Search Results (538)

Since the development of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, these therapies have revolutionized patients’ health. They are now the most effective treatment for people with cystic fibrosis (pwCF). In fact, elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor, the latest combination therapies consisting of a CFTR potentiator and two CFTR correctors, improved lung function by 14% in pwCF. Other modulator therapies targeting CFTR mRNA and/or protein are currently under preclinical/clinical investigation. However, due to the variant-specific nature of these therapies, about 10% of pwCF in Europe remains without effective treatment, and many treated pwCF experience various adverse events such as headaches, infections, hepatotoxicity, hypertension, and depression. Therefore, mutation-agnostic strategies such as gene therapy are needed. They could expand treatment eligibility for all pwCF and improve outcomes. In fact, nucleic acid delivery (e.g., pDNA, mRNA, oligonucleotides, genome editing) or targeting non-CFTR channels to restore ion transport represent promising future additional directions for CF therapy. This review aims to discuss a potential combination between gene therapy approaches and existing modulators to improve treatment eligibility, safety, and efficacy. Full article

Cystic fibrosis (CF) is one of the most common rare genetic diseases. It is caused by pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 2200 variants have been identified in the CFTR gene that need detailed knowledge and functional characterization in order to develop specific therapeutic strategies. The traditional therapy for CF relied on addressing symptoms through mucolytic and antibiotic treatments, respiratory physiotherapy and aerosol therapy. However, in the last few years, the development of small new molecules targeting and restoring the underlying CFTR channel defect marked an important step in CF treatment. In addition, the implementation of patient-specific cellular models allowed the evaluation of pharmacological responses, leading to therapeutic advances in the direction of personalized treatment. The focus of this review is to describe and discuss the strategies for restoring the CFTR functional defects depending on the specific CFTR pathogenic variants. In particular, the review highlights the possible application of experimental and clinical drugs to CF treatment, which may allow improvements in patients’ quality of life and life expectancy. The in vitro testing of therapeutic drugs (theratyping) is performed nowadays through the use of several cellular models, especially those derived from patient-specific tissues. This topic is a hot point in CF research and the review also aims to provide an overview of the state of the art in theratyping. The novelty of this review is the integrated view of the most recent achievements in precision diagnostics and therapy of CF at the molecular, cellular and clinical level, which are able to change the natural history of this disease. Full article

Concentration polarization is a common phenomenon in membrane separation processes and generally impairs mass transfer efficiency. Electrodialysis (ED) is considered a promising technology for concentrating high-salinity solutions used in air-conditioning systems; however, concentration polarization under high-concentration operating conditions remains insufficiently understood. In this study, a numerical framework combining a simplified model and a coupled transport model was developed to characterize concentration distributions within an ED concentrate channel. The effects of flow velocity, current density, and feed concentration on concentration profiles were systematically investigated. The results show that transmembrane water transport plays an important role in concentration polarization, and neglecting this effect leads to significant overestimation of ion concentration near the membrane surface. Although ion concentration increases markedly in the vicinity of the ion-exchange membranes, it remains nearly constant in the bulk region along the flow direction. Based on this non-uniform concentration distribution, a conceptual ED configuration with separated flow channels was proposed and evaluated. The results indicate that selectively extracting the enriched boundary-layer region can enhance the outlet concentration of the product stream, whereas increasing the intermediate channel width reduces volumetric yield, revealing a clear trade-off between concentration enhancement and production capacity. Full article

