Search Results (1,030)

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article

Scorpion neurotoxins are small peptides that target ion channels and offer opportunities for novel therapeutic discovery. This study analyzed the functional effects of the venom and toxins from the Costa Rican endemic scorpion, Tityus championi. Initially, crude venom was tested on different isoforms of voltage-gated sodium channels. Our findings revealed that the venom contains toxins that affect mammalian Na_V1.6 and Na_V1.7, as well as the cockroach BgNa_V1 channel. Increased currents through Na_V1.6 and BgNa_V1 channels were associated with bigger window currents and inhibition of inactivation. Decreased Na_V1.7 currents were associated with smaller conductance. Crude venom and TCh3 toxin inhibited action potential generation in invertebrate neurons expressing Na_V1.7-like channels. In these neurons, Tch2 and Tch4 toxins shifted voltage sensitivity to more negative potentials, ultimately widening the window current but decreasing channel availability. Conversely, Tch3 behaved as an inhibitory toxin, closing window currents and decreasing channel availability. Structural modeling showed that Tch3 adopts an αββ fold and binds the S3–S4 loop of Domain II in human Na_V1.7. These data show the diverse effects of scorpion venoms on channels and neurons, characterize its principal toxins, and show that Tch3 has therapeutic potential for pain relief. Full article

Alkali-activated solid waste-based geopolymer represents a novel form of inorganic cementitious material, which is one of the key research directions in the building materials field to achieve the targets of carbon peak and carbon neutrality. Therefore, taking solid waste materials as raw materials to prepare the alkali-activated solid waste-based geopolymers with better mechanical properties is of significant importance for expanding the utilization channels of industrial solid waste materials in Hebei Province. In this study, three solid waste materials, slag, iron tailings sand and coal gangue powder, were used as the precursors of geopolymer, and solid sodium silicate was used as the activator to prepare the solid waste-based geopolymer. Response surface methodology was adopted to design the composition of the geopolymer, and the dosages of slag, Na₂O and coal gangue powder were taken as design variables, and the compressive strength of the geopolymer at 7 days and 28 days were taken as response variables. The results show that it is feasible to optimize the composition of solid sodium silicate-activated solid waste-based geopolymer (SSG) by using response surface methodology. The error value of the SSG-mortar compressive strength prediction model is below 2.0%. The slag contents exhibit a positive correlation with the compressive strength of SSG-mortar, but the coal gangue powder contents and Na₂O contents have a negative correlation. The optimized compositions of SSG-mortar are 20% iron tailings sand, 26% coal gangue powder, 54% slag, and 6.41% Na₂O (regulated by 6.23% solid sodium silicate and 6.23% solid NaOH granules), and the corresponding compressive strengths of SSG-mortar at 7 days and 28 days are 37.1 MPa and 44.9 MPa, respectively. In addition, dry shrinkage tests, wet–dry cycling tests, freeze–thaw cycling tests, salt corrosion tests, SEM analysis and XRD analysis were conducted on the SSG-mortar with the optimal composition to evaluate its shrinkage behavior, freeze–thaw resistance, salt corrosion resistance and microstructural strengthening mechanisms. The results show that SSG-mortar has relatively good frost resistance and salt erosion resistance. The mass loss rate value and compressive strength loss rate value of SSG-mortar are 1.67% and 18.7%, respectively, after 100 freeze–thaw cycles. Furthermore, the corrosion resistance coefficient value of SSG-mortar is greater than 92%, and the mass loss rate value is lower than 2.4%. The SEM and XRD test results display that, in an alkaline environment, the interwoven consolidation of hydrated gels (including C-S-H gel, C-A-S-H gel, C-(N)-A-S-H gel and N-A-S-H gel) and the filling effect of solid wastes jointly achieve an improvement in the properties of SSG-mortar. Full article

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D₁-like receptor family (D₁R and D₅R) and the D₂-like receptor family (D₂R, D₃R, and D₄R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension. Full article

