Search Results (855)

Neuroblastoma is an aggressive pediatric malignancy with limited therapeutic options for high-risk disease, underscoring the need for alternative treatment strategies. Drug repurposing offers a promising approach to accelerate the identification of effective anti-cancer agents. In this study, we investigated the anti-carcinogenic effects of hydroquinidine, a class IA antiarrhythmic ion channel blocker, and spiramide, a dopamine D₂/serotonin 5-HT₂ receptor antagonist and endoplasmic reticulum stress inducer, in SH-SY5Y human neuroblastoma cells. Cells were treated with increasing concentrations of each compound and evaluated using cell viability, colony formation, wound healing, proliferation, apoptosis, and quantitative gene expression assays. Both compounds induced a dose-dependent reduction in cell viability, with spiramide exhibiting greater potency than hydroquinidine. Functional assays revealed significant suppression of clonogenic survival, cell migration, and DNA synthesis, accompanied by increased oxidative stress and cell death. Molecular analyses demonstrated coordinated transcriptional regulation of apoptosis- and cell cycle-related genes, characterized by upregulation of BAX, CDKN1A, and CDKN1B, and downregulation of BCL-2 and CCND1. Notably, spiramide consistently produced stronger cytotoxic and wound-closure inhibitory effects, suggesting a greater contribution of oxidative stress- and apoptosis-associated pathways. Collectively, these findings indicate that hydroquinidine and spiramide disrupt neuroblastoma cell growth through complementary stress- and cell cycle-associated pathways and identify them as promising candidates for further preclinical evaluation. Full article

Chloride (Cl⁻) is an essential micronutrient for plants that supports multiple physiological functions throughout plant growth and development. Its effects are strongly concentration-dependent: low Cl⁻ availability promotes beneficial physiological processes, whereas excessive accumulation can induce cytotoxicity. In plants, the movement of Cl⁻ across plasma and organellar membranes is primarily mediated by three principal channel and transporter families: chloride channels (CLC), aluminum-activated malate transporters (ALMT), and slow anion channel-associated homologs (SLAC/SLAH). These families differ in gating mechanisms, ion selectivity, transport properties, and subcellular localization. This review synthesizes current knowledge of plant chloride transport proteins, with emphasis on their phylogenetic distribution, structural organization, and functional diversification. We summarize their core physiological roles in stomatal regulation, water-use efficiency, nutrient uptake, ion homeostasis, growth modulation, and abiotic stress tolerance. We also discuss how their activities are regulated by post-translational modifications, notably phosphorylation and dephosphorylation, as well as by ion concentrations, pH shifts, and phytohormone signaling. Unlike earlier reviews that primarily focused on individual transporter families or specific stress responses, this work provides an integrated framework linking structure–function relationships with regulatory networks. It also evaluates recent advances in high-resolution structural biology, electrophysiological approaches, and in vivo imaging techniques. Furthermore, we delineate current technical bottlenecks and unresolved questions, such as the molecular determinants of substrate specificity and potential cross-talk among transporter families, and propose future directions for crop improvement. By integrating structural, physiological, and regulatory perspectives, this review aims to serve as a valuable reference and stimulate interdisciplinary research on plant chloride biology. Full article

Mastication is a fundamental rhythmic motor behavior controlled by a brainstem central pattern generator (CPG) located within the pontine and medullary reticular formations. Coordinated activation of jaw-opening and jaw-closing muscles is generated by this network and continuously refined through sensory feedback from periodontal mechanoreceptors and muscle spindles, together with descending inputs from the cortical masticatory area (CMA), basal ganglia, and cerebellum. Thus, mastication is regulated by distributed neural circuits rather than a single central locus. At the cellular level, the rhythmic activity of the masticatory CPG depends on the coordinated action of voltage-gated and ligand-gated ion channels. Recent electrophysiological and computational studies have identified candidate conductances that are proposed to underlie rhythm generation. Persistent sodium currents are proposed to facilitate burst initiation, whereas T-type calcium channels are thought to promote burst activation through post-inhibitory rebound. HCN channels may contribute to rhythmic timing, while calcium-activated potassium channels are thought to participate in burst termination. This review summarizes the hierarchical neural control of mastication and the biophysical mechanisms by which ion channels shape CPG rhythmogenesis. It also discusses the impact of channelopathies and neurodegenerative disorders on masticatory function, highlighting potential ion-channel-targeted therapeutic approaches for temporomandibular disorders, bruxism, and impaired mastication. Full article

