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The long-lasting interest in bioactive molecules (namely toxins) produced by (microalga) dinoflagellates has risen in recent years. Exhibiting wide diversity and complexity, said compounds are well-recognized for their biological features, with great potential for use as pharmaceutical therapies and biological research probes. Unfortunately, provision of those compounds is still far from sufficient, especially in view of an increasing demand for preclinical testing. Despite the difficulties to establish dinoflagellate cultures and obtain reasonable productivities of such compounds, intensive research has permitted a number of advances in the field. This paper accordingly reviews the characteristics of some of the most important biotoxins (and other bioactive substances) produced by dinoflagellates. It also presents and discusses (to some length) the main advances pertaining to dinoflagellate production, from bench to large scale—with an emphasis on material published since the latest review available on the subject. Such advances encompass improvements in nutrient formulation and light supply as major operational conditions; they have permitted adaptation of classical designs, and aided the development of novel configurations for dinoflagellate growth—even though shearing-related issues remain a major challenge. © 2017 by the authors.

Marine algal toxins have garnered significant attention in the research community for their unique biochemical properties and potential medical applications. These bioactive compounds, produced by microalgae, pose significant risks due to their high toxicity, yet offer promising therapeutic benefits. Despite extensive research identifying over 300 marine algal toxins, including azaspiracids, brevetoxins, cyclic imines, and yessotoxins, gaps remain in the understanding of their pharmacological potential. In this paper, we critically review the classification, bioactive components, toxicology, pharmacological activities, and mechanisms of these toxins, with a particular focus on their clinical applications. Our motivation stems from the increasing interest in marine algal toxins as candidates for drug development, driven by their high specificity and affinity for various biological receptors. We aim to bridge the gap between toxicological research and therapeutic application, offering insights into the advantages and limitations of these compounds in comparison to other bioactive substances. This review not only enhances the understanding of marine algal toxins’ complexity and diversity, but also highlights their extensive application potential in medicine and bioscience, providing a foundation for future research and development in this field.

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

The mixotrophic dinoflagellate Akashiwo sanguinea is known to have acute toxic effects on multiple marine organisms, while the composition and chemical properties of its toxins remain unclear. In this study, we established a method for separation and purification of A. sanguinea toxins using chromatographic techniques. The acetone extract of A. sanguinea exhibited higher hemolytic activity and shorter incubation time compared to methanol and ethyl acetate extracts. Five fractions were obtained by solid-phase extraction (SPE), of which SPE3 (acetone/water ratio 3:2) and SPE4 (acetone/water ratio 4:1) exhibited the highest hemolytic activities and allelopathic effects. Further purification on SPE3 and SPE4 using reverse-phase high-performance liquid chromatography (RP-HPLC) coupled with a diode array detector (DAD) resulted in 11 subfractions, among which Fr4-5 displayed the strongest hemolytic activity. Nearly all active subfractions exhibited higher hemolytic activities incubated under light than those in the dark (p < 0.05), suggesting that A. sanguinea can produce both photosensitive and non-photosensitive toxins, with the former being the primary contributors to its hemolytic activity. Molecular characterization by UV-Vis, FTIR, and HRMS/MS analysis revealed that the structural features of Fr4-5 were highly consistent with porphyrin analogs and could be derived from chlorophyll c-related precursors. These findings highlight that the photosensitive toxins in A. sanguinea may serve dual roles in stress adaptation and ecological competition, potentially contributing to the formation of the blooms.

Voltage-gated sodium channels (VGSCs) are considered to be one of the most important ion channels given their remarkable physiological role. VGSCs constitute a family of large transmembrane proteins that allow transmission, generation, and propagation of action potentials. This occurs by conducting Na+ ions through the membrane, supporting cell excitability and communication signals in various systems. As a result, a wide range of coordination and physiological functions, from locomotion to cognition, can be accomplished. Drugs that target and alter the molecular mechanism of VGSCs’ function have highly contributed to the discovery and perception of the function and the structure of this channel. Among those drugs are various marine toxins produced by harmful microorganisms or venomous animals. These toxins have played a key role in understanding the mode of action of VGSCs and in mapping their various allosteric binding sites. Furthermore, marine toxins appear to be an emerging source of therapeutic tools that can relieve pain or treat VGSC-related human channelopathies. Several studies documented the effect of marine toxins on VGSCs as well as their pharmaceutical applications, but none of them underlined the principal marine toxins and their effect on VGSCs. Therefore, this review aims to highlight the neurotoxins produced by marine animals such as pufferfish, shellfish, sea anemone, and cone snail that are active on VGSCs and discuss their pharmaceutical values.