This paper presents a comprehensive theoretical derivation of a membrane potential formula based on the Association-Induction Hypothesis (AIH), challenging traditional membrane theory and the Goldman–Hodgkin–Katz equation (GHK equation). The study demonstrates that membrane potential is not primarily a result of transmembrane ion transport through channels and pumps, but rather a consequence of the Boltzmann distribution of mobile ions influenced by their adsorption onto cell constituents. By employing a variational principle to minimize the total free energy of the system—consisting of ion mixing entropy, electrostatic energy, and adsorption energy—the authors derive a generalized membrane potential formula. Unlike the GHK equation, this model explicitly incorporates fixed charge density and the specific adsorption affinity of ion species such as $K^{+}$ and $N{H}_3^{+}$ onto carboxyl ($CO{O}^{-}$) groups. The derivation shows that cell potential (so-called membrane potential) can be generated even in the absence of a plasma membrane, suggesting that the transmembrane ion transport mediated by channels and pumps may not be the principal cause of the membrane potential generation but rather that the ion adsorption and desorption must govern the membrane potential generation. Ultimately, this research suggests that the fundamental mechanism of potential generation in biological systems is the equilibrium distribution of ions governed by thermodynamic stability rather than non-equilibrium steady-state flux. Full article

Aluminum-activated malate transporter (ALMT) channels mediate root malate efflux, a key response for plant survival in acidic, aluminum-toxic soils. The acidophilic genus Vaccinium is horticulturally important, yet its ALMT family has remained uncharacterized. Leveraging two newly available chromosome-level genomes (Vaccinium darrowii and Vaccinium duclouxii), we present the first genus-wide characterization of this family. Across 11 angiosperms we identified 145 non-redundant ALMT loci, partitioned into six major subfamilies. MCScanX synteny revealed compact retention rather than expansion: diploid Vaccinium genomes encode only 8–10 ALMTs each, with at most one intra-species syntenic paralog pair, versus multiple whole-genome-duplication-derived pairs in apple (Malus domestica, 24 loci). Pairwise Ka/Ks was elevated within Vaccinium in three subfamilies, and codon-based PAML branch-site tests detected Bonferroni-significant positive selection on terminal Vaccinium branches in Subfamilies 5 and 4 (2ΔlnL = 40.65 and 12.95), yielding three Bayes Empirical Bayes candidate sites in Subfamily 5 (F249, E410, L411) and two in Subfamily 4 (E249, G399); Subfamily 2 was non-significant and is interpreted as relaxed constraint. All candidate residues map to C-terminal cytoplasmic regulatory regions rather than the transmembrane pore. These findings indicate that the compact Vaccinium ALMT repertoire retained its ancestral channel architecture while accumulating lineage-associated divergence in cytoplasmic regulatory regions; the identified residues are candidates for downstream functional validation rather than demonstrated drivers of acid-soil adaptation. Full article

Ion channels are validated drug targets, but they remain difficult to study as their pharmacology is influenced by rapid gating, conformational state transitions, cell-type-specific expression, and narrow safety margins. Recent advances in cryo-electron microscopy, structure-based in silico screening, machine-learning-guided prioritization, optical high-throughput screening, automated patch-clamp electrophysiology, and human-relevant organoid or microphysiological system (MPS) models are transforming this field. In this expanded review, we examine how these modalities can be integrated into a hybrid discovery pipeline that begins with computational triage, proceeds through scalable functional screening and state-aware electrophysiological validation, and concludes with multi-channel safety de-risking and translational analysis in complex human models. We also discuss disease-associated channel remodeling in cancer and inflammatory disorders, with an emphasis on transient receptor potential channels, voltage-gated potassium channel 1.3 (Kv1.3), Piezo channels, transmembrane protein 16A/anoctamin-1 (TMEM16A/ANO1), chloride channels, and proarrhythmic safety risks. Additionally, we highlight unresolved challenges, including bias in artificial intelligence models, incomplete conformational sampling, assay interference, organoid heterogeneity, and regulatory acceptance of MPS platforms. This review proposes a staged decision framework in which computational prioritization, scalable functional screening, direct electrophysiological confirmation, safety pharmacology, DMPK assessment, and disease-relevant human models serve as complementary filters rather than competing platforms for the identification of selective and translatable ion-channel therapeutics. Full article