Sperm activation and movement are pivotal determinants of fertilization success in teleosts, yet the molecular mechanisms in euryhaline species remain largely unresolved. Here, we integrated physiology and multi-omics to elucidate the osmolality, ions, and regulatory networks underlying sperm activation and movement in spotted seabass (Lateolabrax maculatus). Spotted seabass sperm showed strong motility across a broad osmotic range of 500 to 1200 mOsm/kg, with Na⁺ and K⁺ promoting motility and Ca²⁺ exerting inhibitory effects. Integrated transcriptomics and proteomics identified 29 genes and 6 proteins as candidate molecules associated with Na⁺ and K⁺ signaling, Ca²⁺ signaling and apoptosis, and energy metabolism. Up-regulation of NHE1 suggested a potential involvement of Na⁺/H⁺ exchange that regulated Na⁺ influx, while K⁺ influx via activated K⁺ channels may depolarize membrane potential. The capn1 was up-regulated, which may be associated with Ca²⁺-mediated apoptosis. Euryhaline fishes exhibited a broader osmotic activation range than freshwater and marine species, underscoring the critical roles of osmotic adaptability in fish sperm physiology. Ionic regulation patterns of euryhaline fishes are generally consistent with their environmental adaptation, with seawater-adapted species resembling marine fishes and freshwater-adapted species resembling freshwater fishes. Our findings highlight the integrated roles of osmotic effects and ionic regulation, providing insights into sperm activation and movement in euryhaline spotted seabass. Full article

Atherosclerosis is a chronic inflammatory disease characterized by progressive vascular dysfunction and remains a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial dysfunction is an early and critical event in atherogenesis, contributing to inflammation, leukocyte recruitment, plaque progression, and thrombotic complications. Increasing evidence indicates that vascular endothelial cells use bioelectrical signaling mechanisms to integrate mechanical, metabolic, and inflammatory cues and maintain vascular homeostasis. At the core of these regulatory networks are ion channels and transporters, which coordinate membrane potential, ionic fluxes, calcium homeostasis, redox balance, and downstream biochemical signaling to regulate endothelial function in vascular health and disease. Dysregulation of these pathways may promote oxidative stress, inflammation, endothelial senescence, apoptosis, endothelial-to-mesenchymal transition, and impaired vasodilatory function, thereby contributing to atherosclerotic progression. Understanding how ion channels regulate endothelial function may provide important insights into atherosclerosis and facilitate the development of novel therapeutic strategies aimed at restoring endothelial homeostasis and reducing cardiovascular risk. Full article

The protective effect of Compound terminalia chebula extract (HL) against colonic injury induced by Porcine epidemic diarrhea virus (PEDV) infection in neonatal piglets remains unclear. This study aimed to evaluate the mitigating effects of HL on PEDV-induced colonic injury and elucidate the underlying mechanisms. Eighteen 7-day-old Duroc × Landrace × Large White piglets (2.58 ± 0.05 kg) were randomly assigned to three groups (n = 6/group): CON (blank control), PEDV (infected), and HL + PEDV (HL-supplemented + infected). The 11-day trial included 3 days of acclimatization (days 0–3) and an 8-day experimental period (days 4–11). HL (10 mg/kg BW) was orally administered daily to the HL + PEDV group. On day 8, PEDV and HL + PEDV groups were challenged with 3 mL PEDV (3 × 10⁶ TCID₅₀/mL), while CON received Dulbecco’s Modified Eagle Medium (DMEM). All piglets were euthanized on day 11 for colonic tissue collection. Results indicated that PEDV infection induced colonic injury, manifested by a significant increase in crypt depth and disruption of intestinal homeostasis. This was evidenced by impaired barrier integrity (upregulation of matrix metalloproteinase-7 gene [MMP7] and matrix metalloproteinase 13 gene [MMP13], mucus disorganization (elevation of mucin 5AC gene [MUC5AC]), oxidative stress (reduced catalase [CAT] activity and increased malondialdehyde [MDA] levels in serum and colon), and inflammation (upregulation of regenerative islet-derived protein 3γ gene [REG3G], S100 calcium-binding protein A8/A9 gene [S100A8/A9], and interleukin-1β gene [IL-1β]). Additionally, PEDV impaired colonic ion transport by downregulating calcium channel genes (Transient Receptor Potential Cation Channel Subfamily V Member 6 gene [TRPV6], Transient Receptor Potential Cation Channel Subfamily M Member 6 gene [TRPM6]). Notably, HL supplementation effectively reversed these adverse effects. HL restored colonic morphology, increased CAT activity, reduced MDA accumulation, and suppressed inflammatory gene expression. Furthermore, HL modulated the expression of genes involved in water and ion transport upregulating Aquaporin 7 gene (AQP7), Chloride Channel Accessory 4 gene (CLCA4), Sodium-Hydrogen Exchanger 3 gene (NHE3), Transient Receptor Potential Vanilloid 6 (TRPV6), and Transient Receptor Potential Melastatin 6 gene (TRPM6) and significantly inhibited PEDV replication, as indicated by the downregulation of the transcription levels of PEDV membranegene (M), nucleocapsid gene (N), and spike gene (S). Taken together, HL alleviates PEDV-triggered colonic tissue damage in suckling piglets via improving colonic antioxidant capacity, mitigating inflammatory response, partially regulating intestinal barrier and ion/water transport-related genes, and downregulating the transcription of PEDV structural genes at molecular and histological levels. Full article

