Search Results (270)

Little is known about how nicotinic signalling in human astrocytes may contribute to the functional neurotoxicity of compounds related to tobacco alkaloids and neonicotinoid pesticides. We generated a single-cell Ca²⁺-imaging assay in induced pluripotent stem cell (iPSC)-derived astrocytes, and profiled functional expressions of some neurotoxicologically relevant receptors. Responses to pharmacological tool compounds indicated the expression of nicotinic, muscarinic, purinergic, glutamatergic receptors and voltage-gated Na⁺/Ca²⁺ channels. Closer investigation of the nicotinic system, e.g., using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective positive allosteric modulator PNU-120596 and alpha7-preferring agonist (AR-R17779) demonstrated that Ca²⁺ signals elicited by nicotine and neonicotinoids are dominated by alpha7 nAChRs and depend on the downstream activation of L-type Ca²⁺ channels and tetrodotoxin-sensitive Na⁺ channels. Crosstalk of nAChR activation/desensitization was not observed for the inflammatory response elicited by TNF or for activation of glutamatergic or purinergic signalling. However, pre-stimulation of nAChR by neonicotinoids significantly blunted the response to the neurotransmitter acetylcholine. Comparative experiments in the human neuronal cultures (LUHMES cells) revealed similar potency ranges and pharmacological fingerprints for several neonicotinoids and their human-relevant metabolites descyanothiacloprid and desnitroimidacloprid. The pesticide metabolites showed a high potency, compared with their respective parent compounds. After this basic system characterization, the hitherto data-poor pesticides cycloxaprid and flupyradifurone were comparatively profiled in astrocytic and neuronal test systems. They showed the typical features of alpha7 nAChR agonists. The disruption of cholinergic signalling in astrocytes suggests that neonicotinoids affect not only neurons in human brains. Therefore, future neurotoxicity screening approaches may need to consider astrocyte toxicity. Full article

Climate change is intensifying the release and dispersion of various hazardous chemicals into marine ecosystems, such as algal biotoxins, heavy metals, persistent organic pollutants, and agricultural and industrial wastes. Eutrophication and global warming are responsible for the increase in known and emerging marine biotoxins, such as brevetoxins, palytoxins, pinnatoxins, and cyclic imines. Furthermore, tetrodotoxins and ciguatoxins, which are primarily found in tropical regions, have recently been identified in fish and bivalve molluscs from temperate areas where they had never been previously reported. These toxicants can accumulate in seafood and enter the human food chain, posing a public health concern. This review describes the interrelationship between climate change and its impact on marine organisms and human health, as well as the environment. It recommends integrating a broad range of scientific knowledge, reviewing regulatory policies, and proactively managing public health to counter these environmental threats. Full article

To investigate the dynamics of paralytic shellfish toxins (PSTs) and tetrodotoxins (TTX) in scallops, PSTs and TTX were analyzed in the hemolymph supernatant (hemolymph-S) and digestive gland in Yesso and Akazara scallops cultured in eastern Japan. In Yesso scallops sampled between 22 April 2025 and 21 October 2025, the PST concentrations in the hemolymph-S were 1.6–17% of those in the digestive gland, showing a positive correlation (r = 0.753). However, the PST composition in the hemolymph-S and digestive gland differed; the hemolymph-S composition initially resembled that of laboratory-cultured dinoflagellates, coinciding with typical onset of toxic dinoflagellate blooms in late April. Following this period, the PST composition in the hemolymph-S gradually converged with that of the digestive gland, via chemical transformation in the digestive gland followed by release into the hemolymph. The ratios of 11β-OSO₃H toxins (C2, GTX4, GTX3) to 11α-OSO₃H toxins (C1, GTX1, GTX2), which exist in chemical equilibrium, exhibited a similar trend. TTX was detected in both tissues of Yesso and Akazara scallops collected from 28 August 2025 to 27 January 2026, with the hemolymph-S concentration being 0.5–5.4% of that in the digestive gland. These results suggest that these toxins are sequestered into the digestive gland from the PST-producing dinoflagellates and certain TTX-bearing organisms, and then they partially flow into the hemolymph for circulation throughout the body. Full article

