity. The most active fractions, without affecting normal cells, were fractions enriched in nucleosides (fraction B) and triglycerides (fraction E) for algae collected in the exponential growth phase and fraction E for stationary phase samples. Overall, transcriptomic and bioactivity data confirmed the activation of metabolic pathways involved in the synthesis of bioactive compounds giving new insights on possible Isochrysis applications in the anticancer sector.
... States to advance marine research and to improve the conservation of marine biodiversity within their own waters (and beyond) (Jaspars et al., 2016;IOC, 2017;Closek et al., 2019). ...
Article
Full-text available
Biological collections are fundamental to marine scientific research and understanding of biodiversity at various scales. Despite their key importance, sample collections and the institutes that house them are often underfunded and receive comparatively little attention in the discussions associated with global biodiversity agreements. Furthermore, access to collections can be limited by inadequate systems, infrastructure, and networks. With negotiations underway for a new implementing agreement on biodiversity beyond national jurisdiction, marine genetic resources (MGR), including questions on the sharing of benefits, remains the most debated and contentious element. Disparities remain between States regarding access to and utilization of marine biological samples (including MGR) from areas beyond national jurisdiction. Addressing capacity gaps related to collections could provide a point of agreement during negotiations and enhance global inclusivity in access to and utilization of MGR. Here, we examine both existing capacity and regional gaps in marine collections. We propose the strengthening of a distributed network of marine biological collections, building on existing initiatives and emphasizing best practices to bridge regional gaps. Our recommendations include: promoting scientific best practice for the curation of collections; alignment with ocean observing, and sampling initiatives; a potential pairing scheme for collections in developing and developed States; raising awareness of collections and benefits to marine science including through a global registry/directory; and promoting sustainable funding mechanisms to support collections and sustain global generation of contributors and users.
... The field of marine drug discovery has been growing over the past 20 years, with currently almost 35,000 research articles on natural products of marine origin [5]. This is also highlighted by the number of novel secondary metabolites being elucidated per year (1554 in 2018) and a significant number of marine-derived drug candidates under clinical trials or pending approval [6][7][8]. Table 1. Information on taxonomy of sponge-associated isolates according to BLAST searches of their partial 16S rRNA gene sequences against nr/nt NCBI database and genome characteristics. ...
Article
Full-text available
Marine sponges harbor diverse microbial communities that represent a significant source of natural products. In the present study, extracts of 21 sponge-associated bacteria were screened for their antimicrobial and anticancer activity, and their genomes were mined for secondary metabolite biosynthetic gene clusters (BGCs). Phylogenetic analysis assigned the strains to four major phyla in the sponge microbiome, namely Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes. Bioassays identified one extract with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity, and more than 70% of the total extracts had a moderate to high cytotoxicity. The most active extracts were derived from the Proteobacteria and Actinobacteria, prominent for producing bioactive substances. The strong bioactivity potential of the aforementioned strains was also evident in the abundance of BGCs, which encoded mainly beta-lactones, bacteriocins, non-ribosomal peptide synthetases (NRPS), terpenes, and siderophores. Gene-trait matching was performed for the most active strains, aiming at linking their biosynthetic potential with the experimental results. Genetic associations were established for the anti-MRSA and cytotoxic phenotypes based on the similarity of the detected BGCs with BGCs encoding natural products with known bioactivity. Overall, our study highlights the significance of combining in vitro and in silico approaches in the search of novel natural products of pharmaceutical interest.
... • Known unknowns. The potential for marine genetic resources to spur novel technological advances, including tools to combat climate change, depends on basic research, exploration, and taxonomy with uncertain timelines and prospects for success (Jaspars et al., 2016). With the majority of marine life still uncharacterized, quantifying the full value of intact deep-sea ecosystems for current and future generations is challenging (e.g., potential impacts of deep-seabed mining to marine ecosystems, as well as benefits and risks to humankind). ...
... Marine genetic resources include the genetic information marine organisms host enabling them to produce a wide range of biochemicals (Jaspars et al., 2016) that can benefit humankind through applications of biodiscovery of pharmaceutical compounds, cosmetics, food supplements, research tools, and in industrial processes (Blasiak et al., 2020a,b;Harden-Davies, 2020). They also include adaptive solutions found in deep-sea organisms that can also inspire novel materials and structural designs (e.g., light conductance and protective materials; Sundar et al., 2003;Yao et al., 2010). ...
Article
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Growing human activity in areas beyond national jurisdiction (ABNJ) is driving increasing impacts on the biodiversity of this vast area of the ocean. As a result, the United Nations General Assembly committed to convening a series of intergovernmental conferences (IGCs) to develop an international legally-binding instrument (ILBI) for the conservation and sustainable use of marine biological diversity of ABNJ [the biodiversity beyond national jurisdiction (BBNJ) agreement] under the United Nations Convention on the Law of the Sea. The BBNJ agreement includes consideration of marine genetic resources (MGR) in ABNJ, including how to share benefits and promote marine scientific research whilst building capacity of developing states in science and technology. Three IGCs have been completed to date with the fourth delayed by the Covid pandemic. This delay has allowed a series of informal dialogues to take place between state parties, which have highlighted a number of areas related to MGR and benefit sharing that require technical guidance from ocean experts. These include: guiding principles on the access and use of MGR from ABNJ; the sharing of knowledge arising from research on MGR in ABNJ; and capacity building and technology transfer for developing states. In this paper, we explain what MGR are, the methods required to collect, study and archive them, including data arising from scientific investigation. We also explore the practical requirements of access by developing countries to scientific cruises, including the sharing of data, as well as participation in research and development on shore whilst promoting rather than hindering marine scientific research. We outline existing infrastructure and shared resources that facilitate access, research, development, and benefit sharing of MGR from ABNJ; and discuss existing gaps. We examine international capacity development and technology transfer schemes that might facilitate or complement non-monetary benefit sharing activities. We end the paper by highlighting what the ILBI can achieve in terms of access, utilization, and benefit sharing of MGR and how we might future-proof the BBNJ Agreement with respect to developments in science and technology.
... In 1969, the first MNP was approved by the Food and Drug Administration (FDA) for leukemia treatment, which also was the first marine-derived anticancer agent to be developed for clinical use, named cytarabine (Ara-C), and commercialized as Cytosar ® by the company Pfizer. The active compound is a synthetic analog of a C-nucleoside isolated from the Caribbean sponge Cryptotethya crypta and is in use today to treat acute myelocytic leukemia and non-Hodgkin's lymphoma [12,26]. Regarding its mechanism of action, cytarabine acts by inhibiting the DNA polymerase. ...
Article
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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.
... [20] Very few therapeutic biochemical acquired from algae have been successfully marketed and many are underneath clinical trials. [21] Hence, the assessment of such properties endures a motivating and worthwhile task, mainly for discovering innovative sources of natural antioxidants. ...
... The marine environment and the organisms living within it are being increasingly exploited as a source of natural defense metabolites and bioactive compounds [1][2][3]. Within marine organisms, jellyfish, particularly scyphomedusae, are raising increasing interest as a source of compounds for biotechnological applications [4][5][6]. Generally considered a nuisance, particularly during their sudden and massive appearances (blooms), because they interfere with human activities at sea along the coasts (e.g., tourism, fisheries and industries) by stinging swimmers, damaging fishing gears and caught fish as well as clogging power plant water inflows [7], jellyfish have been an important part of the diet of eastern populations, particularly the Chinese [8]. ...