Hysteresis seems to play a critical role in the generation and modulation of electrical signal events in neurons, muscles, and other excitable tissues. In voltage-gated ion channels, hysteretic conductance manifests under cycling changes in transmembrane voltage when conductance is delayed in response to voltage changes. Such dynamic behavior emerges naturally when the frequency of the oscillatory voltage becomes comparable to the characteristic relaxation time associated with transitions between channel conductance states and is reminiscent of hysteresis observed in transistors, memristors or solar cells. To investigate this delayed response, various discrete-state Markov models have been proposed. In these frameworks, an ion channel is represented as a finite set of states—typically corresponding to closed and open conformations—with transitions governed by voltage-dependent rates. As an alternative, the progress of activation and transition between opening and closing states of a channel is described in terms of a diffusive, collective “reaction coordinate” which fulfills a Langevin equation and the Smoluchowski–Fokker–Planck equation associated with it. Here we review this approach in modeling dynamic memory of ion channels. Full article

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction is increasingly recognized as a key contributor to a broad spectrum of human diseases beyond classical cystic fibrosis (CF). CFTR is a cAMP-regulated chloride and bicarbonate ion channel expressed in both epithelial and non-epithelial tissues, where it regulates ion homeostasis, mucosal hydration, and cellular signaling. Both inherited CFTR mutations and acquired dysfunction resulting from environmental or inflammatory factors can disrupt these physiological processes and drive disease progression. Current evidence linking CFTR dysregulation to respiratory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and HIV-associated airway disease, as well as cardiovascular, renal, neurological diseases, and cancer, is comprehensively discussed. Mechanistically, impaired CFTR function promotes oxidative stress, chronic inflammation, epithelial barrier dysfunction, altered mucociliary clearance, and dysregulation of signaling pathways, including NF-κB, TGF-β, PI3K/Akt, MAPK, and Wnt/β-catenin. In the context of HIV infection and cigarette smoke exposure, CFTR suppression is mediated in part by TGF-β signaling and miRNA-dependent mechanisms, resulting in compromised airway defense and increased susceptibility to pulmonary complications. Recent studies further demonstrate that CFTR dysregulation alters the expression of genes involved in fibrosis, inflammation, angiogenesis, and epithelial–mesenchymal transition (EMT). Notably, CFTR may act as either a tumor suppressor or a context-dependent oncogene, depending on tissue type and signaling milieu, highlighting its complex role in cancer biology. Advances in CFTR-targeted therapies, including potentiators, correctors, gene therapy, and combination approaches, have markedly improved outcomes in CF and may offer therapeutic potential for diseases associated with acquired CFTR dysfunction. We summarize the systemic consequences of CFTR dysregulation and the need for further mechanistic and translational research to clarify its role across diverse human diseases. Full article

Background: Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by recurrent episodes of intermittent hypoxia and systemic inflammation. Pannexin-1 (Panx1) is a transmembrane channel involved in ATP release and purinergic signaling and has been implicated in hypoxia-related inflammatory responses. However, the clinical relevance of circulating Panx1 levels in patients with OSA remains poorly understood. This study aimed to evaluate serum Panx1 concentrations in patients with OSA and to investigate their association with nocturnal hypoxemic burden. Methods: In this cross-sectional study, 40 patients with obstructive sleep apnea (OSA) and 40 control subjects underwent overnight polysomnography for diagnostic evaluation. Serum Panx1 concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Logistic regression models were constructed to evaluate the association between Panx1 and OSA status while adjusting for clinical covariates. In addition, a propensity score–matched sensitivity analysis based on age, sex, and body mass index was performed to further assess potential confounding. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of Panx1 alone and in combination with clinical variables. Results: Serum Panx1 levels were significantly lower in patients with OSA than in controls (4.27 ± 2.66 vs. 6.24 ± 4.75 ng/mL, p = 0.013). Although Panx1 was not an independent predictor of OSA after adjustment for age, sex, and body mass index, its integration with clinical variables significantly improved diagnostic discrimination. The area under the receiver operating characteristic curve increased from 0.662 for Panx1 alone to 0.858 in the fully adjusted model. Sensitivity analyses attenuated the observed association after matching for major baseline characteristics, suggesting a potential contribution of demographic and anthropometric factors. In addition, Panx1 concentrations were inversely correlated with markers of nocturnal hypoxemic burden, particularly the cumulative time spent with oxygen saturation below 90% (T90). Conclusions: Lower serum Panx1 concentrations were associated with OSA status and nocturnal hypoxemic burden. While Panx1 alone demonstrated modest discriminatory ability, its integration with established clinical factors improved diagnostic performance. These findings suggest that Panx1 may represent a biologically plausible adjunct biomarker reflecting hypoxic burden and may contribute to multi-parameter approaches for OSA risk assessment; however, further validation in larger matched cohorts is warranted. Full article