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management. Full article

Dental fluorosis (DF) is a common endemic disease that damages dental enamel. Traditionally, DF has been attributed to environmental fluoride overload. Accumulating evidence has demonstrated that genetic factors also modulate individual susceptibility. No dedicated fluoride ion channels have been identified in mammalian cells; fluoride uptake is believed to occur mainly through passive diffusion of HF and nonspecific anion pathways, including chloride channels. Different types of chloride channels are expressed in dental tissues, such as CFTR and voltage-gated chloride channels (ClCs), but it remains unknown whether these channels transport fluoride and whether their variants influence DF risk. This study combined human population-based investigations, mouse and zebrafish models, and in vitro experiments to confirm the significant genetic association of CFTR and CLCN3 variants with DF. A total of 889 DF cases and 834 matched controls were recruited from the same fluoride-contaminated region. Tag SNP screening of CFTR and eight ClC chloride channel genes (CLCNs) revealed that rs213950 in CFTR and three SNPs in CLCN3 were significantly associated with DF. CFTR and ClC-3 showed different fluoride tolerances. rs213950 in CFTR affected the efficiency of fluoride ion transport in Xenopus oocytes. ClC-3 enabled yeast cells to resist fluoride toxicity, whereas clcn3 deficiency disrupted tooth and craniofacial development in zebrafish. Fluoride exposure altered nucleoprotein binding to the rs10520161 region and changed the mRNA levels of various ClC-3 transcripts. These transcripts displayed different subcellular locations and fluoride conductances and acted synergistically to confer fluoride resistance. Together, these findings raise the possibility that variants in CFTR and CLCN3 may act synergistically to influence DF susceptibility. This potential interplay highlights DF as a complex trait involving dysregulated fluoride handling and underscores the multifactorial, gene-directed regulation of fluoride transport. Full article

Piezo1 mechanosensitive ion channels convert mechanical stimuli into biochemical signals across diverse tissues, yet their role in the contractile function of adult skeletal muscle remains unclear. Here, we demonstrate that Piezo1 regulates skeletal muscle mechanics through a channel-independent mechanism that tunes the length-tension relationship. We examined the effects of pharmacological modulation using the Piezo1 agonist Yoda1 and antagonist Dooku1 in individual muscle fibers from wild-type mice and from muscles with reduced Piezo1 expression (anti-Piezo1 shRNA) using calcium influx and electrophysiological assays. Ex vivo force measurements were performed on these muscles and compared with the dystrophic mdx model. Piezo1 activation had no effect on force at resting length, whereas its inhibition significantly reduced contractile force at stretched lengths, indicating a selective role in length-dependent force regulation. This effect was independent of extracellular calcium and diminished by Piezo1 knockdown. This reduction was absent in mdx muscle, demonstrating dependence on an intact dystrophin-associated cytoskeleton. These findings identify Piezo1 as a previously unrecognized regulator of muscle mechanical performance that operates independently of ion conduction. Our results uncover a mechanobiological interface between Piezo1 and cytoskeletal integrity, expanding current concepts of muscle mechanoregulation and highlighting Piezo1 as a potential therapeutic target for improving muscle function. Full article