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Jellyfish are commonly considered a nuisance for their negative effects on human activities (e.g., fisheries, power plants and tourism) and human health. However, jellyfish provide several benefits to humans and are commonly eaten in eastern countries. Additionally, recent studies have suggested that jellyfish may become a source of high-value molecules. In this study, we tested the effects of the methanolic extracts and enriched fractions, obtained by solid-phase extraction fractionation, from the scyphomedusae Pelagia noctiluca, Rhizostoma pulmo, Cotylorhiza tuberculata and the cubomedusa Caryddea marsupialis on different human cancer cell lines in order to evaluate a potential antiproliferative activity. Our results indicated that fraction C from Caryddea marsupialis-(CM) and C. tuberculata oral arms (CTOA) were the most active to reduce cell viability in a dose-dependent manner. LC/MS based dereplication analyses highlighted that both bioactive fractions contained mainly fatty acids and derivatives, with CM additionally containing small peptides (0.7–0.8 kDa), which might contribute to its higher biological activity. The mechanism of action behind the most active fraction was investigated using PCR arrays. Results showed that the fraction C of CM can reduce the expression of genes involved in apoptosis inhibition in melanoma-treated cells, which makes jellyfish a potential new source of antiproliferative drugs to be exploited in the future.
... Marine genetic resources include the genetic information marine organisms host enabling them to produce a wide range of biochemicals (Jaspars et al., 2016) that can benefit humankind through applications of biodiscovery of pharmaceutical compounds, cosmetics, food supplements, research tools, and in industrial processes (Blasiak et al., 2020a,b;Harden-Davies, 2020). They also include adaptive solutions found in deep-sea organisms that can also inspire novel materials and structural designs (e.g., light conductance and protective materials; Sundar et al., 2003;Yao et al., 2010). ...
... Thus, it is a conjoint reflection for marine imitative bioactive molecules and enzymes to harbours peculiar features. In addition to that, the cellular biosynthetic machinery is unsurprisingly reformed for survival under hostile environments featuring anoxygenic, hypersaline, barophilic and sometimes sulphur-rich habitats, where none of the ordinary enzymes of terrestrial origin is executable (Jaspars et al. 2016; Baria et al. 2020). ...
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In the current scenario, considerable attention is being given to the enzyme L-glutaminase (EC 3.5.1.2). It belongs to the amidohydrolase class adherent to the family of serine-reliant β-lactamases and the penicillin-binding proteins due to its higher affinity to polymerize and modify peptidoglycan synthesis. However, based on the catalytic proficiency, L-glutaminase is characterized as a proteolytic endopeptidase that cleaves peptide linkage and emancipates various byproducts, viz. ammonia along with glutamate. L-glutamine is considered the key amino acid reportedly involved in multiple metabolic pathways such as nitrogen metabolism. The present review is focused on the recent development and aspects concomitant to the biotechnological applicability of L-glutaminase predominantly from the marine habitat. Additionally, a majority of L-glutaminases finds application in cancer therapy as therapeutic agents, especially for acute lymphocytic leukaemia. The in vitro studies have been effective against various human cancer cell lines. L-glutaminase enhances the growth of probiotic bacteria. Apart from all these applications, it is suitably applicable in fermented foods as a flavour enhancer especially the umami flavour and content. Marine habitats have largely been exploited for their bio-catalytic potential but very scarcely for therapeutic enzymes. Some of the reports of such marine bacterial isolates from Bacillus sp., Pseudomonas sp. and Vibrio sp. are in the domain, but none highlights the therapeutic applications predominantly as anticancer and anti-proliferative agents. Key points The exploration of marine habitats along the Gujarat coasts mainly for bacteria secreting L-glutaminase is scarcely reported, and even more scarce are the amidohydrolases from these marine niches as compared to their terrestrial counterparts. Microbial sourced amidohydrolase has wide bio-applicability that includes food, cosmetics and therapeutics especially as anticancer/anti-proliferative agent making it of immense biotechnological significance.
... The demand for newer bioactive compounds is increased and many researchers have shown their interest in innovative approaches to launch the competitive products in the market, having marine origin [143]. At present 23 marine compounds (Table 3) are reported as anti-cancer out of 26 marine compounds which are under clinical trials, also 4 drugs are approved for their anticancer property [144]. ...
Article
It is a major concern to treat cancer successfully, due to the distinctive pathophysiology of cancer cells and the gradual manifestation of resistance. Specific action, adverse effects and development of resistance has prompted the urgent requirement of exploring alternative anti-tumour treatment therapies. The naturally derived microbial toxins as a therapy against cancer cells are a promisingly new dimension. Various important microbial toxins such as Diphtheria toxin, Vibrio cholera toxin, Aflatoxin, Patulin, Cryptophycin-55, Chlorella are derived from several bacterial, fungal and algal species. These agents act on different biotargets such as inhibition of protein synthesis, reduction in cell growth, regulation of cell cycle and many cellular processes. Bacterial toxins produce actions primarily by targeting protein moieties and some immunomodulation and few acts through DNA. Fungal toxins appear to have more DNA damaging activity and affect the cell cycle. Algal toxins produce alteration in mitochondrial phosphorylation. In conclusion, microbial toxins and their metabolites appear to have a great potential to provide a promising option for the treatment and management to combat cancer.
... There are more than 100 types of cancer, and this is why it is considered a conglomerate of diseases and not a single disease, with the disadvantage that it can spread all over the human body via metastasis. The number of cases in Europe (EU-27 countries) rose to approximately 3 million new cases registered in 2020 according to the European Cancer Observatory. 1 The demand for new drugs for the treatment of cancer diseases has triggered a growing interest in marine sources for the biodiscovery of new molecules with the potential to become anticancer drugs (Jaspars et al., 2016;Romano et al., 2017). Among all marine sources with potential in drug discovery, marine microalgae represent a poorly explored resource for drug discovery but with huge potential for their exploitation (Mimouni et al., 2012;Samarakoon et al., 2013;Lauritano et al., , 2018Lauritano et al., , 2019Lauritano et al., , 2020Lauritano and Ianora, 2016;Park et al., 2017;Brillatz et al., 2018;Giordano et al., 2018;Martínez Andrade et al., 2018;Guzmán et al., 2019;Riccio et al., 2020a,b;Riccio and Lauritano, 2020;Saide et al., 2020). ...
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Dunaliella tertiolecta is a green flagellated microalga with a high tolerance to salinity and high production of pigments such as zeaxanthin, a xanthophyll carotenoid present in higher plants known for its antioxidant potential. In the current study, the antiproliferative activity of raw extracts and fractions of D. tertiolecta (clone CCMP 1320) was evaluated against four different human cancer cell lines: melanoma, hepatocellular liver carcinoma, and two lung adenocarcinoma cell lines. In addition, a normal cell line (lung fibroblast) was used as toxicity control. The activity was evaluated by treatment with the extracts/fractions following the MTT colorimetric assay procedures. HPLC-UV-HRMS based dereplication helped to identify the bioactive metabolites. A glycoglycerolipid was identified in the active fraction, being involved in the bioactivity of this microalga. This compound, glycerol 1-(9 Z ,12 Z ,15 Z -octadecatrienoate)-2-(4 Z ,7 Z ,10 Z ,13 Z -hexadecatetraenoate)-3- O -β-D-galactopyranoside ( 1 ), was purified and its antiproliferative activity was confirmed. This work gives new insights on the antiproliferative activity of the green alga D. tertiolecta and its potential industrial applications.
... Therefore, we interested to explore the potential of compounds contained in natural substances as SARS-CoV-2 main protease inhibitors, here we specifically identify marine natural products in marine organisms namely sponges (Clathria Sp.). Marine organism since ancient times has been used in traditional medicine, but currently research on its activity as a drug still underdeveloped (Jaspars et al., 2016), while the novelty of the marine natural products tends to be higher than terrestrial natural products (Products, 2011). Clathria is a genus of the family Microconidia with 544 species, which one of the species can be found in the Province of Southeast Sulawesi, Indonesia (Sahidin et al., 2019). ...