Emerging contaminants (ECs) encompass a wide spectrum of pollutants, from endocrine disruptors and persistent organic pollutants to microplastics and pharmaceutical residues. These contaminants often exhibit distinct chemical and physical properties compared with traditional pollutants and potentially pose risks to human health, especially as they have become pervasive in environmental and biological systems. ECs can also pose a significant threat to cardiovascular health, as they may target the ion channels that are critical to regulating cardiac excitability and contraction. However, the impact of ECs on the cardiovascular system, particularly on cardiac ion channels, remains elusive. In this review, we aim to provide an overview of the knowledge base concerning the impact of emerging contaminants on cardiac ion channels, with an emphasis on the effects of these compounds on cardiac excitability, contractility, and overall cardiovascular function. We first outline the structural and functional characteristics of ion channels, along with how these transmembrane proteins regulate cardiac physiology. Subsequently, we detail how typical ECs directly or indirectly interact with various ion channels—including sodium, calcium, potassium channels, as well as ion transporters and exchangers. Special attention is given to studies that have demonstrated cell-level responses or examined how pollutant concentration and chemical structure affect the modulation of ion channels. This review compiles recent research reports to elucidate the mechanisms by which EC exposure disrupts cardiac ion channels, potentially leading to cardiotoxicity. Moreover, the insights gathered herein illuminate critical research gaps and outline essential directions for future investigations. Full article

Antimicrobial resistance genes threaten the effective treatment of infectious diseases, underscoring the importance of their control in line with the EU One Health policy. Wastewater treatment plants are recognized hotspots for antimicrobial resistance. We assessed whether multi-channel mixed-matrix membranes (MCMMMs)—polyethersulfone (PES)/polyvinylpyrrolidone (PVP) ultrafiltration membranes with embedded activated carbon—can concurrently reduce microorganisms and extracellular DNA in wastewater effluent, building on prior reports of micropollutant removal. We evaluated the performance of MCMMMs in removing Escherichia coli and Saccharomyces cerevisiae as model organisms, as well as colony-forming units (CFUs) from wastewater effluent at a transmembrane pressure of 1 bar with a filtration area of 66 cm² over 1 h. DNA was extracted from wastewater effluent following filtration and analyzed to assess changes in microbial community composition. MCMMMs achieved log₁₀ reductions of 5.47 ± 0.42 (Escherichia coli), 5.99 ± 0.46 (Saccharomyces cerevisiae), and 2.79 ± 0.31 (wastewater CFU); reductions by pure PES/PVP membranes were comparable: higher for Escherichia coli and wastewater CFUs, lower for Saccharomyces cerevisiae. Amplicon sequencing showed altered relative abundances in wastewater effluent. Collectively, these findings demonstrate the potential of MCMMMs to simultaneously remove microorganisms, extracellular DNA, and micropollutants, highlighting their suitability for water treatment applications within the One Health framework. Full article

