Search Results (83)

Saxitoxin (STX) is a potent toxin produced by marine dinoflagellates and freshwater or brackish water cyanobacteria, and is a member of the paralytic shellfish toxins (PSTs). As a highly specific blocker of voltage-gated sodium channels (NaVs), STX blocks sodium ion influx, thereby inhibiting nerve impulse transmission and leading to systemic physiological dysfunctions in the nervous, respiratory, cardiovascular, and digestive systems. Severe exposure can lead to paralysis, respiratory failure, and mortality. STX primarily enters the human body through the consumption of contaminated shellfish, posing a significant public health risk as the causative agent of paralytic shellfish poisoning (PSP). Beyond its acute toxicity, STX exerts cascading impacts on food safety, marine ecosystem integrity, and economic stability, particularly in regions affected by harmful algal blooms (HABs). Moreover, the complex molecular structure of STX—tricyclic skeleton and biguanide group—and its diverse analogs (more than 50 derivatives) have made it the focus of research on natural toxins. In this review, we traced the discovery history, chemical structure, molecular biosynthesis, biological enrichment mechanisms, and toxicological actions of STX. Moreover, we highlighted recent advancements in the potential for detection and treatment strategies of STX. By integrating multidisciplinary insights, this review aims to provide a holistic understanding of STX and to guide future research directions for its prevention, management, and potential applications. Full article

The by-products that may contain tetrodotoxin (TTX) produced during the processing of farmed pufferfish have caused food safety risks and environmental pollution. Peptidoglycan (PG) of lactic acid bacteria could adsorb TTX; however, its complex structure and poor solubility limited adsorption efficiency. In this study, hydroxyl modifications of three PGs (A3α, A1γ and A4α) were realized via TEMPO-mediated selective oxidation of the primary hydroxyl group. Compared with PGs, it was found that the carboxyl density of hydroxyl-modified PGs (HM-PGs) increased from 1.66 mmol/g to 3.33 mmol/g and the surface electronegativity increased from −36 mV to −59 mV. The adsorption capacity of HM-PGs to TTX reached 1.48 μg/mg, which was comparable to the adsorption of the conventional adsorbent chitosan for aflatoxin B1 (1.39 μg/mg). Moreover, HM-PGs decreased the toxicity of TTX from strong toxic to nearly non-toxic, with the toxicity reduction rate reached 99.85%. After treatment with HM-PGs, the mouse hippocampus and neuronal cell model confirmed that lower neural injury and sodium channel blocking effects were observed in the residual TTX, whose neurotoxicity was lower. Molecular docking simulation and physicochemical analysis revealed that the adsorption of TTX by HM-PGs was a complex adsorption mode driven by the synergy of physicochemical interaction. There were both physical adsorptions based on electrostatic and hydrophobic interactions and chemical binding with strong hydrogen bonding (1.46 Å) and Mayer bond order (0.1229). This study not only developed a new, efficient and safe tool for TTX removal, but also provided a theoretical basis for the development of biological toxin removal material. Full article

Anesthesia is a cornerstone of modern medicine, enabling surgery, pain management, and critical care. Despite its widespread use, the precise molecular mechanisms of anesthetic action remain incompletely understood. Recent advancements in structural biology, including cryo-electron microscopy (Cryo-EM), X-ray crystallography, and computational modeling, have provided high-resolution insights into anesthetic–target interactions. This review examines key molecular targets, including GABA_A receptors, NMDA receptors, two-pore-domain potassium (K2P) channels (e.g., TREK-1), and voltage-gated sodium (Nav) channels. General anesthetics modulate GABA_A and NMDA receptors, affecting inhibitory and excitatory neurotransmission, while local anesthetics primarily block Nav channels, preventing action potential propagation. Structural studies have elucidated anesthetic binding sites and gating mechanisms, providing a foundation for drug optimization. Advances in computational drug design and AI-assisted modeling have accelerated the development of safer, more selective anesthetics, paving the way for precision anesthesia. Future research aims to develop receptor-subtype-specific anesthetics, Nav1.7-selective local anesthetics, and investigate the neural mechanisms of anesthesia-induced unconsciousness and postoperative cognitive dysfunction (POCD). By integrating structural biology, AI-driven drug discovery, and neuroscience, anesthesia research is evolving toward safer, more effective, and personalized strategies, enhancing clinical outcomes and patient safety. Full article

Background/Objectives: As vestibular paroxysmia (VP) has recently been described in children, with an incidence of up to 4% of vertigo, and a promising therapeutic response to sodium-channel-blocking drugs has also been reported, the aim of this paper is to review the available literature on this topic and to provide the best possible guidance for diagnosis and treatment. Methods: PubMed, Medline, Cochrane, and Crossref databases were searched, and all studies on VP in children and sodium channel blockers were selected. Results: Only five articles reporting small case series or single case reports were identified. To date, oxcarbazepine (OXC) and carbamazepine (CBZ) are the only two molecules prescribed. The recommended doses were 300 to 360 mg/day and 50 to 200 mg/day for OXC and CBZ, respectively, for a total duration of 6 weeks. Fast efficacy (one week) was reported. Conclusions: VP has been identified in pediatric patients and appears to respond to sodium channel blockers in a manner similar to adults. Only a limited number of cases have been reported to date; thus, there is a need to raise awareness about this treatable cause of episodic vertigo in children. Full article

Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD₉₀), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the I_Kr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD₉₀ and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD₉₀, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation. Full article

The voltage-gated sodium channel Na_v1.7 is essential for pain perception and is an interesting target for the development of pain-relieving substances. Here, we investigated whether the Na_v1.7 channel is sensitive to harmaline, an alkaloid produced by the North African plant Peganum harmala. To this end, we used Chinese hamster ovary (CHO) cells expressing the human Na_v1.7 channel and studied Na⁺ channel pharmacology with an automated patch-clamp technique. Cells stimulated with depolarizing voltage pulses responded with typical transient inward currents. The Na⁺ channel blocker ranolazine inhibited whole-cell currents in a concentration-dependent manner (IC₅₀: 12.1 µM). Harmaline inhibited both peak and late Na⁺ currents. A complete block was achieved at 300 µM of harmaline, with half maximum inhibition occurring at 35.5 µM. In contrast to ranolazine, the effect of harmaline was voltage independent. Neither the current/voltage curves nor the steady-state inactivation curves were shifted in response to drug application (30 µM). We conclude that the plant alkaloid harmaline, which is used in traditional medicine in North Africa, is an effective blocker of the voltage-gated Na⁺ channel Na_v1.7. Our results offer a rationale for the use of harmaline against certain pain syndromes and rise hopes for the development of a new class of anti-nociceptive drugs targeting Na_v1.7. Full article

Peripheral nerve injuries are a significant concern in surgical procedures, often leading to chronic pain and functional impairment. Despite advancements in imaging, preoperative and intraoperative visualization of peripheral nerves remains a challenge. This study introduces and evaluates a novel tri-iodinated lidocaine-based contrast agent for computed tomography neurography, aiming to enhance the intraoperative visibility of peripheral nerves in vivo. A tri-iodinated lidocaine analogue was synthesized and characterized for its radiodensity, sodium channel binding and nerve affinity. Sodium channel affinity was performed using molecular docking. In vitro contrast enhancement was assessed by comparing the agent’s Hounsfield unit (HU) values with those of Omnipaque, a clinically approved contrast medium. In vivo imaging was conducted on rat sciatic nerves using micro-CT, followed by ex vivo validation. Nerve conduction blockade was assessed via electrical stimulation and histological analysis was performed to evaluate neurotoxicity. Experimental results revealed the tri-iodinated lidocaine analogue to have similar or higher affinity toward voltage-gated sodium channels than the parent lidocaine and a radiodensity comparable to the commercial CT contrast agent Omnipaque in vitro. In vivo, the contrast agent provided CT visualization of the sciatic nerve, with a significant increase in HU values compared to untreated nerves. Electrical stimulation confirmed transient nerve conduction blockade without observable histological damage, supporting its dual role as an imaging and nerve-blocking agent. This study presents a novel tri-iodinated lidocaine-based contrast agent that enables clear CT visualization of peripheral nerves while maintaining reversible nerve inhibition. These findings support its potential application in preoperative planning and intraoperative nerve protection to reduce surgical nerve injuries. Further studies are warranted to optimize imaging conditions and evaluate its clinical feasibility. Full article

Background/Objectives: Low-frequency alternating current (LFAC) has been shown to induce nerve conduction block (LFACb). However, the effects of LFAC on conduction delay prior to block remain unclear. This study investigates the impact of LFACb on conduction velocity and blocking thresholds in myelinated and unmyelinated fibers using experimental and computational models. Methods: Four models were employed to analyze LFACb effects: (1) in-vivo experiments in earthworms examined conduction delays across nerve bundles with distinct conduction velocities; (2) ex-vivo experiments in canine vagus nerves assessed the upstream and downstream effects of LFAC waveforms ranging from 50 mHz to 500 mHz; (3) in-silico simulations using the Horn, Yoshida, and Schild (HYS) model for unmyelinated fibers explored size-dependent conduction delays and blocking thresholds; and (4) in-silico simulations using the McIntyre, Richardson, and Grill (MRG) model extended to 504 Nodes of Ranvier characterized myelination effects, localized nodal interactions, and diameter-dependent thresholds. Results: LFAC-induced conduction delays were independent of LFAC frequency but strongly influenced by fiber diameter and conduction velocity. Larger fibers exhibited lower block thresholds and shorter delays before block onset. In contrast, smaller fibers demonstrated prolonged subthreshold conduction delays before achieving full block. Conclusions: These findings suggest that LFACb could serve as a neuromodulation tool for selectively blocking larger fibers while preserving smaller fiber function. This has potential applications in functional electrical stimulation (FES) and temporary, non-destructive nerve blocks for clinical and research applications. Full article