Background: The growing demand for sustainable, high-performance energy storage systems has intensified interest in biomass-derived materials for supercapacitor applications. This study presents a green and scalable approach to fabricating novel electrodes and solid-state electrolytes using Phoenix dactylifera (Ajwa date) seed biomass and palm waste-derived activated carbon. Methods: KOH-activated carbon from date pits was employed to enhance surface area and redox activity. A double-network hydrogel electrolyte (DSHC) was synthesized by incorporating 0.5 g of date seed powder with sodium alginate and wheat starch (0.2 g each), followed by chemical crosslinking in 2 M H₂SO₄. Structural and physicochemical properties were analyzed using SEM, XRD, and FTIR, while electrochemical performance was evaluated through cyclic voltammetry and galvanostatic charge–discharge measurements. Results: SEM revealed a densely ordered porous network with regular cylindrical channels favorable for ion transport. XRD and FTIR confirmed amorphous carbon formation and effective molecular crosslinking. The hydrogel electrolyte exhibited a wide potential window of ~2 V and strong pseudocapacitive behavior, delivering a maximum specific capacitance of 179 F g⁻¹ at 5 mV s⁻¹ and a discharge capacitance of 159 F g⁻¹ at 0.2 A g⁻¹, with excellent stability over 5500 cycles. Conclusions: Agricultural waste-derived materials demonstrate strong potential as low-cost, eco-friendly, and mechanically robust components for flexible supercapacitors, suitable for sustainable energy storage and rapid-charging applications. Full article

Graphene-based ion-sensitive field-effect transistors can operate as biosensors by utilizing the formation of an electric double layer at the interface between the electrolyte and the graphene channel, enabling high sensitivity, scalability, and cost-effective fabrication. In this work, we focus on the working principles and current methodologies associated with these devices, making a comparative analysis of different models that describe the electric double layer in the electrolyte, referring to sodium ions (Na⁺) as a case study for the detection performance of the graphene biosensor, and taking into account the impact of graphene quantum capacitance. Our study addresses the sensitivity of graphene field-effect transistors within the framework of the Gouy–Chapman model, as well as the Stern model, computing device sensitivities of 3200 V/M and 5500 V/M, respectively. By incorporating the impact of graphene’s quantum capacitance in the calculations, increased sensitivity up to 5620 V/M was found. The present work shines light on the rationalization of graphene-based biosensors’ operation and performance. Full article

Salt stress inhibits plant growth, requiring salt-tolerant genes for the development of resilient plants. A key tolerance mechanism is potassium/sodium homeostasis, governed by Shaker K⁺ channels. Given that Shaker K⁺ channels from salt-sensitive species have been extensively studied while their counterparts in salt-tolerant plants remain largely unexplored, this study investigates the evolution and function of these channels in salt-tolerant bermudagrass to address this knowledge gap. Genomic analysis identified 25 Shaker K⁺ channel genes, an expanded family relative to other species. Phylogenetics placed them into five groups (I–V), with groups I, II, III, and V expanded via segmental duplication. Salt stress response screening revealed that only CdKAT1.1 was rapidly upregulated. Functional assays in yeast demonstrated that both CdKAT1.1 and its closest homolog CdKAT1.2 improve potassium uptake and salt tolerance, but the enhancement from CdKAT1.1 was significantly greater. This work elucidates the expansion and functional divergence of Shaker K⁺ channels in bermudagrass. CdKAT1.1 emerges as a superior regulator of potassium efficiency and salt tolerance, making it a prime candidate for molecular breeding to improve plant resilience in saline-alkaline soils. Full article

Dry eye disease (DED) is an ocular surface disorder characterized by tear film instability, inflammation, epithelial damage, and neurosensory abnormalities. Due to its multifactorial etiology and pathophysiology, conventional therapies that focus on lubrication and immunosuppression often fall short in addressing the neuropathic component of ocular pain experienced by a growing subset of patients. Recent developments in sensory neuroscience have highlighted the pivotal role of ion channels in mediating ocular surface homeostasis, pain signaling, and inflammation. This review examines the role of the following major ion channel families in the pathophysiology of DED and neuropathic ocular pain: transient receptor potential (TRP) channels, voltage-gated sodium (Nav) channels, and purinergic P2X receptors. The review details their anatomical distribution, molecular function, and responses to environmental stimuli such as heat, cold, osmolarity, and injury. Current treatments, such as artificial tears, anti-inflammatory drops, and systemic neuromodulators, are also reviewed in relation to their effects on ion channel modulation. Additionally, emerging therapies that directly target sensory transduction pathways are introduced. This review highlights the therapeutic potential of ion channel modulation in personalizing treatment for patients with ocular surface pain, particularly those with neuropathic features unresponsive to standard care. Full article