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The target for COVID-19 has been successfully crystallized along with its inhibitor, named SARS-CoV-2 main protease, making it easier for drug discovery and development. Sponge (Clathria Sp.) is a marine species that can be found in Indonesia and has a unique chemical structure that is still rarely explored in its properties. Therefore, this study aims to examined the potential of marine natural products from sponge (Clathria Sp.) as SARS-CoV-2 main protease inhibitor using in silico method. The ligand structures were obtained from the Knapsack database and the protein structure obtained from the RCSB site with the PDB code: 6LU7. The molecular docking method was validated by re-docked the native ligand and calculated the RMSD value. The compounds contained in Sponge were docked into the active site of the protein based on the validated methods. Afterward, the molecular dynamics were performed for 100 ns simulation, then analyzed its system complex stability. The RMSD 1.329 Å was obtained by re-docked of native ligand which indicates that the docking method was valid. Molecular docking of the ligands showed mirabilin_G has binding energy −7.38 kcal/mol, compared to the native ligand N3 inhibitor that is −7.30 kcal/mol, and the ligand showed good stability from molecular dynamics simulation indicated by RMSD, RMSF and MM-PBSA binding free energy similar to the inhibitor during 100 ns simulation. Its indicated the potential of the compounds contained in the sponge as inhibitor of SARS-CoV-2 main protease. Communicated by Ramaswamy H. Sarma
... accessed on 20 November 2020). This is also highlighted by the number of novel secondary metabolites being elucidated per year (1554 in 2018) and a significant number of marine-derived drug candidates under clinical trials or pending approval(Mayer et al., 2010;Hu et al., 2015;Jaspars et al., 2016). Despite the intensive research effort, the marine environment can be considered rather underexplored for prospecting bioactive molecules in comparison with terrestrial ecosystems(Hughes and Fenical, 2010;Santos et al., 2020a). ...
... The first compound used for drug production was cytarabine (marketed name, Cytosar-U ® ) that derived from Caribbean marine sponge, spongian nucleoside, in 1959 and approved for cancer in 1969, and then vidarabine approved in 1979 as antiviral (Martins et al. 2014). In totally, eight natural product-derived drugs have been approved by Food and Drug Administration (FDA) and/or the European Medical Agency (EMA) that the origin of two drugs is marine peptides (Jaspars et al. 2016;Jimenez et al. 2020). In recent years, increased desire to study biological and pharmaceutical properties of peptides has been observed, so that over 60 peptides are as market drug and many peptides are in clinical pipeline, too (Arumugam et al. 2019). ...
Chapter
Marine organisms contain valuable chemical compounds as secondary metabolites such as bioactive peptides that survive in harsh marine environments produced by organisms. They have been considered by scientists for use in medicine and pharmaceutical researches due to their unique and unknown biological properties. Studies on a variety of marine-derived peptides have shown that these compounds as antimicrobial, antiviral, antioxidant, antihypertensive, and anticancer agents can be useful in the treatment of various diseases. While many marine peptides are in various phases of clinical trials, two marine peptide-derived drugs have been approved by the Food and Drug Administration (FDA), too. This chapter highlights the recent two decades of researches on the biological properties of peptides derived from a variety of living organisms, including microbes, plants, and marine animals, in vivo, vitro, and clinical trials and their potential for disease treatment.
... Despite the large number of new natural products from marine fungi, Plinabulin (diketopiperazine class) is the only one isolated from a marine fungus (Aspergillus sp.) that is currently under clinical trials by BeyondSpring Pharmaceuticals [165]. This compound is currently in the late-stage of a world-wide phase III clinical trial for anticancer therapy of non-small cell lung cancer and for the reduction of chemotherapy-induced neutropenia [166]. Despite the research efforts towards marine fungi, most studies are focused only on the description of new natural compounds with in vitro biological activities. ...
Article
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Marine fungi play a crucial role in energy flow and nutrient recycling, mediating the cycling of dissolved organic matter in marine environments. However, despite being a prolific group of organisms, marine fungi have been largely neglected for a long time. Besides their importance in the marine food web, marine fungi represent an active source of natural products. Over the last years, researchers have focused on studying marine organisms to discover new metabolites with antibacterial, antiviral, and anticancer activities. Moreover, with the advances in high-throughput sequencing technologies and mass spectrometry techniques, genomic and metabolomic approaches have revealed to be of paramount importance in natural products discovery. The marine mycobiome includes many organisms still to be identified, and the ones already known are still underutilized in biotechnological applications. For this reason, it is undeniable that exploring the marine mycobiome including new habitats and substrates, even those of remote access, is fundamental for describing the true magnitude of the Earth’s mycobiome.
... To date, the global pharmaceutical pipeline from marine sources consists of thirteen approved drugs, ten of which are anticancer drugs (Table 17.1). Currently, there are about 23 marine natural products or antibody-drug conjugates in Phase I to Phase III clinical trials mainly in the area of cancer therapy (Jaspars et al. 2016; https://www.midwestern.edu/departments/marinepharmacology/clinical-pipe line.xml). ...
Chapter
Marine-associated microbiome is known as a hub for novel chemistry and biology by producing interesting pharmacophores. Thus, in the area of natural product drug discovery, contribution and attention toward marine natural product investigation is a growing trend. The rapid swift in exploring the sea for harvest untapped plethora of marine resources to investigate associated microorganisms such as bacteria, fungi, and cyanobacteria are facilitated by technological advances. This chapter discusses the importance of chemical diversity of the marine microbiome in the natural product drug discovery pipeline giving specific reported examples of promising marine-derived bioactive candidates, as well as intriguing strategies to ramp up the discovery of pharmacologically inspiring secondary metabolites out of the marine microbial biosynthesis process.
... Cytarabine (Cytosar-U ® , Ara-C, DepoCyt ® ), an anticancer medication derived from the Caribbean sponge Tethya crypta, is used to treat acute myelocytic leukemia and non-Hodgkin's lymphoma [155,156]. ET-743 (Yondelis ® ), derived from the tunicate Ecteinascidia turbinata, is approved for the treatment of tissue sarcomas and ovarian cancer, and eribulin (Halaven ® ), derived from the sponge Halichondria okadai [157], is approved for the treatment of metastatic breast cancer and advanced liposarcoma. Marine compounds like ziconotide (Prialt ® ), obtained from the cone snail Conus magus is used to treat severe and chronic pain [158], and vidarabine (Ara-A), isolated from the sponge Tethya crypta is used to treat herpes simplex infections [159]. ...
Article
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Background The marine environment hosts a wide variety of species that have evolved to live in harsh and challenging conditions. Marine organisms are the focus of interest due to their capacity to produce biotechnologically useful compounds. They are promising biocatalysts for new and sustainable industrial processes because of their resistance to temperature, pH, salt, and contaminants, representing an opportunity for several biotechnological applications. Encouraged by the extensive and richness of the marine environment, marine organisms’ role in developing new therapeutic benefits is heading as an arable field. Main body of the abstract There is currently much interest in biologically active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Studies are focused on bacteria and fungi, isolated from sediments, seawater, fish, algae, and most marine invertebrates such as sponges, mollusks, tunicates, coelenterates, and crustaceans. In addition to marine macro-organisms, such as sponges, algae, or corals, marine bacteria and fungi have been shown to produce novel secondary metabolites (SMs) with specific and intricate chemical structures that may hold the key to the production of novel drugs or leads. The marine environment is known as a rich source of chemical structures with numerous beneficial health effects. Presently, several lines of studies have provided insight into biological activities and neuroprotective effects of marine algae, including antioxidant, anti-neuroinflammatory, cholinesterase inhibitory activity, and neuronal death inhibition. Conclusion The application of marine-derived bioactive compounds has gained importance because of their therapeutic uses in several diseases. Marine natural products (MNPs) display various pharmaceutically significant bioactivities, including antibiotic, antiviral, neurodegenerative, anticancer, or anti-inflammatory properties. The present review focuses on the importance of critical marine bioactive compounds and their role in different diseases and highlights their possible contribution to humanity.