Potassium (K⁺) channels have been frequently linked to cancer progression; however, their contribution varies across tumour types and experimental models. This heterogeneity indicates that gene-level characteristics such as expression, co-expression, or mutational status are inadequate for explaining channel involvement in oncogenic signalling. Here, we performed a cross-study comparison of experimentally validated K⁺ channel interactomes, we show that K⁺ channel regulation is highly context-dependent and does not exhibit conserved pan-cancer signatures. By directly comparing proximity-labeling and affinity-purification datasets across different K⁺ channel families, we identify a limited number of recurrent organizational architectures rather than universal signalling modules. KCa3.1 (encoded by KCNN4), Kir2.1 (KCNJ2), and TASK-1 (KCNK3) assemble signalling-permissive interactomes integrating adhesion complexes, junctional scaffolds, vesicular trafficking pathways, and receptor-associated signalling nodes. In contrast, Kv11.1 (encoded by KCNH2) displays an interactome predominantly enriched for proteostasis and endoplasmic reticulum–associated components, indicating a proteostasis-centered organizational profile with comparatively limited signalling integration. Kv1.3 (encoded by KCNA3), instead, consistently associates with mitochondrial and metabolism-linked proteins and functionally connects metabolic state to downstream transcriptional regulators, rather than regulating its own transcription. Higher-order intersection and pathway-specific analyses indicate that functional convergence across the above channels emerges from shared architectural principles rather than extensive molecular overlap. In conclusion, this study identifies interactome architecture as a central organizational level for understanding K⁺ channel function in cancer. The integration of pan-cancer gene-level analyses with systematic comparison of interaction architectures offers a coherent framework for interpreting the functional heterogeneity observed across channels, families, and tumor contexts. This perspective suggests that therapeutic strategies may benefit from targeting channel-centered network architectures rather than isolated channels alone, highlighting ion channels as structural components of broader signalling systems rather than solely bioelectrical regulators. Full article

Cancer remains one of the deadliest health problems worldwide. Traditional and multifaceted treatment approaches often fail to achieve expected outcomes. Consequently, it is essential to develop innovative and effective treatment strategies. Ion channels play a critical role in regulating fundamental cellular events, such as cell proliferation, differentiation, and programmed cell death. In this context, the current literature increasingly demonstrates the potential of ion channel modulators to suppress tumor growth. Approaches targeting ion channels have gained increasing importance in cancer research in recent years. Drug delivery systems, particularly hydrogels, play crucial roles in enhancing the therapeutic efficacy of these agents. This review addresses the current developments in the antitumor effects of ion channel modulators within the context of hydrogel-based delivery strategies. Considering the pharmacokinetic advantages, controlled release properties, and targeted delivery capacity of these systems, their biocompatibility, stability, and limitations in clinical applications are also evaluated. Thus, innovative perspectives are presented to address the shortcomings in current cancer treatment approaches. Full article

Voltage-gated ion channels (VGICs) are traditionally associated with electrically excitable cells; however, increasing evidence indicates that they are also expressed in non-excitable cells, including vascular endothelial cells. This review aims to summarize the current knowledge on the expression, regulation, and functional role of VGICs in the vascular endothelium, and to highlight their potential contribution to endothelial signaling. We examined the molecular structure, biophysical properties, and functional roles of voltage-gated Na⁺ (Na_V), Ca²⁺ (Ca_V), and K⁺ (K_V) channels in vascular endothelial cells. Particular attention was given to studies investigating VGIC activity in native endothelium and to emerging mechanisms regulating their activation. Endothelial cells express multiple VGIC subtypes at low densities, which are insufficient to generate action potentials but can modulate membrane potential (V_M) and Ca²⁺-dependent signaling. The dynamic regulation of the endothelial V_M, through the interplay between hyperpolarizing and depolarizing conductances, emerges as a key determinant of VGIC availability and activation. VGICs contribute to essential endothelial functions, including angiogenesis, vasomotor responses, blood–brain barrier permeability, and inflammation. Dysregulated VGIC expression and/or activity may be implicated in several pathological conditions, such as atherosclerosis, calcific aortic stenosis, and tumor vascularization. VGICs represent an unexpected but functionally relevant component of endothelial signaling. Elucidating their role in native vascular beds and disease contexts may uncover novel mechanisms of endothelial regulation and identify new therapeutic targets in cardiovascular and cancer biology. Full article