The first line of defence The inflammasome is a complex of proteins involved in the activation of the innate immune system, an evolutionarily ancient antimicrobial defence found in most multicelled animals. When activated the inflammasome sets in motion a cascade of events that leads to the production of active molecules including interleukins. Three papers in this issue report the identification of endogenous danger signals and bacterial components that activate inflammasomes containing cryopyrin (also known as NALP3). Mariathasan et al . show that cryopyrin activates the inflammasome in response to bacterial toxins and to ATP. Kanneganti et al . show that cryopyrin is activated by bacterial RNA and by the immune response modifiers R837 and R848. And Martinon et al . show that gout-associated uric acid crystals have a similar effect. In sum these results show that cryopyrin has a vital role in host antibacterial defences and may act as a sensor of cellular stress. In addition, this work provides insight into the mechanisms of autoinflammatory disorders in which abnormalities in the innate immune system have been implicated. A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1β and IL-18. The adaptor protein ASC is essential for inflammasome function 1 , 2 , binding directly to caspase-1 (refs 3 , 4 ), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1) 5 , 6 . Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1β 5 , 7 . Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X 7 receptor to decrease intracellular K + levels 8 , 9 . The release of IL-1β in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc -/- macrophages, cells deficient in the gene encoding cryopyrin ( Cias1 -/- ) activated caspase-1 and secreted normal levels of IL-1β and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis . Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes , however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1β. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

Within only three years since 2018, five (!) new drugs have been approved for the treatment of different cancer types all over the world; two of them have been approved only recently in 2020. [...]to the four “marine” pharmaceuticals listed above, the following medications were added: Plitidepsin (Aplidin®, produced by PharmaMar), dehydrodidemnin B, is an ascidian depsipeptide binding to eEF1A2 and inducing an oxidative stress in cancer cells; the drug was first approved in 2018 in Australia for the treatment of multiple myeloma, leukemia, and lymphoma [4]. According to the Marine Pharmacology web page provided by Prof. Alejandro M. S. Mayer and colleagues (https://www.midwestern.edu/departments/marinepharmacology.xml), there are currently another 23 “marine” molecules in different stages of clinical development in various cancer entities [9]. In their research, using a microarray-based gene expression analysis, the authors revealed an effect of the treatment on caspase-dependent intrinsic apoptosis, DNA repair executed via an inhibition of CDKs p53/p21/p27 cell cycle arrest, and mRNA metabolism [24].

Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.

Bioactive compounds are abundant in animals originating from marine ecosystems. Ion channels, which include sodium, potassium, calcium, and chloride, together with their numerous variants and subtypes, are the primary molecular targets of the latter. Based on their cellular targets, these venom compounds show a range of potencies and selectivity and may have some therapeutic properties. Due to their potential as medications to treat a range of (human) diseases, including pain, autoimmune disorders, and neurological diseases, marine molecules have been the focus of several studies over the last ten years. The aim of this review is on the various facets of marine (or marine-derived) molecules, ranging from structural characterization and discovery to pharmacology, culminating in the development of some “novel” candidate chemotherapeutic drugs that target potassium channels.

Spirolide and gymnodimine macrocyclic imine phycotoxins belong to an emerging class of chemical agents associated with marine algal blooms and shellfish toxicity. Analysis of 13-desmethyl spirolide C and gymnodimine A by binding and voltage-clamp recordings on muscle-type α1 2 βγδ and neuronal α3β2 and α4β2 nicotinic acetylcholine receptors reveals subnanomolar affinities, potent antagonism, and limited subtype selectivity. Their binding to acetylcholine-binding proteins (AChBP), as soluble receptor surrogates, exhibits picomolar affinities governed by diffusion-limited association and slow dissociation, accounting for apparent irreversibility. Crystal structures of the phycotoxins bound to Aplysia -AChBP (≈2.4Å) show toxins neatly imbedded within the nest of ar-omatic side chains contributed by loops C and F on opposing faces of the subunit interface, and which in physiological conditions accommodates acetylcholine. The structures also point to three major features: ( i ) the sequence-conserved loop C envelops the bound toxins to maximize surface complementarity; ( ii ) hydrogen bonding of the protonated imine nitrogen in the toxins with the carbonyl oxygen of loop C Trp147 tethers the toxin core centered within the pocket; and ( iii ) the spirolide bis -spiroacetal or gymnodimine tetrahydrofuran and their common cyclohexene-butyrolactone further anchor the toxins in apical and membrane directions, along the subunit interface. In contrast, the se-quence-variable loop F only sparingly contributes contact points to preserve the broad receptor subtype recognition unique to phycotoxins compared with other nicotinic antagonists. These data offer unique means for detecting spiroimine toxins in shellfish and identify distinctive ligands, functional determinants and binding regions for the design of new drugs able to target several receptor subtypes with high affinity.