Background: Corylin (3-(2,2-dimethylchromen-6-yl)-7-hydroxychromen-4-one), a bioactive flavonoid, has been reported to exercise anti-inflammatory, antineoplastic, and antioxidant effects, and may also possess lifespan-extending properties. Objectives: Any modifications of transmembrane ionic currents produced by corylin remain largely unknown. Methods: The patch-clamp technique and docking prediction were used in this study. Results: In pituitary GH₃ somatolactotrophs, corylin concentration-dependently increased the magnitude of the M-type K⁺ current (I_K(M)), with an EC₅₀ of 3.8 μM. Concurrently, the activation time constant of I_K(M) was shortened. The addition of linopirdine (10 μM), an I_K(M) inhibitor, suppressed the current amplitude. Corylin also induced a leftward shift in the steady-state activation curve and enhanced I_K(M) during pulse-train stimulation. Moreover, corylin increases the hysteretic strength of I_K(M) evoked by a long-lasting triangular ramp pulse; this effect was attenuated by linopirdine. The stimulatory effect of corylin on I_K(M) was not altered by carvedilol or iberiotoxin but was reduced by dapagliflozin. In contrast, depolarization-activated I_K(M) was not affected by 17β-estradiol alone. In cell-attached recordings, corylin increased M-type K⁺ (K_M)-channel activity with minimal change in single-channel amplitude, while prolonging the mean open time. This stimulatory effect was reversed by linopirdine or dapagliflozin. Additionally, corylin slightly inhibited the erg-mediated current. Docking analysis further suggested that corylin potentially interacts with residues in KCNQ2 or KCNH2 channels via hydrogen bonding and hydrophobic interactions. Conclusions: These findings suggest that corylin modulates ionic currents, primarily through K_M (KCNQ/K_V7) channels, which may underlie its in vivo actions and those of related flavonoids. These effects may contribute to the regulation of functional activities of neuronal, neuroendocrine, and endocrine cells. Full article

The olfactory and gustatory systems are essential for survival, enabling organisms to detect and respond to environmental chemical cues. Although canonical signaling pathways in smell and taste have been well defined, growing evidence highlights additional ion channel families as key modulators of sensory responses. Recent studies identify the anoctamin, transmembrane channel-like, and TMEM63 superfamily as a class of non-canonical sensory effectors that regulate signal amplification, excitability, and epithelial homeostasis across chemosensory systems. In the mammalian olfactory epithelium, specific anoctamin channels enhance odor-evoked responses and contribute to tissue homeostasis. In the gustatory system, salt detection is now understood to involve multiple parallel signaling pathways, with TMC4 emerging as a key contributor to high-salt and salt-associated taste sensing. These channel families are evolutionarily conserved across species, including C. elegans, Drosophila, and aquatic organisms, where they mediate chemosensation, mechanosensation, humidity detection, and osmoregulation. This functional versatility is supported by a shared structural architecture that enables selective ion conduction and, in some members, regulated phospholipid scrambling. This review proposes a unifying framework in which anoctamin and transmembrane channel-like proteins act as multimodal regulators of sensory signaling, linking environmental cues to cellular excitability and microenvironmental control and highlighting new principles of chemosensory organization and therapeutic potential. Full article

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article

Aquaporins (AQPs) are transmembrane channel proteins that transport water and small solutes. Their dysregulation in cancer reveals functions beyond maintaining osmotic balance. This review summarizes that AQPs drive tumor progression through three core mechanisms: metabolic reprogramming, enhanced motility, and remodeling of the immune microenvironment. Specifically, AQP3, AQP7, and AQP9 serve as metabolic hubs for glycerol, while AQP3 and AQP8 help maintain redox homeostasis. AQP1 and AQP4 facilitate cell migration via hydrodynamic mechanisms, and AQP5 promotes invasion through signaling pathways such as Ras/NF-κB. In immune regulation, AQP9 and AQP3 modulate immune cell function by transporting metabolites, and AQP1 influences angiogenesis. Other isoforms, including AQP0, AQP2, AQP6, AQP10, and AQP11, also play roles in malignancy. Collectively, AQPs form a multifunctional network linking tumor metabolism, physical properties, and immunity, offering insights for novel diagnostic and therapeutic strategies. However, tissue-specific functions, complex regulatory mechanisms, and challenges in developing targeted therapies remain significant hurdles in translational medicine. Full article