Interpreting the Possible Ecological Role(s) of Cyanotoxins: Compounds for Competitive Advantage and/or Physiological Aide?

To date, most research on freshwater cyanotoxin(s) has focused on understanding the dynamics of toxin production and decomposition, as well as evaluating the environmental conditions that trigger toxin production, all with the objective of informing management strategies and options for risk reduction. Comparatively few research studies have considered how this information can be used to understand the broader ecological role of cyanotoxin(s), and the possible applications of this knowledge to the management of toxic blooms. This paper explores the ecological, toxicological, and genetic evidence for cyanotoxin production in natural environments. The possible evolutionary advantages of toxin production are grouped into two main themes: That of “competitive advantage” or “physiological aide”. The first grouping illustrates how compounds produced by cyanobacteria may have originated from the need for a cellular defence mechanism, in response to grazing pressure and/or resource competition. The second grouping considers the contribution that secondary metabolites make to improved cellular physiology, through benefits to homeostasis, photosynthetic efficiencies, and accelerated growth rates. The discussion also includes other factors in the debate about possible evolutionary roles for toxins, such as different modes of exposures and effects on non-target (i.e., non-competitive) species. The paper demonstrates that complex and multiple factors are at play in driving evolutionary processes in aquatic environments. This information may provide a fresh perspective on managing toxic blooms, including the need to use a “systems approach” to understand how physico-chemical conditions, as well biological stressors, interact to trigger toxin production.     

Indole Alkaloids of the Stigonematales (Cyanophyta): Chemical Diversity,Biosynthesis and Biological Activity

The cyanobacteria are well recognized as producers of a wide array of bioactive metabolites including toxins, and potential drug candidates. However, a limited number of taxa are generally considered with respect to both of these aspects. That said, the order Stigonematales, although largely overlooked in this regard, has become increasingly recognized as a source of bioactive metabolites relevant to both human and environmental health. In particular, the hapalindoles and related indole alkaloids (i.e., ambiguines, fischerindoles, welwitindolinones) from the order, represent a diverse, and phylogenetically characteristic, class of secondary metabolites with biological activity suggestive of potential as both environmental toxins, and promising drug discovery leads. The present review gives an overview of the chemical diversity of biologically active metabolites from the Stigonematales—and particularly the so-called hapalindole-type alkaloids—including their biosynthetic origins, and their pharmacologically and toxicologically relevant bioactivities. Taken together, the current evidence suggests that these alkaloids, and the associated cyanobacterial taxa from the order, warrant future consideration as both potentially harmful (i.e., “toxic”) algae, and as promising leads for drug discovery.     

Mycosporine-like amino acids and marine toxins--the common and the different

Marine microorganisms harbor a multitude of secondary metabolites. Among these are toxins of different chemical classes as well as the UV-protective mycosporine-like amino acids (MAAs). The latter form a group of water-soluble, low molecular-weight (generally < 400) compounds composed of either an aminocyclohexenone or an aminocyclohexenimine ring, carrying amino acid or amino alcohol substituents. So far there has been no report of toxicity in MAAs but nevertheless there are some features they have in common with marine toxins. Among the organisms producing MAAs are cyanobacteria, dinoflagellates and diatoms that also synthesize toxins. As in cyclic peptide toxins found in cyanobacteria, amino acids are the main building blocks of MAAs. Both, MAAs and some marine toxins are transferred to other organisms e.g. via the food chains, and chemical modifications can take place in secondary consumers. In contrast to algal toxins, the physiological role of MAAs is clearly the protection from harmful UV radiation by physical screening. However, other roles, e.g. as osmolytes and antioxidants, are also considered. In this paper the common characteristics of MAAs and marine toxins are discussed as well as the differences.     