... Marine organisms are able to produce metabolites with bioactivities useful for the treatment or prevention of human pathologies (127)(128)(129)(130). There are currently on the market fourteen compounds derived from marine species used for various types of cancer (such as multiple myeloma, leukemia, lymphoma, breast, ovarian, lung and urothelial cancer), hypertriglyceridemia, pain and infections (https://www. ...
Article
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Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients.
... One of these derives from the deep sea ( Figure 3). Ziconotide (Prialt ® ) is a synthetic calcium channel-binding conotoxin isolated from the sea snail Conus magus living at depths greater than 1000 m, used for the treatment of severe pain (it was approved by the FDA in 2004) [18]. In 2015, an anticancer agent isolated from the tunicate Ecteinascidia turbinate, sampled at 289 m depth, was FDA approved as trabectedin (Yondelis ® ) for the treatment of soft tissue sarcomas and ovarian cancer [19]. ...
Article
The deep-sea environment is a unique, challenging extreme habitat where species have had to adapt to the absence of light, low levels of oxygen, high pressure and little food. In order to survive such harsh conditions, these organisms have evolved different biochemical and physiological features that often have no other equivalent in terrestrial habitats. Recent analyses have highlighted how the deep sea is one of the most diverse and species-rich habitats on the planet but less explored compared to more accessible sites. Because of their adaptation to this extreme environment, deep-sea species have the potential to produce novel secondary metabolites with potent biological activities. Recent advances in sampling and novel techniques in microorganism culturing and chemical isolation have promoted the discovery of bioactive agents from deep-sea organisms. However, reports of natural products derived from deep-sea species are still scarce, probably because of the difficulty in accessing deep-sea samples, sampling costs and the difficulty in culturing deep-sea organisms. In this review, we give an overview of the potential treasure represented by metabolites produced by deep marine species and their bioactivities for the treatment and prevention of various human pathologies.
... Molecular structure of suberitenones A (1) and B (2), and mycalols(3)(4)(5)(6)(7)(8)(9). ...
Article
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Sponges are known to produce a series of compounds with bioactivities useful for human health. This study was conducted on four sponges collected in the framework of the XXXIV Italian National Antarctic Research Program (PNRA) in November-December 2018, i.e., Mycale (Oxymycale) acerata, Haliclona (Rhizoniera) dancoi, Hemimycale topsenti, and Hemigellius pilosus. Sponge extracts were fractioned and tested against hepatocellular carcinoma (HepG2), lung carcinoma (A549), and melanoma cells (A2058), in order to screen for antiproliferative or cytotoxic activity. Two different chemical classes of compounds, belonging to mycalols and suberitenones, were identified in the active fractions. Mycalols were the most active compounds, and their mechanism of action was also investigated at the gene and protein levels in HepG2 cells. Of the differentially expressed genes, ULK1 and GALNT5 were the most down-regulated genes, while MAPK8 was one of the most up-regulated genes. These genes were previously associated with ferroptosis, a programmed cell death triggered by iron-dependent lipid peroxidation, confirmed at the protein level by the down-regulation of GPX4, a key regulator of ferroptosis, and the up-regulation of NCOA4, involved in iron homeostasis. These data suggest, for the first time, that mycalols act by triggering ferroptosis in HepG2 cells.
... Marine organisms living in extreme environments experience conditions close to the limit of life, e.g., polar and hot regions, deep sea, hydrothermal vents, marine areas of high pressure or high salinity. They have evolved unique strategies for surviving in these harsh conditions, as well as biosynthesizing novel bioactive compounds, which are potentially useful for pharmaceutical, cosmeceutical, nutraceutical, and biotechnological applications [2]. Research on extreme environments often requires complex and expensive infrastructure, as well as access. ...
Article
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Marine organisms are known to produce a wide variety of natural products that are unique in terms of diversity, structural, and functional properties [...]
... In the market, there are seven drugs which are marine-based and four of these are for anticancer. With nearly twenty-six marine-based natural products in clinical trials, twenty-three are for cancer therapeutics (Jaspars et al., 2016;Martínez Andrade et al., 2018). ...
Article
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This study evaluated the cytotoxic activity of Tamoxifen (TMX), an anti-estrogen drug, with microalgal crude extracts (MCEs) in single and synergistic application (TMX-MCEs) on MCF-7 and 4T1 breast cancer cells, and non-cancerous Vero cells. The MCEs of Nannochloropsis oculata, Tetraselmis suecica and Chlorella sp. from five different solvents (methanol, MET; ethanol, ETH; water, W; chloroform, CHL; and hexane, HEX) were developed. The TMX-MCEs-ETH and W at the 1:2 and 1:3 ratios, attained IC50 of 15.84-29.51 μg/mL against MCF-7; 13.8-31.62 μg/mL against 4T1; and 24.54-85.11 μg/mL against Vero cells. Higher late apoptosis was exhibited against MCF-7 by the TMX-N. oculata-ETH (41.15 %); and by the TMX-T. suecica-ETH (65.69 %) against 4T1 cells. The TMX-T. suecica-ETH also showed higher ADP/ATP ratios, but comparable Caspase activities to control. For Vero cells, overall apoptotic effects were lowered with synergistic application, and only early apoptosis was higher with TMX-T. suecica-ETH but at lower levels (29.84 %). The MCEs-W showed the presence of alanine, oleic acid, linoleic acid, lactic acid, and fumaric acid. Based on Principle Component Analysis (PCA), the spectral signals for polar solvents such as MET and ETH, were found in the same cluster, while the non-polar solvent CHL was with HEX, suggesting similar chemical profiles clustered for the same polarity. The CHL and HEX were more effective with N. oculata and T. suecica which were of the marine origin, while the ETH and MET were more effective with Chlorella sp., which was of the freshwater origin. The synergistic application of microalgal bioactive compounds with TMX can maintain the cytotoxicity against breast cancer cells whilst reducing the toxicity against non-cancerous Vero cells. These findings will benefit the biopharmaceutical, and functional and healthy food industries.
... Over 60% of the current anti-tumor drug molecules under clinical trials are derived from natural sources (Smyrniotopoulos et al., 2019). Most of the marine biomolecules are sourced from macro-organisms such as sponges, but due to difficulties in culturing and sustainability led to major bottlenecks for product development (Jaspars et al., 2016). Unicellular protists like diatoms can biosynthesize, accumulate, metabolize, and secrete an array of primary and secondary metabolites with potential applications in food, pharmaceutical, nutraceutical and biofuel industry (Lauritano et al., 2016). ...
Article
Marine diatoms are unique reservoirs of bioactive compounds having enormous applications in therapeutics. But high-throughput screening methods are needed to elucidate the interaction between numerous biomolecules and their targets, facilitating rapid screening for novel drug molecules. So, in the present study chemical constituents were extracted from five marine diatoms using un-targeted metabolite profiling and in-silico virtual screening bioinformatics was employed to predict their bioactivity and molecular targets. A total of 17 chemical constituents out of 51 showed interactions with 76 protein targets associated with 213 pathways. Ingredient-target-pathway network revealed oleic acid, linoleic acid and cholest-5-en-3-ol as major active constituents. Core subnetwork and protein association network showed involvement of these compounds in key metabolic pathways related to cell signaling, cell growth and metabolism of xenobiotics. Thus, the present study for the first time revealed the main active ingredients and their associated pathways from marine diatoms using complex network approach.
... Some of the marine algal strains are reported to have higher number of secondary metabolites like alkaloids, terpenes, steroids, polyketides, Phenolic compounds, tannins, fucoidans and polyphenols. These secondary metabolites can reduce the risk of chronic disorders such as cancer [5]. Hence, in this review we will focus on micro algal bioactive compounds and their potentialactivities on different cancer cells. ...