Background: Pulmonary arterial hypertension (PAH) is a rare and progressive disorder characterized by increased pulmonary vascular resistance and vascular remodeling. Genetic polymorphisms, epigenetic modifications, and ion channel dysregulation are increasingly recognized as key contributors to disease pathogenesis. Anoctamin-1 (ANO1/TMEM16A), a calcium-activated chloride channel, plays a critical role in vascular tone regulation. Objective: This study aimed to investigate the association between ANO1 gene polymorphisms (rs7127129 and rs2509153), promoter methylation status, and serum chloride levels in patients with idiopathic pulmonary arterial hypertension (IPAH), congenital heart disease (CHD), and chronic thromboembolic pulmonary hypertension (CTEPH). Methods: A total of 106 IPAH patients, 40 CHD patients, and 30 CTEPH patients, together with 125 healthy controls, were included. The control group had a comparable age distribution, with a balanced sex ratio, whereas females predominated in all three PH groups. Genotyping was performed using TaqMan-based real-time PCR. Promoter methylation was analyzed using bisulfite conversion followed by quantitative real-time PCR. Serum chloride levels were measured using an ion-selective electrode method. Results: No significant association was observed between rs7127129 and rs2509153 polymorphisms and IPAH or CTEPH (p > 0.05). However, rs7127129 showed a significant association with CHD (p < 0.05). After excluding hypertensive patients, both polymorphisms remained significantly associated with CHD. Serum chloride levels differed significantly among groups (p < 0.001), with higher levels observed particularly in the CTEPH and CHD groups compared to controls, while IPAH patients exhibited intermediate but still elevated levels relative to controls. In contrast, promoter methylation levels were significantly lower in all patient groups compared to controls. An inverse relationship between chloride levels and methylation status was observed. Conclusions: ANO1 polymorphisms are not major determinants of IPAH or CTEPH but may contribute to CHD susceptibility. Increased serum chloride levels, together with decreased promoter methylation, suggest a potential mechanistic link between ion channel dysregulation and epigenetic alterations in pulmonary hypertension. Further large-scale and functional studies are warranted. Full article

Lipids are commonly viewed as membrane components, energy sources, or precursors of signaling molecules, yet accumulating evidence indicates a broader role in determining the functional state of cells. In this review, we present an integrative cross-domain synthesis in which lipids are discussed as important modulators of cellular functional state across inflammation, tissue regeneration, and chronic disease. We discuss how membrane lipid composition shapes receptor and ion-channel signaling, how bioactive lipid mediators govern the balance between inflammatory initiation and resolution, and how lipid metabolism regulates stem-cell quiescence, activation, and regenerative capacity. We integrate these mechanisms to show how disruption of lipid-regulated processes may bias tissues toward persistent inflammation, impaired repair, and disease progression in conditions such as rheumatic disorders, fibrosis, and neurodegeneration. Depending on context, such lipid alterations may function as causal contributors, permissive conditions, or downstream signatures of pathological state transitions. Finally, we consider how pharmacological and nutritional modulation of lipid pathways may influence cellular states, while emphasizing that the main contribution of this review is a conceptual state-transition framework that links membrane architecture, mediator balance, and lipid metabolic flux across inflammation, regeneration, and chronic disease. Full article

Rising demand for high-performance battery thermal management systems (BTMSs) has rendered single-mode cooling insufficient for advanced lithium-ion batteries (LIBs) in new energy vehicles (NEVs), particularly under high discharge rates. This study proposes a synergistic hybrid BTMS integrating composite phase-change material (CPCM)–aluminum foam with liquid cooling to enhance thermal regulation of cylindrical battery modules under 5 C discharge conditions. Multiple liquid-cooled plate (LCP) configurations, including serpentine, straight, and leaf-shaped designs, together with different flow channel topologies (FCTs), were systematically investigated and optimized. The effects of coolant flow speed (CFS) and ambient temperature were also analyzed. Results indicate that the optimized leaf-shaped LCP with FCT #2 delivers superior performance, limiting the maximum temperature to 309.98 K, reducing temperature difference by 7.6%, and decreasing pressure drop by 88.79% compared to the serpentine configuration. Increasing CFS improves heat dissipation and delays PCM melting, although it raises pressure losses. Furthermore, the proposed system maintains a cell-to-cell temperature difference below 0.51 K, indicating excellent thermal uniformity. Compared to a CPCM-only system, the hybrid BTMS reduces peak temperature by 8.81 K under elevated ambient conditions (309.15 K), demonstrating strong potential for reliable and efficient thermal management in demanding operating environments. Full article