Potential of cyanobacteria for biorational management of plant parasitic nematodes: A review

Cyanobacteria or blue green algae are prokaryotic oxygenic phototrophs that require little moisture and diffused light for growth and are ubiquitous in nature. Both the heterocystous and non-heterocystous forms of cyanobacteria are reported to produce a large number of compounds with varying bioactivities including toxins such as microcystins, nodularins and neurotoxins. Extracts and exudates of cyanobacteria have been reported to inhibit hatching and to cause immobility and mortality of juvenile plant parasitic nematodes in vitro. Application of cyanobacteria in soil may reduce nematode infestation and increase plant yield. There are reports of several cyanobacterial formulations that are being developed and tested against plant pathogens but none have been commercialised. Screening of extracts or metabolites against plant parasitic nematodes is the initial step to determine the usefulness of cyanobacteria for nematode management. Therefore, a large scale screening programme is necessary for selection of strains with greater nematicidal potential. The nitrogen fixation abilities of some species of cyanobacteria also render them useful as biofertilizers. A combination of nitrogen fixation and nematode suppressive attributes can provide a dual advantage in several crops. Future research is needed in this direction to exploit these organisms for biorational management of plant parasitic nematodes.     

On the Chemistry,Toxicology and Genetics of the Cyanobacterial Toxins,Microcystin, Nodularin,Saxitoxin and Cylindrospermopsin

The cyanobacteria or “blue-green algae”, as they are commonly termed, comprise a diverse group of oxygenic photosynthetic bacteria that inhabit a wide range of aquatic and terrestrial environments, and display incredible morphological diversity. Many aquatic, bloom-forming species of cyanobacteria are capable of producing biologically active secondary metabolites, which are highly toxic to humans and other animals. From a toxicological viewpoint, the cyanotoxins span four major classes: the neurotoxins, hepatotoxins, cytotoxins, and dermatoxins (irritant toxins). However, structurally they are quite diverse. Over the past decade, the biosynthesis pathways of the four major cyanotoxins: microcystin, nodularin, saxitoxin and cylindrospermopsin, have been genetically and biochemically elucidated. This review provides an overview of these biosynthesis pathways and additionally summarizes the chemistry and toxicology of these remarkable secondary metabolites.     

Cyanobactins from Cyanobacteria: Current Genetic and Chemical State of Knowledge

Cyanobacteria are considered to be one of the most promising sources of new, natural products. Apart from non-ribosomal peptides and polyketides, ribosomally synthesized and post-translationally modified peptides (RiPPs) are one of the leading groups of bioactive compounds produced by cyanobacteria. Among these, cyanobactins have sparked attention due to their interesting bioactivities and for their potential to be prospective candidates in the development of drugs. It is assumed that the primary source of cyanobactins is cyanobacteria, although these compounds have also been isolated from marine animals such as ascidians, sponges and mollusks. The aim of this review is to update the current knowledge of cyanobactins, recognized as being produced by cyanobacteria, and to emphasize their genetic clusters and chemical structures as well as their bioactivities, ecological roles and biotechnological potential.     

Lignin and polyphenols as allelochemicals

By the microbiological action, lignin from vegetal wastes is transformed at soil level in organic prebiotic products with physiological activity on plants development. On the other hand, some micromolecular compounds resulted from plant wastes decomposition, along with polyphenols coming from extraction of plant residues could play a role of allelochemicals. The understanding of the allelochemical action mechanisms allow us to use these compounds to enhance crop production and develop a more sustainable agriculture, including weed and pest control through crop rotations, residue management and a variety of approaches in biocontrol. Other goals are to adopt allelochemicals as herbicides, pesticides and growth stimulants, modify crop genomes to manipulate allelochemicals production and better elucidate chemical communications between the components of ecosystem. The result obtained in the utilization of lignins and polyphenols as allelochemicals are presented in this review.     

Effects of Marine Toxins on the Reproduction and Early Stages Development of Aquatic Organisms

Marine organisms, and specially phytoplankton species, are able to produce a diverse array of toxic compounds that are not yet fully understood in terms of their main targets and biological function. Toxins such as saxitoxins, tetrodotoxin, palytoxin, nodularin, okadaic acid, domoic acid, may be produced in large amounts by dinoflagellates, cyanobacteria, bacteria and diatoms and accumulate in vectors that transfer the toxin along food chains. These may affect top predator organisms, including human populations, leading in some cases to death. Nevertheless, these toxins may also affect the reproduction of aquatic organisms that may be in contact with the toxins, either by decreasing the amount or quality of gametes or by affecting embryonic development. Adults of some species may be insensitive to toxins but early stages are more prone to intoxication because they lack effective enzymatic systems to detoxify the toxins and are more exposed to the toxins due to a higher metabolic growth rate. In this paper we review the current knowledge on the effects of some of the most common marine toxins on the reproduction and development of early stages of some organisms.     