... Therefore, due to these oceanic peculiarities, natural marine products are more robust and bioactive than those of their terrestrial counterparts, thus having a higher chance of drug discovery [34]. The ocean, being the greatest biodiversity on earth, represents a treasure trove of new beneficial natural products [35,36]. These ranges of natural products can be obtained from invertebrates and marine microorganisms. ...
Article
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Microbial secondary metabolites are an important source of antibiotics currently available for combating drug-resistant pathogens. These important secondary metabolites are produced by various microorganisms, including Actinobacteria. Actinobacteria have a colossal genome with a wide array of genes that code for several bioactive metabolites and enzymes. Numerous studies have reported the isolation and screening of millions of strains of actinomycetes from various habitats for specialized metabolites worldwide. Looking at the extent of the importance of actinomy-cetes in various fields, corals are highlighted as a potential hotspot for untapped secondary metab-olites and new bioactive metabolites. Unfortunately, knowledge about the diversity, distribution and biochemistry of marine actinomycetes compared to hard corals is limited. In this review, we aim to summarize the recent knowledge on the isolation, diversity, distribution and discovery of natural compounds from marine actinomycetes associated with hard corals. A total of 11 new species of actinomycetes, representing nine different families of actinomycetes, were recovered from hard corals during the period from 2007 to 2022. In addition, this study examined a total of 13 new compounds produced by five genera of actinomycetes reported from 2017 to 2022 with antibacterial, antifungal and cytotoxic activities. Coral-derived actinomycetes have different mechanisms of action against their competitors.
Article
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This study aimed to assess the diversity and antimicrobial activity of cultivable bacteria associated with Vietnamese sponges. In total, 460 bacterial isolates were obtained from 18 marine sponges. Of these, 58.3% belonged to Proteobacteria, 16.5% to Actinobacteria, 18.0% to Firmicutes, and 7.2% to Bacteroidetes. At the genus level, isolated strains belonged to 55 genera, of which several genera, such as Bacillus, Pseudovibrio, Ruegeria, Vibrio, and Streptomyces, were the most predominant. Culture media influenced the cultivable bacterial composition, whereas, from different sponge species, similar cultivable bacteria were recovered. Interestingly, there was little overlap of bacterial composition associated with sponges when the taxa isolated were compared to cultivation-independent data. Subsequent antimicrobial assays showed that 90 isolated strains exhibited antimicrobial activity against at least one of seven indicator microorganisms. From the culture broth of the isolated strain with the strongest activity (Bacillus sp. M1_CRV_171), four secondary metabolites were isolated and identified, including cyclo(L-Pro-L-Tyr) (1), macrolactin A (2), macrolactin H (3), and 15,17-epoxy-16-hydroxy macrolactin A (4). Of these, compounds 2-4 exhibited antimicrobial activity against a broad spectrum of reference microorganisms.
Thesis
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This thesis investigates if public international law manages to function as a coherent system in the case of deep-sea bioprospecting, where rules in three regimes provide seemingly inconsistent obligations for states. Based on an investigation of the development of bioprospecting and patenting of deep-sea genetic resources, the study explores how rules in the United Nations Convention on the Law of the Sea (UNCLOS), the Convention on Biological Diversity (CBD) and the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (WTO TRIPS) apply to such activities. It is illustrated how rules of these treaties provide different and seemingly inconsistent obligations for states in the context of deep-sea bioprospecting. This is explained by their origin in different regimes of public international law with distinctively dissimilar perspectives on the appropriation of genetic resources. It is discussed how the prima facie norm conflict in some cases can be resolved on the basis of the principles on treaty application and interpretation under the Vienna Convention on the Law of Treaties. In other cases, such as the obligations for bioprospecting of deep-seabed micro-organisms, states are faced with an irreconcilable dilemma; the different treaty obligations cannot be simultaneously applied. In order to prevent such conflicts and ensure the credibility of international law as a functioning system, new approaches are suggested, in particular the development of holistic conflict clauses and lex specialis. The case of deep-sea bioprospecting calls for a more state-oriented perspective in the debate on the fragmentation of international law.
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COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material obtained from marine species, including griffithsin, plitidepsin and fingolimod are in clinical trials to evaluate their anti-SARS-CoV-2 and anti-HIV efficacies. The current review highlights the anti-SARS-CoV-2 potential of marine-derived phytochemicals explored using in silico, in vitro and in vivo models. The current literature suggests that these molecules have the potential to bind with various key drug targets of SARS-CoV-2. In addition, many of these agents have anti-inflammatory and immunomodulatory potentials and thus could play a role in the attenuation of COVID-19 complications. Overall, these agents may play a role in the management of COVID-19, but further preclinical and clinical studies are still required to establish their role in the mitigation of the current viral pandemic.
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The prevalence of antimicrobial resistance reduces the effectiveness of antimicrobial drugs in preventing and treating infectious diseases caused by pathogenic organisms, such as bacteria, fungi, and viruses. Because of the burgeoning growth of microbes with antimicrobial-resistant traits, there is a dire need to identify and develop novel and effective antimicrobial agents to treat infections from antimicrobial-resistant strains. The marine environment is rich in ecological biodiversity and can be regarded as an untapped resource for prospecting novel bioactive compounds. Therefore, exploring the marine environment for antimicrobial agents plays a significant role in drug development and biomedical research. Several earlier scientific investigations have proven that bacterial diversity in the marine environment represents an emerging source of structurally unique and novel antimicrobial agents. There are several reports on marine bacterial secondary metabolites, and many are pharmacologically significant and have enormous promise for developing effective antimicrobial drugs to combat microbial infections in drug-resistant pathogens. In this review, we attempt to summarize published articles from the last twenty-five years (1996–2020) on antimicrobial secondary metabolites from marine bacteria evolved in marine environments, such as marine sediment, water, fauna, and flora.
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Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ±1.08 μM, respectively. Subsequently, cellular mechanism study suggested that b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.
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Fucosterol, a sterol isolated from brown algae, has been demonstrated to have anti-cancer properties. However, the effects and underlying molecular mechanism of fucosterol on non-small cell lung cancer remain to be elucidated. In this study, the corresponding targets of fucosterol were obtained from PharmMapper, and NSCLC related targets were gathered from the GeneCards database, and the candidate targets of fucosterol-treated NSCLC were predicted. The mechanism of fucosterol against NSCLC was identified in DAVID6.8 by enrichment analysis of GO and KEGG, and protein–protein interaction data were collected from STRING database. The hub gene GRB2 was further screened out and verified by molecular docking. Moreover, the relationship of GRB2 expression and immune infiltrates were analyzed by the TIMER database. The results of network pharmacology suggest that fucosterol acts against candidate targets, such as MAPK1, EGFR, GRB2, IGF2, MAPK8, and SRC, which regulate biological processes including negative regulation of the apoptotic process, peptidyl-tyrosine phosphorylation, positive regulation of cell proliferation. The Raf/MEK/ERK signaling pathway initiated by GRB2 showed to be significant in treating NSCLC. In conclusion, our study indicates that fucosterol may suppress NSCLC progression by targeting GRB2 activated the Raf/MEK/ERK signaling pathway, which laying a theoretical foundation for further research and providing scientific support for the development of new drugs.
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Beneficial marine microorganisms are not only of significance for the production of useful variety of substances, but also perform unique roles in element cycles with animals and plants. Beneficial marine microorganisms have been recognized as a repository of useful beneficial biomolecules with several industrial applications. Moreover, there are several challenges that mitigate against the successful determination of these molecules of special interest as well as the detection of these beneficial microorganisms from the microbial marine environments, biological and biodiversity. The application of molecular biology techniques are valuable methods for evaluating the biodiversity and biological characteristics of marine bacterial communities and its biomolecules. These techniques are generally adopted for two different types of bacterial species such as the culturable and nonculturable bacteria. Therefore, this chapter intends to explore the industrial relevance of several compounds derived from marine environment. These molecules and bioactive peptides have been identified to perform diverse biological functions such as antimicrobial activity, antioxidant activity, antihypertensive activity, anticancer activity, and anti-inflammatory activity, respectively. Moreover, more emphasis was placed on the different types of methods that could be utilized for evaluating different types of marine bioactive peptides such as organic synthesis, chemical hydrolysis, microwave-assisted extraction, and enzyme hydrolysis, respectively. Also, the modes of action of these biologically active compounds were highlighted.