In recent years, the pufferfish Lagocephalus lagocephalus has been recorded with unusual frequency in coastal areas of the Canary Islands. The most notable episodes occurred in March and November 2017, when numerous shoals were observed along the coasts of the Western Canary Islands. A toxicological study of these episodes was carried out, analyzing liver, kidney, gonads, skin, and muscle of a representative population. In all toxic samples (33.3% and 41.7% of specimens in March and November 2017, respectively), only the liver extract showed toxicities, using a mouse biological assay (MBA). The toxicological profile was determined by UHPLC-MS-MS, identifying saxitoxin (STX) and tetrodotoxin (TTX) congeners. This analytical methodology was optimized to determine 26 marine toxins. Thus, in the March 2017 episode, the toxicological profile was characterized by the co-occurrence of tetrodotoxins (TTX and 4-epiTTX) and paralytic shellfish toxin (PST) analogues (dcSTX, dcneoSTX, and doSTX); however, STX and neoSTX emerged as the dominant toxins in specimens collected during the November 2017 episode. The results show that L. lagocephalus in the Canary Islands presents a variable and dynamic toxicological profile, strongly influenced by environmental factors. These findings highlight the need for continued monitoring and for analytical approaches capable of capturing this complexity and assessing potential risks to public health. Full article

Pregabalin (PGB) exerts its therapeutic effects by binding to the α₂δ auxiliary subunits of voltage-gated calcium channels and modulates synaptic transmission in the brain. However, its influence on cerebellar parallel fiber–Purkinje cell (PF–PC) synaptic transmission remains unclear. In the present study, we investigated the effects of PGB on PF–PC synaptic transmission using whole-cell patch-clamp recording, glutamate fluorescence imaging, immunohistochemistry, co-immunoprecipitation, Western blotting, and pharmacological approaches. Micro-application of PGB to the cerebellar molecular layer induced a concentration-dependent inhibition of PF–PC excitatory postsynaptic currents (EPSCs), accompanied by an increased paired-pulse ratio. The inhibitory effect of PGB on PF–PC EPSCs was abolished by extracellular blockade of N-methyl-D-aspartate receptors (NMDAR) or their GluN2A subtype, as well as by disruption of α₂δ-1–NMDAR complexes, but not by intracellular NMDAR inhibition. Glutamate sensor imaging further showed that PGB markedly reduced the fluorescence intensity of glutamate release evoked by PF stimulation. In the presence of tetrodotoxin (TTX) and a gamma-aminobutyric acid type A (GABAA) receptor antagonist, PGB reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude. The PGB-induced reduction in mEPSC frequency was fully abolished by extracellular blockade of GluN2A-containing NMDARs or disruption of α₂δ-1–NMDAR complexes. Similarly, the inhibitory effects of PGB on PF–PC EPSCs and mEPSCs were eliminated by extracellular PKA inhibition, but not by intracellular protein kinase A (PKA) inhibition. Western blot analysis showed that PGB significantly increased PKA phosphorylation in the molecular layer of the cerebellar cortex. Immunoreactivity for GluN2A and α₂δ-1 subunits was colocalized within the molecular layer and abundantly distributed around the dendrites and somata of PCs. Co-immunoprecipitation further verified that α₂δ-1 was co-precipitated with GluN1 in cerebellar molecular layer tissue samples. The results indicate that PGB depresses glutamate release from parallel-fiber terminals in the mouse cerebellar cortex through the presynaptic α₂δ-1-coupled GluN2A-containing NMDAR/PKA signaling pathway, thereby attenuating PF–PC synaptic transmission. Full article

This study was performed to elucidate the mechanism underpinning the nodal swelling induced by equinatoxin II (EqtII), a cation-selective pore-forming toxin derived from the sea anemone Actinia equina. Experiments were conducted using frog myelinated nerve fibers as a model system. Application of EqtII led to an approximately two-fold increase in the nodal volume of myelinated axons, but only when extracellular Ca²⁺ was present. Replacing extracellular Cl⁻ with isethionate had no measurable effect on this response, whereas substitution of NaCl with either sucrose or LiCl, an established Na⁺/Ca²⁺ exchanger (NCX) inhibitor, abolished the swelling. The persistence of the effect in the presence of tetrodotoxin indicates that voltage-gated Na⁺ channels are not involved in the underlying mechanism. Our data suggest that Ca²⁺ influx through EqtII-induced membrane pores raises intracellular Ca²⁺ levels, thereby stimulating the NCX in its forward-operating mode. This process promotes Ca²⁺ extrusion in exchange for Na⁺ entry. The resulting accumulation of intracellular Na⁺ increases osmotic pressure within the axon, leading to water influx and nodal swelling. Full article