Breast cancer remains the leading cause of cancer-related mortality among women worldwide, with limited therapeutic efficacy due to treatment resistance and adverse effects. Emerging evidence suggests that ion channels play crucial roles in tumor progression, regulating proliferation, apoptosis, migration, and metastasis. Voltage-gated potassium (Kv) and sodium (Nav) channels have been implicated in oncogenic signaling pathways. Scorpion venom peptides, known for their selective ion-channel-blocking properties, have demonstrated promising antineoplastic activity. This study explores the potential therapeutic applications of bioactive fractions derived from Chihuahuanus coahuilae, in breast cancer cell lines. Through chromatographic separation, mass spectrometry, and functional assays, we assess their effects on cell viability, proliferation, and ion channel modulation. Our preliminary data suggest that these venom-derived peptides interfere with cancer cell homeostasis by altering ion fluxes, promoting apoptosis, and inhibiting metastatic traits. These findings support the therapeutic potential of ion-channel-targeting peptides as selective anticancer agents. Further investigations into their molecular mechanisms may pave the way for novel, targeted therapies with improved efficacy and specificity for breast cancer treatment. Full article

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (I_Na), and transient potassium (I_TO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking I_To. Dose-response analysis indicated that 2Nal acts as a partial antagonist of I_TO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting I_Na. Our lab previously found that an imbalance between I_To and I_Na currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most I_To blockers are cardiotoxic. The selective blockade of I_To by 2Nal that we describe here helps restore the balance of electrical currents between I_To and I_Na. Our study presents a novel, safe partial antagonist of I_To that may help prevent arrhythmias associated with Brugada syndrome. Full article

Tetrodotoxin (TTX) is a neurotoxin that binds to sodium channels and blocks sodium conduction. Importantly, TTX has been increasingly detected in edible aquatic organisms. Because of this and the lack of specific antidotes, TTX poisoning is now a major threat to public health. However, it is of note that ultra-low dose TTX is an excellent analgesic with great medicinal value. These contradictory effects highlight the need for further research to elucidate the impacts and functional mechanisms of TTX. This review summarizes the latest research progress in relation to TTX sources, analogs, mechanisms of action, detection methods, poisoning symptoms, therapeutic options, biosynthesis pathways, and mechanisms of transport and accumulation in pufferfish. This review also provides a theoretical basis for reducing the poisoning risks associated with TTX and for establishing an effective system for its use and management to ensure the safety of fisheries and human health. Full article

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective chloride ion channels. This leads to thick, dehydrated mucus that severely disrupts mucociliary clearance in the respiratory system and triggers infection that eventually is the cause of death of CF patients. Current therapeutic strategies primarily focus on restoring CFTR function, blocking epithelial sodium channels to prevent mucus dehydration, or directly targeting mucus to reduce its viscosity. Among the ion channels expressed in ciliated bronchial epithelial cells, the transient receptor potential vanilloid 4 (TRPV4) channel emerges as a significant channel in CF pathogenesis. Activation of TRPV4 channels affects the regulation of airway surface liquid by modulating sodium absorption and intracellular calcium levels, which indirectly influences CFTR activity. TRPV4 is also involved in the regulatory volume decrease (RVD) process and enhances inflammatory responses in CF patients. Here, we combine current findings on TRPV4 channel modulation as a promising therapeutic approach for CF. Although limited studies have directly explored TRPV4 in CF, emerging evidence indicates that TRPV4 activation can significantly impact key pathological processes in the disease. Further investigation into TRPV4 modulators could lead to innovative treatments that alleviate severe respiratory complications and improve outcomes for CF patients. Full article

High fat diets have been used as complementary treatments for seizure disorders for more than a century. Moreover, many fatty acids and derivatives, including the broad-spectrum antiseizure medication valproic acid, have been explored and used as pharmacological agents to treat epilepsy. In this work, we have explored the anticonvulsant potential of a large library of fatty acids and fatty acid derivatives, the LIPID MAPS Structure Database, using structure-based virtual screening to assess their ability to block the voltage-gated sodium channel 1.2 (NaV1.2), a validated target for antiseizure medications. Four of the resulting in silico hits were submitted for experimental confirmation using in vitro patch clamp experiments, and their protective role was evaluated in an acute mice seizure model, the Maximal Electroshock seizure model. These four compounds were found to protect mice against seizures. Two of them exhibited blocking effects on NaV1.2, CaV2.2, and CaV3.1. Full article

Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory–secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE^−/−) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel. Full article

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was studied. The stability constants demonstrated a greater affinity of SBE-β-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-β-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed. Full article