Microalgae as Contributors to Produce Biopolymers

Biopolymers are very favorable materials produced by living organisms, with interesting properties such as biodegradability, renewability, and biocompatibility. Biopolymers have been recently considered to compete with fossil-based polymeric materials, which rase several environmental concerns. Biobased plastics are receiving growing interest for many applications including electronics, medical devices, food packaging, and energy. Biopolymers can be produced from biological sources such as plants, animals, agricultural wastes, and microbes. Studies suggest that microalgae and cyanobacteria are two of the promising sources of polyhydroxyalkanoates (PHAs), cellulose, carbohydrates (particularly starch), and proteins, as the major components of microalgae (and of certain cyanobacteria) for producing bioplastics. This review aims to summarize the potential of microalgal PHAs, polysaccharides, and proteins for bioplastic production. The findings of this review give insight into current knowledge and future direction in microalgal-based bioplastic production considering a circular economy approach. The current review is divided into three main topics, namely (i) the analysis of the main types and properties of bioplastic monomers, blends, and composites; (ii) the cultivation process to optimize the microalgae growth and accumulation of important biobased compounds to produce bioplastics; and (iii) a critical analysis of the future perspectives on the field.     

Can Some Marine-Derived Fungal Metabolites Become Actual Anticancer Agents?

Marine fungi are known to produce structurally unique secondary metabolites, and more than 1000 marine fungal-derived metabolites have already been reported. Despite the absence of marine fungal-derived metabolites in the current clinical pipeline, dozens of them have been classified as potential chemotherapy candidates because of their anticancer activity. Over the last decade, several comprehensive reviews have covered the potential anticancer activity of marine fungal-derived metabolites. However, these reviews consider the term “cytotoxicity” to be synonymous with “anticancer agent”, which is not actually true. Indeed, a cytotoxic compound is by definition a poisonous compound. To become a potential anticancer agent, a cytotoxic compound must at least display (i) selectivity between normal and cancer cells (ii) activity against multidrug-resistant (MDR) cancer cells; and (iii) a preferentially non-apoptotic cell death mechanism, as it is now well known that a high proportion of cancer cells that resist chemotherapy are in fact apoptosis-resistant cancer cells against which pro-apoptotic drugs have more than limited efficacy. The present review thus focuses on the cytotoxic marine fungal-derived metabolites whose ability to kill cancer cells has been reported in the literature. Particular attention is paid to the compounds that kill cancer cells through non-apoptotic cell death mechanisms.     

Cyanotoxins: bioaccumulation and effects on aquatic animals

Cyanobacteria are photosynthetic prokaryotes with wide geographic distribution that can produce secondary metabolites named cyanotoxins. These toxins can be classified into three main types according to their mechanism of action in vertebrates: hepatotoxins, dermatotoxins and neurotoxins. Many studies on the effects of cyanobacteria and their toxins over a wide range of aquatic organisms, including invertebrates and vertebrates, have reported acute effects (e.g., reduction in survivorship, feeding inhibition, paralysis), chronic effects (e.g., reduction in growth and fecundity), biochemical alterations (e.g., activity of phosphatases, GST, AChE, proteases), and behavioral alterations. Research has also focused on the potential for bioaccumulation and transferring of these toxins through the food chain. Although the herbivorous zooplankton is hypothesized as the main target of cyanotoxins, there is not unquestionable evidence of the deleterious effects of cyanobacteria and their toxins on these organisms. Also, the low toxin burden in secondary consumers points towards biodilution of microcystins in the food web as the predominant process. In this broad review we discuss important issues on bioaccumulation and the effects of cyanotoxins, with emphasis on microcystins, as well as drawbacks and future needs in this field of research.     