Synthesized more than 60 years ago, vinpocetine—the active ingredient of Cavinton^®, with over five decades of clinical use—has remained the subject of extensive investigation, particularly during the past 15 years. During this time, a large body of experimental preclinical evidence has accumulated demonstrating its neuroprotective potential and complex mechanisms of action in cerebral ischemia–hypoxia. Comprehensive in vitro studies and animal experiments have significantly elucidated the molecular basis of vinpocetine and the signaling pathways through which it prevents or mitigates ischemic injury. In this review, we summarize earlier and more recent experimental results that highlight the multifaceted nature of vinpocetine’s neuroprotective actions, which include inhibition of phosphodiesterase type 1, blockade of voltage-dependent NaV1.8 channels, reduction of oxidative stress, and suppression of neuroinflammatory processes triggered by cerebral ischemia–hypoxia. Taken together, it can be hypothesized that, under in vivo conditions, vinpocetine’s individual actions are additive or synergistic, thereby contributing in a combined manner to recovery from cerebral ischemic insult. Full article

The mechanism of action of drugs used to treat ADHD has not been fully elucidated. The aim of the study was to assess the effect of clonidine, a drug used to treat ADHD, on interictal-like epileptiform events in prefrontal cortex pyramidal neurons. Epileptiform events (lasting less than 3 s) were recorded in a zero-magnesium and elevated-potassium proepileptic extracellular solution using the patch-clamp methodology. Clonidine 100 µM reduced the frequency of epileptiform events. Moreover, clonidine hyperpolarized the membrane potential recorded in the proepileptic extracellular solution. In the constant presence of the alpha-2 adrenergic receptor antagonist idazoxan 20 µM in all solutions, clonidine 100 µM also inhibited the frequency of interictal-like epileptiform events. This suggests that clonidine inhibited the frequency of interictal events via a direct influence on ionic channels. Furthermore, clonidine inhibited tonic NMDA receptor currents and did not influence tonic AMPA currents. The tested drug inhibited fast-inactivating voltage-gated sodium currents. Blockade of NMDA currents and voltage-gated sodium currents likely contributed to the inhibition of epileptiform events exerted by clonidine. The potential translational relevance of the study is discussed. Full article

Background: Brugada syndrome (BrS) is a genetic cardiac arrhythmia disorder inherited in an autosomal dominant manner, characterized by ST-segment elevation in the right precordial leads (V1–V3) on electrocardiograms (ECGs). This syndrome predominantly affects young individuals with structurally normal hearts and significantly increases the risk of ventricular arrhythmias and sudden cardiac death (SCD). The most common genotype found among BrS patients is caused by variants in the SCN5A gene, which lead to a loss of function of the cardiac sodium channel Nav1.5 by different mechanisms. Methods: Plasmids containing SCN5A were constructed using PCR and site-directed mutagenesis to create the D372H variant. HEK293 cells were cultured and transfected with the WT, D372H, or a combination of both plasmids. Patch-clamp recordings assessed sodium current characteristics. Confocal microscopy visualized channel localization. Quantitative RT-PCR was used to analyze mRNA expression levels, while Western blot evaluated protein expression using specific antibodies. Results: In HEK293 cells expressing the D372H mutant, functional assays revealed a near-complete loss of sodium currents. Co-transfection of WT and D372H plasmids resulted in a significant reduction in current density compared with WT alone, while activation, inactivation, and recovery kinetics were unaffected. In addition, both the mutant protein and protein expressed in co-transfected cells exhibited reduced fluorescence intensity, indicating decreased expression levels. These findings were further supported by Western blot and RT-qPCR analyses. Conclusions: In summary, our findings indicate that the D372H variant produces a marked reduction in Nav1.5 function through reduced sodium current density and decreased channel expression. Given its critical position within the DI-pore loop, this defect is expected to markedly diminish the inward sodium current necessary for normal depolarization. Such impaired excitability—particularly relevant in the right ventricular outflow tract—may accentuate regional differences in repolarization and create conditions that favor reentrant activity. These findings provide mechanistic insights into how the p.D372H variant alters Nav1.5 channel function in vitro and offer functional evidence that may assist in interpreting its potential relevance to Brugada syndrome. Full article