The potent toxicity of tetrodotoxin (TTX) has long constrained sustainable growth in pufferfish aquaculture. Takifugu bimaculatus, an economically important species farmed along the coast of Fujian, China, remains poorly understood regarding how it transports and accumulates this potent neurotoxin. To address this gap, we combined transcriptomic and proteomic analyses to characterize the molecular responses of T. bimaculatus to TTX exposure. After oral administration, TTX primarily accumulated in the liver, ovaries, and skin. Multi-omics profiling revealed 163 differentially expressed genes (DEGs) and 88 differentially expressed proteins (DEPs) in liver tissue, together with 239 DEGs and 179 DEPs in ovarian tissue. KEGG pathway analysis suggests that the liver maintains homeostasis by regulating ion concentrations and restructuring lipid raft architectures, alongside coordinated carrier protein activity. This likely supports active TTX uptake and directed transport toward the ovaries and skin, followed by metabolic clearance. By contrast, ovarian tissues appear to establish a stable, long-term reservoir through cytoskeletal remodeling, enhanced interactions with the extracellular matrix, and activated endocytic pathways. Together, these findings offer insights into how T. bimaculatus accumulates and transports TTX, laying groundwork for identifying key transporter genes, clarifying TTX metabolic pathways, and developing practical food safety controls. Full article

Saxitoxin (STX) is one of the most potent natural neurotoxins known and is the only marine toxin to be declared a chemical weapon. In both marine and freshwater systems filter feeding organisms can accumulate saxitoxin and human consumption of toxin-contaminated food can result in paralytic shellfish poisoning. Here we highlight for the first time a human cell-based assay for the detection and neutralisation of STX activity on an automated patch clamp (APC) system. We demonstrate that a human embryonic kidney (HEK) cell line expressing human Nav1.6 can rapidly and sensitively detect the presence of a range of sodium ion channel blockers including STX. The use of neutralising monoclonal antibody GT13-A and/or saxiphilin was found to confer specificity to the assay by being able to dissociate between STX (along with closely related analogues) and tetrodotoxin. Finally, the application of the functional assay for the detection of STX in complex samples was evaluated during an international exercise led by the Organisation for the Prohibition of Chemical Weapons (OPCW). The neutralisation of STX activity in blinded samples enabled the indirect detection of the toxin in the relevant samples and provided an alternative orthogonal technique to corroborate the findings of liquid chromatography–mass spectrometry (LC-MS). Collectively this work demonstrates the significant potential for functional assays in the analysis of samples suspected of being contaminated with STX and related sodium ion channel targeting toxins; complementing traditional direct identification methods such as high-performance liquid chromatography with fluorescence detection (HPLC-FLD), LC-MS or enzyme-linked immunosorbent assay (ELISA). Full article

Tetrodotoxin (TTX), widely known as pufferfish venom, is a low-molecular-weight guanidinium neurotoxin. It can accumulate to extremely high concentrations in certain animals, including pufferfish, blue-ringed octopuses, flatworms, and nemerteans. However, the origin of TTX and the mechanisms that enable such extreme accumulation in these animals remain poorly understood. In this study, using confocal laser scanning microscopy combined with electron immunocytochemistry and ultrastructural analysis, we demonstrate the presence of TTX-positive bacteria associated with specialized cellular structures—type II phagosomes of gut enterocytes—in the highly toxic nemertean Cephalothrix cf. simula. We hypothesize that TTX production in C. cf. simula results from interactions between the nemertean host and its endosymbionts. These findings clarify the origin and accumulation of the toxin in nemerteans and have broader implications for other TTX-bearing species. Full article