Phytoplankton Toxins and Their Potential Therapeutic Applications: A Journey toward the Quest for Potent Pharmaceuticals

Phytoplankton are prominent organisms that contain numerous bioactive substances and secondary metabolites, including toxins, which can be valuable to pharmaceutical, nutraceutical, and biotechnological industries. Studies on toxins produced by phytoplankton such as cyanobacteria, diatoms, and dinoflagellates have become more prevalent in recent years and have sparked much interest in this field of research. Because of their richness and complexity, they have great potential as medicinal remedies and biological exploratory probes. Unfortunately, such toxins are still at the preclinical and clinical stages of development. Phytoplankton toxins are harmful to other organisms and are hazardous to animals and human health. However, they may be effective as therapeutic pharmacological agents for numerous disorders, including dyslipidemia, obesity, cancer, diabetes, and hypertension. In this review, we have focused on the properties of different toxins produced by phytoplankton, as well as their beneficial effects and potential biomedical applications. The anticancer properties exhibited by phytoplankton toxins are mainly attributed to their apoptotic effects. As a result, phytoplankton toxins are a promising strategy for avoiding postponement or cancer treatment. Moreover, they also displayed promising applications in other ailments and diseases such as Alzheimer’s disease, diabetes, AIDS, fungal, bacterial, schizophrenia, inflammation, allergy, osteoporosis, asthma, and pain. Preclinical and clinical applications of phytoplankton toxins, as well as future directions of their enhanced nano-formulations for improved clinical efficacy, have also been reviewed.     

Microalgae as Sustainable Biofactories to Produce High-Value Lipids: Biodiversity,Exploitation, and Biotechnological Applications

Microalgae are often called “sustainable biofactories” due to their dual potential to mitigate atmospheric carbon dioxide and produce a great diversity of high-value compounds. Nevertheless, the successful exploitation of microalgae as biofactories for industrial scale is dependent on choosing the right microalga and optimum growth conditions. Due to the rich biodiversity of microalgae, a screening pipeline should be developed to perform microalgal strain selection exploring their growth, robustness, and metabolite production. Current prospects in microalgal biotechnology are turning their focus to high-value lipids for pharmaceutic, nutraceutic, and cosmetic products. Within microalgal lipid fraction, polyunsaturated fatty acids and carotenoids are broadly recognized for their vital functions in human organisms. Microalgal-derived phytosterols are still an underexploited lipid resource despite presenting promising biological activities, including neuroprotective, anti-inflammatory, anti-cancer, neuromodulatory, immunomodulatory, and apoptosis inductive effects. To modulate microalgal biochemical composition, according to the intended field of application, it is important to know the contribution of each cultivation factor, or their combined effects, for the wanted product accumulation. Microalgae have a vital role to play in future low-carbon economy. Since microalgal biodiesel is still costly, it is desirable to explore the potential of oleaginous species for its high-value lipids which present great global market prospects.     

First Identification of 12β-Deoxygonyautoxin 5 (12α-Gonyautoxinol 5) in the Cyanobacterium Dolichospermum circinale (TA04) and 12β-Deoxysaxitoxin (12α-Saxitoxinol) in D. circinale (TA04) and the Dinoflagellate Alexandrium pacificum (Group IV) (120518KureAC)