The Hodgkin–Huxley equations have successfully described neuronal excitability for over seventy years, yet their mathematical structure remains empirically justified rather than theoretically explained. Why are gating variables bounded between 0 and 1? Why does sodium conductance depend on m³h rather than other combinations? Why does potassium depend on n⁴? Why do all rate functions contain exponential voltage dependencies? Why are the kinetics first-order? We demonstrate that these structural features arise naturally from three fundamental physical symmetries governing ion channel dynamics: the compactness of conformational state space, the scaling invariance of membrane conductance, and temporal translation invariance. Using Lie group theory, we show that these symmetries uniquely determine a mathematical structure in which: (1) gating variables are necessarily bounded, (2) voltage dependencies must be exponential, (3) exponents must be integers, and (4) kinetics must be first-order. The Hodgkin–Huxley equations, rather than mere empirical fits, emerge from fundamental symmetry principles. This framework establishes that neural electrophysiology obeys the same theoretical principles as modern physics, where symmetries constrain the form of dynamical equations. It further provides a principled basis for interpreting deviations from classical behavior as manifestations of additional symmetries or symmetry breaking. Full article

Maintaining a membrane electrical potential of biological cells is a dynamic process, as some cells have a continually changing potential, like pacemaker cells, while other cells may function with large or small changes in the membrane potential. Additionally, some cells may change their electrical potential when stimulated or inhibited by electrical signals, chemical compounds, or both—either simultaneously or episodically. The persistent leak of K⁺ through two-pore-domain potassium channels (K2P) and of Na⁺ through Na⁺ leak channels (NALCNs) and the action of pumps and exchangers are primarily responsible for maintaining a resting potential. Ca²⁺ ions are known to block the NALCNs and result in a more hyperpolarized membrane potential, with a reduction in Ca²⁺ resulting in a depolarized state. Using the larval muscles of Drosophila, the membrane potentials were monitored as Ca²⁺ and Mg²⁺ concentrations were altered. Changes as large as 20 mM of Mg²⁺ had only small effects (1 to 2 mV) on the membrane potential compared to 3–5 mM changes in Ca²⁺ having larger effects (5–10 mV). Although, it appears raised [Mg²⁺] may dampen the changes induced by Ca²⁺. Simulations of the G-H-K equation estimate the changes in permeability of Na+ (pNa). These experiments are significant, as the clinical severity of hypocalcemia and hypercalcemia may also depend on Mg²⁺ levels. Full article

Huwentoxin-XI (HWTX-XI) is a 55-amino acid peptide belonging to the family of spider Kuntiz-type toxins (KTTs), isolated from the venom of the Chinese tarantula Cyriopagopus schmidti. Under whole-cell voltage-clamp conditions, HWTX-XI was found to block Kv1.1 potassium channels but had no effect on other potassium channel subunits (Kv1.4, Kv2.1, Kv3.1 and Kv4.2), sodium channels or calcium channels. In the present study, it was found that the substitution of Tyr379 by the valine in the filter region significantly decreased the affinity of toxin HWTX-XI by about 90-fold, indicating that the Kv1.1 filter region is a critical determinant of HWTX-XI potassium channel activity. After intrathecal or intraplantar injections, HWTX-XI decreased the mechanical nociceptive threshold (hyperalgesia) for a long-lasting period. HWTX-XI also significantly increased the firing frequency in mouse DRG neurons. The novel function of HWTX-XI makes it a new tool for studying the relationship between spider toxins and Kv1.1 channels and suggests that Kv1.1 channels might be a novel potential target for preventing and/or treating neuropathic pain. Full article

Peptides from scorpion venom, mainly in species such as Olivierus martensii (formerly Olivierus martensii Karsch, often designated BMK) (BmK) and Tityus serrulatus from the Buthidae family, show real promise as painkillers that skip opioids altogether. They work by hitting specific ion channels and dialing down inflammation. This review gathers information on their molecular setups: disulfide-bridged types and those without, weighing in at 3 to 10 kilodaltons (kDa). Structural features include motifs stabilized by cysteines. In pain signaling, they block voltage-gated sodium channels (NaV) such as NaV1.7 and NaV1.8; take the BmK analgesic–antitumor peptide (BmK-AGAP) for example. Additionally, scorpion venom heat-resistant peptide (SVHRP) reduces microglia activity. Tests on rodents using formalin injections, acetic acid writhing, and chronic constriction injury (CCI) setups reveal pain relief that depends on dose and stacks up to morphine. Pairings like AGAP with lidocaine decrease the effective dose by half. In terms of safety, therapeutic levels have low-toxicity with a median lethal dose (LD50) over 20 mg/kg. Issues crop up with immune responses, unintended targets, and differences in venom batches. Clinical information remains thin, so gaps persist. Engineered versions could change the game for neuropathic pain, inflammatory conditions, and cancer-related discomfort. Standardization plus Phase I studies would help move this forward. Full article