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Marine natural products (MNPs) provide an ample source of pharmacologically bioactive compounds with great chemical diversity and complexity. Peptide-derived MNPs are a class of compounds with diverse and interesting biological properties, such as antiinfective, anticancer, cytotoxic, and antiallodynic. Their biosynthetic production machinery from the ribosomal origin or non-ribosomal origin and the hybrid with other compounds confer these compounds remarkable diversity in terms of structural complexity as well as biological activity. The interest in these peptide compounds is their potential to produce valuable therapeutics and pharmaceuticals. Some of these peptides or their derivatives have reached the pharmaceutical market, while some are currently under clinical trials for developing new drugs. This review focuses on marine peptide-based compounds in advanced drug development for clinical use or pharmaceutical applications. The drug development process and clinical status of ribosomal peptides, non-ribosomal peptides and their hybrids, or the derivatives, are hereby described.
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Marine organisms have developed physiological and biochemical strategies to survive under the exposure of UV-B radiation. In particular, Antarctic marine bacteria, exposed to extremes of temperature, UV and ice, have adapted to cope with UV radiation by producing photoprotective molecules. Here, we describe (1) the sampling strategy to collect marine samples (surface water/ice and sediment samples) and (2) the selection strategy to isolate in these samples only UV-resistant marine bacteria.
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The demand for new alternatives is very high in the cosmetic world and hence it provides a new dimension of opportunities. Marine resources play a pivotal role in the field of cosmetic industry. The macronutrients (proteins, amino acids, carbohydrates, and lipids) and micronutrients (copper, zinc, iron, etc.) are richly present in marine organisms. These ingredients serve properties in photoprotection, anti-aging along with antioxidant potential. Yet more exploration is called for optimization of production and extraction of the active ingredients from marine resources. Also, more research is claimed to ensure the effectiveness and safety of new components for cosmetic applications.
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The marine environment offers an extensive source of secondary metabolites with promising biological activities to start drug discovery processes. Marine polyketides are a class of compounds with diverse and interesting biological properties. Their biosynthetic production mechanism of versatile assembly confers these compounds remarkable diversity both in terms of structural complexity and biological activity. This review focuses on marine aliphatic polyketides or mixed non-ribosomal peptide-polyketide compounds in advanced drug discovery stages. The isolation, drug development process, supply sources and clinical status of these polyketide or mixed peptide-polyketide compounds, as well as their potential as drug candidates, is hereby described.
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This review covers the literature published in 2013 for marine natural products (MNPs), with 982 citations (644 for the period January to December 2013) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1163 for 2013), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.
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The first marine natural products that served as leads or scaffolds for medicines were discovered in the middle of last century: the arabinosyl glycosides from the marine sponge Tectitethya crypta. Synthesis and modifications of the natural molecules generated antiviral and antileukemic drugs developed in the 1970’s and in the following decades, including the first effective treatment against HIV infection. With the improvement of techniques for the elucidation of chemical structure of the molecules, as well for chemical synthesis, especially from the 1990’s, there was an increase in the number of bioactive natural products characterized from marine organisms. New chemical structures with high specificity towards molecular targets in cells allowed the development of new drugs with indication for the treatment of several illnesses, from cancer to new antibiotics, and even neurological disorders. Currently there are at least 13 molecules derived from marine natural products on advanced clinical trials, and nine were approved to be used as medicines. Considering that in the past eight years, more than 1,000 new compounds from marine organisms were described, per year, the expectation is that many more drugs will be derived from marine natural products in a near future.
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Nowadays the global tendency towards physical activity reduction and an augmented dietary intake of fats, sugars and calories is leading to a growing propagation of overweight, obesity and lifestyle-related diseases, such diabetes, hypertension, dyslipidemia and metabolic syndrome. In particular, obesity, characterized as a state of low-level inflammation, is a powerful determinant both in the development of insulin resistance and in the progression to type 2 diabetes. A few molecular targets offer hope for anti-obesity therapeutics. One of the keys to success could be the induction of uncoupling protein 1 (UCP1) in abdominal white adipose tissue (WAT) and the regulation of cytokine secretions from both abdominal adipose cells and macrophage cells infiltrated into adipose tissue. Anti-obesity effects of fucoxanthin, a characteristic carotenoid, exactly belonging to xanthophylls, have been reported. Nutrigenomic studies reveal that fucoxanthin induces UCP1 in abdominal WAT mitochondria, leading to the oxidation of fatty acids and heat production in WAT. Fucoxanthin improves insulin resistance and decreases blood glucose levels through the regulation of cytokine secretions from WAT. The key structure of anti-obesity effect is suggested to be the carotenoid end of the polyene chromophore, which contains an allenic bond and two hydroxyl groups. Fucoxanthin, which can be isolated from edible brown seaweeds, recently displayed its many physiological functions and biological properties. We reviewed recent studies and this article aims to explain essential background of fucoxanthin, focusing on its promising potential anti-obesity effects. In this respect, fucoxanthin can be developed into promising marine drugs and nutritional products, in order to become a helpful functional food.
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The peer-reviewed marine pharmacology literature from 2009 to 2011 is presented in this review, following the format used in the 1998-2008 reviews of this series. The pharmacology of structurally-characterized compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacological activities were reported for 102 marine natural products. Additionally, 60 marine compounds were observed to affect the immune and nervous system as well as possess antidiabetic and anti-inflammatory effects. Finally, 68 marine metabolites were shown to interact with a variety of receptors and molecular targets, and thus will probably contribute to multiple pharmacologicalclasses upon further mechanism of action studies. Marine pharmacology during 2009-2011 remained a global enterprise, with researchers from 35 countries, and the United States, contributing to the preclinical pharmacology of 262 marine compounds which are part of the preclinical pharmaceutical pipeline. Continued pharmacological research with marine natural products will contribute to enhance the marine pharmaceutical clinical pipeline, which in 2013 consisted of 17 marine natural products, analogs or derivatives targeting a limited number of disease categories.
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A bioassay guided fractionation of the ethyl acetate extract from culture broths of the strain Streptomyces zhaozhouensis CA-185989 led to the isolation of three new polycyclic tetramic acid macrolactams (1–3) and four known compounds. All the new compounds were structurally related to the known Streptomyces metabolite ikarugamycin (4). Their structural elucidation was accomplished using a combination of electrospray-time of flight mass spectrometry (ESI-TOF MS) and 1D and 2D NMR analyses. Compounds 1–3 showed antifungal activity against Aspergillus fumigatus, Candida albicans and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).
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As long ago as the sixteenth century, Paracelsus recognized that 'the dose makes the poison'. Indeed, environmental concentrations of pharmaceuticals excreted by humans are limited, most importantly because a defined dose is given to just a fraction of the population. By contrast, recent studies have identified direct emission from drug manufacturing as a source of much higher environmental discharges that, in some cases, greatly exceed toxic threshold concentrations. Because production is concentrated in specific locations, the risks are not linked to usage patterns. Furthermore, as the drugs are not consumed, metabolism in the human body does not reduce concentrations. The environmental risks associated with manufacturing therefore comprise a different, wider set of pharmaceuticals compared with those associated with risks from excretion. Although pollution from manufacturing is less widespread, discharges that promote the development of drug-resistant microorganisms can still have global consequences. Risk management also differs between production and excretion in terms of accountability, incentive creation, legal opportunities, substitution possibilities and costs. Herein, I review studies about industrial emissions of pharmaceuticals and the effects associated with exposure to such effluents. I contrast environmental pollution due to manufacturing with that due to excretion in terms of their risks and management and highlight some recent initiatives.