Saxitoxin and its analogues, paralytic shellfish toxins (PSTs), are potent and specific voltage-gated sodium channel blockers. These toxins are produced by some species of freshwater cyanobacteria and marine dinoflagellates. We previously identified several biosynthetic intermediates of PSTs, as well as new analogues, from such organisms and proposed the biosynthetic and metabolic pathways of PSTs. In this study, 12β-deoxygonyautoxin 5 (12α-gonyautoxinol 5 = gonyautoxin 5-12(R)-ol) was identified in the freshwater cyanobacterium, Dolichospermum circinale (TA04), and 12β-deoxysaxitoxin (12α-saxitoxinol = saxitoxin-12(R)-ol) was identified in the same cyanobacterium and in the marine dinoflagellate Alexandrium pacificum (Group IV) (120518KureAC) for the first time from natural sources. The authentic standards of these compounds and 12α-deoxygonyautoxin 5 (12β-gonyautoxinol 5 = gonyautoxin 5-12(S)-ol) were prepared by chemical derivatization from the major PSTs, C1/C2, produced in D. circinale (TA04). These standards were used to identify the deoxy analogues by comparing the retention times and MS/MS spectra using high-resolution LC-MS/MS. Biosynthetic or metabolic pathways for these analogues have also been proposed based on their structures. The identification of these compounds supports the α-oriented stereoselective oxidation at C12 in the biosynthetic pathway towards PSTs.     

Marine Microorganism-Invertebrate Assemblages: Perspectives to Solve the “Supply Problem” in the Initial Steps of Drug Discovery

The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the “blue gold” in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts.     

Cyanobacteria Secondary Metabolites as Biotechnological Ingredients in Natural Anti-Aging Cosmetics: Potential to Overcome Hyperpigmentation,Loss of Skin Density and UV Radiation-Deleterious Effects

The loss of density and elasticity, the appearance of wrinkles and hyperpigmentation are among the first noticeable signs of skin aging. Beyond UV radiation and oxidative stress, matrix metalloproteinases (MMPs) assume a preponderant role in the process, since their deregulation results in the degradation of most extracellular matrix components. In this survey, four cyanobacteria strains were explored for their capacity to produce secondary metabolites with biotechnological potential for use in anti-aging formulations. Leptolyngbya boryana LEGE 15486 and Cephalothrix lacustris LEGE 15493 from freshwater ecosystems, and Leptolyngbya cf. ectocarpi LEGE 11479 and Nodosilinea nodulosa LEGE 06104 from marine habitats were sequentially extracted with acetone and water, and extracts were analyzed for their toxicity in cell lines with key roles in the skin context (HaCAT, 3T3L1, and hCMEC). The non-toxic extracts were chemically characterized in terms of proteins, carotenoids, phenols, and chlorophyll a, and their anti-aging potential was explored through their ability to scavenge the physiological free radical superoxide anion radical (O₂^•−), to reduce the activity of the MMPs elastase and hyaluronidase, to inhibit tyrosinase and thus avoid melanin production, and to block UV-B radiation (sun protection factor, SPF). Leptolyngbya species stood out for anti-aging purposes: L. boryana LEGE 15486 presented a remarkable SPF of 19 (at 200 µg/mL), being among the best species regarding O₂^•− scavenging, (IC₅₀ = 99.50 µg/mL) and also being able to inhibit tyrosinase (IC₂₅ = 784 µg/mL), proving to be promising against UV-induced skin-aging; L. ectocarpi LEGE 11479 was more efficient in inhibiting MMPs (hyaluronidase, IC₅₀ = 863 µg/mL; elastase, IC₅₀ = 391 µg/mL), thus being the choice to retard dermal density loss. Principal component analysis (PCA) of the data allowed the grouping of extracts into three groups, according to their chemical composition; the correlation of carotenoids and chlorophyll a with MMPs activity (p < 0.01), O₂^•− scavenging with phenolic compounds (p < 0.01), and phycocyanin and allophycocyanin with SPF, pointing to these compounds in particular as responsible for UV-B blockage. This original survey explores, for the first time, the biotechnological potential of these cyanobacteria strains in the field of skin aging, demonstrating the promising, innovative, and multifactorial nature of these microorganisms.     