Boron is a chemically distinctive bioelement whose electron-deficient structure enables reversible coordination with oxygen-rich functional groups such as diols and hydroxyls. This property allows boron to modulate molecular stability, conformation, and biological reactivity, giving rise to both beneficial pharmacological effects and toxicological outcomes. This review examines the dual biological role of boron through the framework of bioactive boron-containing natural products and natural compounds capable of forming reversible boron complexes. Particular attention is given to naturally occurring boron-containing antibiotics, including the polyketide macrodiolides boromycin, aplasmomycin, tartrolons, and hyaboron, where boron plays a direct structural and functional role in antimicrobial activity. These compounds demonstrate how boron coordination can influence ion transport, membrane interactions, and molecular assembly, contributing to potent antibacterial properties. Beyond intrinsically boron-containing metabolites, many natural antibiotics and toxins possess oxygen-rich architectures capable of forming transient borate complexes through vicinal 1,2-diol motifs. Examples include polyene macrolide antibiotics such as amphotericin B, fungichromin, and nystatin, as well as tetracyclines, rifamycins, and macrolides such as sorangicin A, where boron coordination may affect solubility, aggregation, ionophoric behavior, and biological selectivity. Similar chemistry is observed in marine neurotoxins and polyether toxins—including tetrodotoxin, saxitoxin derivatives, azaspiracids, pectenotoxins, ciguatoxins, and gambierones—whose hydroxyl-rich frameworks enable reversible interactions with boron species present in seawater. Such complexation may enhance aqueous stability and contribute to trophic transfer and bioaccumulation within marine ecosystems. By framing boron as a molecular “double edge,” this review integrates chemical, biological, and environmental perspectives to highlight how boron coordination can simultaneously enhance antimicrobial activity while influencing toxicity and ecological persistence. Recognizing the role of boron in shaping the activity of natural products provides new insight into antibiotic function, toxin behavior, and the broader impact of boron chemistry in biological systems. Full article

This study documents the presence of two uncommon tetraodontiform fishes and reviews the occurrence of species from this order in Spanish marine waters. Two tetraodontid specimens (Family Tetraodontidae) were caught in the Atlantic waters off the coast of Galicia, northwestern Spain. A specimen of Sphoeroides pachygaster was collected in 2021 off the Costa da Vela, while a specimen of Ephippion guttifer was captured in 2025 in the Ría de Pontevedra, both locations situated in southern Galicia. Morphological analyses, supported by photographic evidence and DNA barcoding, confirmed the preliminary taxonomic identification of the two species. Histological reproductive analysis of the Ephippion guttifer specimen revealed a female in the spawning-capable phase. These findings constitute the first verified record of S. pachygaster and the second of E. guttifer in Galician waters. An updated comprehensive list of tetraodontiform species found in Spanish waters across five geographical demarcations was compiled. Historically, a total of 26 species across five families have been reported in Spanish waters, with 22 in the Canary Islands and 15 in the Spanish Iberian Peninsula and Balearic Islands. Additionally, a review of the presence of neurotoxic tetrodotoxins (TTXs) or paralytic shellfish toxins (PSTs) in each species is included, providing an up-to-date overview of a largely unexplored field in European waters. The increasing occurrence of tetraodontiform fishes in Spanish waters provides further evidence of the progressive tropicalization of the Spanish marine environment. Full article

Depression remains a major global health challenge, with a significant proportion of patients failing to respond to conventional antidepressants. This study aimed to evaluate the potential antidepressant effects and toxicological profile of a novel tetrodotoxin (TTX) oral film formulation in a mouse model of chronic unpredictable mild stress (CUMS). Male C57BL/6J mice were subjected to CUMS and treated daily with TTX oral film at doses of 10, 20, and 40 μg/kg, with fluoxetine (18 mg/kg) serving as a positive control. Behavioral assessments, including sucrose preference test, open field test, forced swimming test, elevated plus maze, and novel object recognition, demonstrated that TTX oral film administration alleviated depression- and anxiety-like behaviors and improved cognitive function. Furthermore, TTX oral film treatment restored hippocampal serotonin levels, which were depleted in CUMS mice, and showed no adverse effects on organ indexes after long-term use. Toxicological evaluation through acute toxicity testing revealed an oral LD₅₀ of 919 μg/kg, indicating a substantially improved safety profile compared to pure TTX and a wide therapeutic window. These findings suggest that the TTX oral film possesses significant antidepressant activity with favorable toxicological properties, supporting its potential as a novel and safe treatment for depression. Full article