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Marine microorganisms continue to be a source of structurally and biologically novel compounds with potential use in the biotechnology industry. The unique physiochemical properties of the marine environment (such as pH, pressure, temperature, osmolarity) and uncommon functional groups (such as isonitrile, dichloroimine, isocyanate, and halogenated functional groups) are frequently found in marine metabolites. These facts have resulted in the production of bioactive substances with different properties than those found in terrestrial habitats. In fact, the marine environment contains a relatively untapped reservoir of bioactivity. Recent advances in genomics, metagenomics, proteomics, combinatorial biosynthesis, synthetic biology, screening methods, expression systems, bioinformatics, and the ever increasing availability of sequenced genomes provides us with more opportunities than ever in the discovery of novel bioactive compounds and biocatalysts. The combination of these advanced techniques with traditional techniques, together with the use of dereplication strategies to eliminate known compounds, provides a powerful tool in the discovery of novel marine bioactive compounds. This review outlines and discusses the emerging strategies for the biodiscovery of these bioactive compounds.
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With the adoption of the Nagoya Protocol in 2010, an additional legal instrument under the Convention on Biological Diversity (1992), the legal landscape surrounding the access to and utilization of genetic resources will change. This is likely to impact working procedures for scientists, turning pre-existing ethics into legal obligations. The aim of this article is to inform scientists on the global access and benefit-sharing framework which has been set by the Convention on Biological Diversity and its Nagoya Protocol, focusing specifically on their application to marine genetic resources for which the United Nations Convention on the Law of the Sea (1982) also has relevance.
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The marine environment harbors a number of macro and micro organisms that have developed unique metabolic abilities to ensure their survival in diverse and hostile habitats, resulting in the biosynthesis of an array of secondary metabolites with specific activities. Several of these metabolites are high-value commercial products for the pharmaceutical and cosmeceutical industries. The aim of this review is to outline the paths of marine natural products discovery and development, with a special focus on the compounds that successfully reached the market and particularly looking at the approaches tackled by the pharmaceutical and cosmetic companies that succeeded in marketing those products. The main challenges faced during marine bioactives discovery and development programs were analyzed and grouped in three categories: biodiversity (accessibility to marine resources and efficient screening), supply and technical (sustainable production of the bioactives and knowledge of the mechanism of action) and market (processes, costs, partnerships and marketing). Tips to surpass these challenges are given in order to improve the market entry success rates of highly promising marine bioactives in the current pipelines, highlighting what can be learned from the successful and unsuccessful stories that can be applied to novel and/or ongoing marine natural products discovery and development programs.
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Carotenoids constitute a ubiquitous group of isoprenoid pigments. They are very efficient physical quenchers of singlet oxygen and scavengers of other reactive oxygen species. Carotenoids can also act as chemical quenchers undergoing irreversible oxygenation. The molecular mechanisms underlying these reactions are still not fully understood, especially in the context of the anti- and pro-oxidant activity of carotenoids, which, although not synthesized by humans and animals, are also present in their blood and tissues, contributing to a number of biochemical processes. The antioxidant potential of carotenoids is of particular significance to human health, due to the fact that losing antioxidant-reactive oxygen species balance results in "oxidative stress", a critical factor of the pathogenic processes of various chronic disorders. Data coming from epidemiological studies and clinical trials strongly support the observation that adequate carotenoid supplementation may significantly reduce the risk of several disorders mediated by reactive oxygen species. Here, we would like to highlight the beneficial (protective) effects of dietary carotenoid intake in exemplary widespread modern civilization diseases, i.e., cancer, cardiovascular or photosensitivity disorders, in the context of carotenoids' unique antioxidative properties.
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The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.
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Although metastatic breast cancer remains essentially incurable, many patients previously treated with an anthracycline, taxane, and capecitabine are relatively fit and keen to receive further therapy. Several drugs are used in this setting, but with little evidence of clinically relevant benefit, and none have previously shown improved survival. Eribulin (Halaven®) is a nontaxane tubulin-binding agent with a novel mode of action, and was recently approved by the European Medicines Agency and US Food and Drug Agency as a single agent for patients with heavily pretreated metastatic breast cancer. This review provides an overview of the discovery, and preclinical and clinical development of eribulin, culminating in the recently published EMBRACE metastatic breast cancer study.
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Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.
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The chemical investigation of the recently described Mediterranean Homoscleromorpha sponge Oscarella balibaloi revealed an original family of five closely related glucosylated sesterterpenes 1-4, named balibalosides. Their structure elucidation was mainly inferred from NMR and HRMS data analyses. Balibalosides differ by the pattern of acetyl substitutions on the three sugar residues linked to the same aglycone sesterterpenoid core. From a biosynthetic perspective, these compounds may represent intermediates in the pathways leading to more complex sesterterpenes frequently found in Dictyoceratida, a sponge Order belonging to Demospongiae, a clade which is phylogenetically distinct from the Homoscleromorpha. While steroid and triterpenoid saponins were already well known from marine sponges, balibalosides are the first examples of glycosilated sesterterpenes.
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The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade® ) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid® ), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
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Covering: 2010. Previous review: Nat. Prod. Rep., 2011, 28, 196. This review covers the literature published in 2010 for marine natural products, with 895 citations (590 for the period January to December 2010) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1003 for 2010), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.
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Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed-Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration.
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The diversity of life is one of the most striking aspects of our planet; hence knowing how many species inhabit Earth is among the most fundamental questions in science. Yet the answer to this question remains enigmatic, as efforts to sample the world's biodiversity to date have been limited and thus have precluded direct quantification of global species richness, and because indirect estimates rely on assumptions that have proven highly controversial. Here we show that the higher taxonomic classification of species (i.e., the assignment of species to phylum, class, order, family, and genus) follows a consistent and predictable pattern from which the total number of species in a taxonomic group can be estimated. This approach was validated against well-known taxa, and when applied to all domains of life, it predicts ~8.7 million (± 1.3 million SE) eukaryotic species globally, of which ~2.2 million (± 0.18 million SE) are marine. In spite of 250 years of taxonomic classification and over 1.2 million species already catalogued in a central database, our results suggest that some 86% of existing species on Earth and 91% of species in the ocean still await description. Renewed interest in further exploration and taxonomy is required if this significant gap in our knowledge of life on Earth is to be closed.
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Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hopedto be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.
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Recent advances in genomics and genome sequencing technologies provide a wealth of DNA sequence data that sheds new light on the causes of epilepsy. Animal models help to elucidate the biological significance of such disease-associated DNA sequence variation by enabling functional relationships between disease genotypes and phenotypes to be defined. Here I review the unique combination of attributes that is allowing the zebrafish to play increasingly prominent roles in investigating the mechanisms underlying epilepsy and in discovering new drugs to treat this condition. New techniques for genome editing now allow the zebrafish genome to be engineered to recapitulate key elements of the patterns of genomic variation that are observed in epilepsy patients. Moreover, a sophisticated range of imaging technologies enables spatio-temporal patterns of neural activity to be visualised in the intact zebrafish nervous system with single-cell levels of resolution. These technologies, together with refined techniques tor electrophysiological analysis and non-invasive modulation of specific neuronal circuit functions, allow the impacts of defined genetic variation on in vivo patterns of neural activity to be analysed in unprecedented depth. The pharmacological tractability of the zebrafish, and the amenability of its embryonic and larval stages to high throughput phenotype analysis, are also enabling advances in anti-epileptic drug discovery. Combining such pharmacological screening approaches with new tools for genome editing, live imaging, electrophysiology, conditional manipulation of circuit activity and behavioural analysis of zebrafish, could facilitate step changes in both understanding of epileptogenesis and in vivo discovery of new and improved anti-epileptic drugs. Copyright © 2015. Published by Elsevier B.V.