Detection of Diarrheic Shellfish Poisoning and Azaspiracid Toxins in Moroccan Mussels: Comparison of the LC-MS Method with the Commercial Immunoassay Kit

Diarrheic shellfish poisoning (DSP) is a recurrent gastrointestinal illness in Morocco, resulting from consumption of contaminated shellfish. In order to develop a rapid and reliable technique for toxins detection, we have compared the results obtained by a commercial immunoassay-“DSP-Check” kit” with those obtained by LC-MS. Both techniques are capable of detecting the toxins in the whole flesh extract which was subjected to prior alkaline hydrolysis in order to detect simultaneously the esterified and non esterified toxin forms. The LC-MS method was found to be able to detect a high level of okadaic acid (OA), low level of dinophysistoxin-2 (DTX2), and surprisingly, traces of azaspiracids 2 (AZA2) in mussels. This is the first report of a survey carried out for azaspiracid (AZP) contamination of shellfish harvested in the coastal areas of Morocco. The “DSP-Check” kit was found to detect quantitatively DSP toxins in all contaminated samples containing only OA, provided that the parent toxins were within the range of detection and was not in an ester form. A good correlation was observed between the two methods when appropriate dilutions were performed. The immunoassay kit appeared to be more sensitive, specific and faster than LC-MS for determination of DSP in total shellfish extract.     

Bioactive peptides and depsipeptides with anticancer potential: sources from marine animals

Biologically active compounds with different modes of action, such as, antiproliferative, antioxidant, antimicrotubule, have been isolated from marine sources, specifically algae and cyanobacteria. Recently research has been focused on peptides from marine animal sources, since they have been found as secondary metabolites from sponges, ascidians, tunicates, and mollusks. The structural characteristics of these peptides include various unusual amino acid residues which may be responsible for their bioactivity. Moreover, protein hydrolysates formed by the enzymatic digestion of aquatic and marine by-products are an important source of bioactive peptides. Purified peptides from these sources have been shown to have antioxidant activity and cytotoxic effect on several human cancer cell lines such as HeLa, AGS, and DLD-1. These characteristics imply that the use of peptides from marine sources has potential for the prevention and treatment of cancer, and that they might also be useful as molecular models in anticancer drug research. This review focuses on the latest studies and critical research in this field, and evidences the immense potential of marine animals as bioactive peptide sources.     

Role of Benzoxazinones in Cereals

Summary

Heterocyclic 1,4-benzoxazin-3-ones and related benzox-azolinones are important natural products of the cereal crops maize, wheat and rye. Much research has focused on the role of these compounds as defensive agents against plant diseases and pests. Studies of a wide variety of biological effects on herbivores and nematodes, plant pathogenic fungi and bacteria are reviewed in this article. Phytotoxic activity of the compounds is also considered with respect to allelopathic interaction with higher plants. Recent investigations of molecular aspects of interactions of cyclic hydroxamic acids and related benzoxazo-linones with acceptor organisms have demonstrated different effective detoxification strategies and tolerance mechanisms. This research has greatly advanced our knowledge about the multiple roles that these allelochemicals play in ecological systems.     

Anti-Chikungunya Viral Activities of Aplysiatoxin-Related Compounds from the Marine Cyanobacterium Trichodesmium erythraeum

Tropical filamentous marine cyanobacteria have emerged as a viable source of novel bioactive natural products for drug discovery and development. In the present study, aplysiatoxin (1), debromoaplysiatoxin (2) and anhydrodebromoaplysiatoxin (3), as well as two new analogues, 3-methoxyaplysiatoxin (4) and 3-methoxydebromoaplysiatoxin (5), are reported for the first time from the marine cyanobacterium Trichodesmium erythraeum. The identification of the bloom-forming cyanobacterial strain was confirmed based on phylogenetic analysis of its 16S rRNA sequences. Structural determination of the new analogues was achieved by extensive NMR spectroscopic analysis and comparison with NMR spectral data of known compounds. In addition, the antiviral activities of these marine toxins were assessed using Chikungunya virus (CHIKV)-infected cells. Post-treatment experiments using the debrominated analogues, namely compounds 2, 3 and 5, displayed dose-dependent inhibition of CHIKV when tested at concentrations ranging from 0.1 µM to 10.0 µM. Furthermore, debromoaplysiatoxin (2) and 3-methoxydebromoaplysiatoxin (5) exhibited significant anti-CHIKV activities with EC₅₀ values of 1.3 μM and 2.7 μM, respectively, and selectivity indices of 10.9 and 9.2, respectively.