Angiogenesis depends on Ca²⁺-mediated endothelial cell migration. The increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) is coordinated by caveolae and the Cx43 hemichannel opening. However, the functional coupling of voltage-dependent Na⁺ channels (Na_v) with Na⁺-Ca²⁺ exchanger reverse mode (NCXrm) activation may contribute to the response, which was evaluated using the wound-healing assay in primary cultures of rat mesenteric endothelial cells. Changes in [Ca²⁺]_i, the hemichannel opening and the association of Na_v channels with caveolin-1, a caveolae structural protein, were analyzed. Both endothelial cell migration and the associated Ca²⁺ signaling were inhibited by tetrodotoxin (TTX), a Na_v channel blocker, lamotrigine, a preferential Na_v1.2 inhibitor, or 4,9-anhydro-TTX, a specific Na_v1.6 blocker. A similar result was found by disrupting caveolae organization with methyl-β-cyclodextrin or blocking NCXrm with SEA0400. TTX and SEA0400 also prevented Cx43 hemichannel opening, and tubular-like structure formation depended on Na_v channels. An analysis using a proximity ligation assay showed that endothelial cell migration was paralleled by the progressive association of caveolin-1 with Na_v1.2, but not Na_v1.6, channels. These results suggest that the functional coupling of Na_v1.2 and Na_v1.6 channels with the activation of NCXrm and Cx43 hemichannels mediates the Ca²⁺ signaling associated with endothelial cell migration and angiogenesis, which provides new targets to modulate angiogenesis in physiological or pathological conditions. Full article

Tetrodotoxin (TTX) is a potent marine neurotoxin, necessitating sensitive and user-friendly on-site assays. To address long workflows of traditional immunoassays and limited signal amplification in colorimetric microfluidics, we developed a nanozyme-catalyzed colorimetric magnetic microfluidic immunosensor (Nano-CMI). This platform combines an aptamer–antibody sandwich capture format with catalytic amplification via AuNR@Pt@m-SiO₂ (APMS) nanozymes on a magnetically actuated microfluidic chip. Magnetic actuation simplifies sample handling and washing, while APMS catalysis enhances sensitivity and visual readout. The Nano-CMI has been used for the detection of TTX samples ranging from 0.2 to 20 ng/mL with a detection limit of 0.2 ng/mL in 10 min, following the linear equation: y = −31.14ln x + 110.15, and the entire “capture-reaction-detection” workflow can be completed within 1 h. With rapid response, minimal hands-on time, and robust performance, this platform offers a practical, high-sensitivity solution for on-site TTX screening in food safety and customs inspection. Full article

Cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality worldwide, underscoring the urgent need for novel therapeutic alternatives. In recent years, marine ecosystems have garnered increasing attention as a promising source of bioactive compounds with unique structural and pharmacological properties. Marine-derived toxins and venoms, including tetrodotoxin, ω-conotoxins, anthopleurins, palytoxin, brevetoxin, aplysiatoxin, and asterosaponins, exert cardioprotective effects through diverse mechanisms such as modulation of ion channels, inhibition of sympathetic overactivity, antioxidative actions, and enhancement of myocardial contractility. These properties make them potential candidates for addressing various CVD manifestations, including arrhythmia, hypertension, ischemia–reperfusion injury, and heart failure. However, despite their therapeutic promise, the clinical application of these marine compounds remains limited due to poor tissue selectivity, narrow therapeutic indices, proinflammatory activity, and limited metabolic stability. Structural modifications, advanced drug delivery platforms, and in vivo validation studies are crucial for overcoming these challenges. This review highlights the pharmacological actions, molecular targets, and cardiovascular relevance of selected marine toxins and venoms while also addressing key translational barriers. Advances in biotechnology and peptide engineering are enabling the safer and more targeted use of these compounds. Collectively, marine-derived toxins and venoms represent a largely untapped but highly promising frontier in cardiovascular drug discovery. Strategic research focused on elucidating mechanisms, optimizing delivery, and translating clinical applications will be critical to unlocking their full therapeutic potential. Full article