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Journal of Antibiotics, official journal of the Japan Antibiotics Research Association, is a print and online publication that focuses on research on antibiotics and related types of medicinal substances
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Conopeptides are the peptidic components of the venoms of marine cone snails from the Conus genus. Aside from their natural function in pharmacologically immobilizing prey, they have attracted the attention of drug designers in recent years because of their potency and selectivity at a range of pharmaceutically important targets in mammals, including ion channels and neurotransmitter transporters. One conopeptide, MVIIA (ziconotide, Prialt®), is on the market for the treatment of intractable neuropathic pain and others are in preclinical or clinical development. This article provides an overview of recent developments in the conopeptide field, with particular reference to their potential applications as drugs for the treatment of pain. Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
Article
New antitumor polyether macrolides were successfully isolated from a marine sponge, Halichondria okadai Kadota. One of them, halichondrin B exhibited remarkable in vivo antitumor activity. Physiological properties and structures of these compounds are reported. The structures have been characterized by a long-straight carbon chain, a polyether macrolide, and a novel 2,6,9-trioxatricyclo left bracket 3. 3. 2. 0**3,**7 right bracket decane system which is the first example in natural products.
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Drug discovery methods often rely on in vitro assays to identify compounds with specific types of biochemical activity, but predicting how a psychoactive drug will affect behavior requires direct testing of candidate compounds in animal models. Rihel et al. devised a high-throughput screen to identify compounds that affect rest-wake activity in zebrafish larvae and quantify the behavioral effects. They sorted the compounds into clusters based on their “behavioral fingerprint,” a set of behavioral changes elicited by each compound. Analysis of the data revealed that compounds that elicit similar behavioral changes often affect the same molecular targets or pathways, and compounds of similar structure produced similar behavioral effects in vivo. The authors were able to use the data set to predict the biological targets of uncharacterized compounds based on those of well-characterized compounds with which they cluster in the behavioral fingerprint analysis. The screen demonstrated that many aspects of neuropharmacology are conserved between mammals and zebrafish, so this model might also be useful for biochemically characterizing the regulation and pharmacology of complex behaviors. The results also suggested additional pathways that might be involved in modulating rest-wake activities. For example, several anti-inflammatory compounds increased wakeful activity during the day but not at night, suggesting that anti-inflammatory signaling pathways not only increase sleep in response to infection but also modulate daytime activity under normal conditions. These findings might enable researchers to predict biological targets or behavioral effects of novel compounds based on structural or biochemical aspects shared with well-characterized drugs, and they may also inform rational drug design.
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Licensed to kill: A new antibiotic, anthracimycin, produced by a marine-derived actinomycete in saline culture, shows significant activity toward Bacillus anthracis, the bacterial pathogen responsible for anthrax infections. Chlorination of anthracimycin gives a dichloro derivative that retains activity against Gram-positive bacteria, like anthrax, but also shows activity against selected Gram-negative bacteria.
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The declining trends in microbial metabolite and natural products research and the refocusing of this research area are discussed. Renewing natural products research requires inexhaustible natural resources, as well as new genetic techniques and microbial sources, including endophytic microbes. The numbers of known bioactive metabolites are summarized according to their microbiological origin, biological activities and chemical structures. Synthetic and natural product-based libraries are also compared. Importantly, the wide range of microbial metabolite bioactivities, future trends and the importance of prioritizing natural products over synthetic compounds are emphasized.
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The global marine pharmaceutical pipeline consists of three Food and Drug Administration (FDA) approved drugs, one EU registered drug, 13 natural products (or derivatives thereof) in different phases of the clinical pipeline and a large number of marine chemicals in the preclinical pipeline. In the United States there are three FDA approved marine-derived drugs, namely cytarabine (Cytosar-U®, Depocyt®), vidarabine (Vira-A®) and ziconotide (Prialt®). The current clinical pipeline includes 13 marine-derived compounds that are either in Phase I, Phase II or Phase III clinical trials. Several key Phase III studies are ongoing and there are seven marine-derived compounds now in Phase II trials. The preclinical pipeline continues to supply several hundred novel marine compounds every year and those continue to feed the clinical pipeline with potentially valuable compounds. From a global perspective the marine pharmaceutical pipeline remains very active, and now has sufficient momentum to deliver several additional compounds to the marketplace in the near future; this review provides a current view of the pipeline.
Article
Marine life forms are an important source of structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. These success stories have had to overcome difficulties inherent to natural products-derived drugs, such as adequate sourcing of the agent and issues related to structural complexity. Nevertheless, several marine-derived agents are now approved, most as "first-in-class" drugs, with five of seven appearing in the past few years. Additionally, there is a rich pipeline of clinical and preclinical marine compounds to suggest their continued application in human medicine. Understanding of how these agents are biosynthetically assembled has accelerated in recent years, especially through interdisciplinary approaches, and innovative manipulations and re-engineering of some of these gene clusters are yielding novel agents of enhanced pharmaceutical properties compared with the natural product.
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Patients with advanced or metastatic non-gastrointestinal stromal tumour soft tissue sarcoma (STS) whose disease progresses during or after chemotherapy with doxorubicin or ifosfamide have few options and very limited life expectancy. In this setting, the DNA and transcription interacting agent trabectedin (ecteinascidin-743), isolated originally from the tunicate Ecteinascidia turbinata, has encouraging activity and is now approved in the European Union. To review evidence for the efficacy of trabectedin in STSs. This review includes material known to the authors through preclinical and clinical work with trabectedin, and information from relevant papers and abstracts. Pooled analysis of Phase II studies suggests that around 50% of STS patients, failing conventional chemotherapy, experienced long lasting tumour control (either objective response or stabilization of disease) when treated with trabectedin. Twenty-nine per cent of patients were alive at 2 years, and median overall survival was 10.3 months. Leiomyosarcomas and liposarcomas appear particularly sensitive to the drug. In myxoid and round-cell liposarcomas trabectedin seems exceptionally active. A link between specific translocations underlying this disease and the drug's mechanism of action is being explored. Trabectedin is also active in synovial, ewing sarcoma and other translocation-related STSs. Trabectedin is not cardio- or neurotoxic. The neutropenia and hepatic toxicity that occur are non-cumulative, reversible, and lessened by steroid premedication. The lack of cumulative toxicities could make trabectedin appropriate for prolonged treatment. The potential of trabectedin should be further explored in STSs in general and in specific subtypes, both in combination with other cytotoxic agents and with modulators of intracellular signalling.
Article
Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt (ziconotide, omega-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis) (trabectedin, ET-743) an antitumor agent scovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.
Article
The objective of the present work was to describe an aerobic, mesophilic and heterotrophic marine bacterium, designated HYD657, able to produce an exopolysaccharide (EPS). It was isolated from a East Pacific Rise deep-sea hydrothermal vent polychaete annelid. This micro-organism, on the basis of the phenotypical features and genotypic investigations, can be clearly assigned to the Alteromonas macleodii species and the name A. macleodii subsp. fijiensis biovar deepsane is proposed. Optimal growth occurs between 30 and 35 degrees C, at pH between 6.5 and 7.5 and at ionic strengths between 20 and 40 g x l(-1) NaCl. The G + C content of DNA was 46.5%. This bacterium excreted, under laboratory conditions, an EPS consisting of glucose, galactose, rhamnose, fucose and mannose as neutral sugars along with glucuronic and galacturonic acids and a diacidic hexose identified as a 3-0-(1 carboxyethyl)-D-glucuronic acid. Its average molecular mass was 1.6 x 10(6) Da. The bacterium HYD657, for which the name A. macleodii subsp. fijiensis biovar deepsane is proposed, produces an unusual EPS in specific medium. Due to its interesting biological activities, applications have been found in cosmetics. Its probable contribution to the filamentous microbial mat in the Alvinella pompejana microenvironment can be also mentioned.