Ion Permeability Research Articles

Characterization of permeability of seawater iron tailings mortar based on inter-pore connection

Permeability is an important factor affecting the durability as the connection between pores provides a channel for water and ion permeation. However, the mechanism governing the influence of inter-pore connection is still unclear. This paper quantitatively calculates the connectivity and complexity of inter-pore connections based on pore structure scan images, and investigates the effect of different aggregates on the resistance of mortar to chloride-ion migration. Seawater ordinary mortar (SOM) and seawater iron tailings mortar (STM) were prepared. Pore scans and tests for chloride migration coefficient and chloride-ion content were conducted. Based on the maximum Feret diameter of the pores, the complexity index, Kci, was defined to characterize the complexity of inter-pore connections, and this extends existing calculation methods from one-dimensional to two-dimensional in nature. However,the complexity index correlates with the chloride migration coefficient and chloride-ion content well for seawater ordinary mortar only but not for seawater iron tailings mortar. Therefore, the critical image diameter, dic, was defined to characterize the connectivity of pores. This also overcomes the shortcomings of the MIP method, which does not give the spatial pore distribution. Last, the modified complexity index, Kmci, which modifies the complexity index using the critical image diameter, was presented. It is shown to correlate with test results well for both seawater ordinary and iron tailings mortars. Replacing Kci with Kmci greatly improves the linear correlation of complexity of inter-pore connection with chloride penetration resistance for seawater iron tailings mortar, with the correlation coefficient R increasing from 0.45 to 0.88.

Lipid and cholesterols modulate the dynamics of SARS-CoV-2 viral ion channel ORF3a and its pathogenic variants

SARS-CoV-2 accessory protein, ORF3a is a putative ion channel which immensely contributes to viral pathogenicity by modulating host immune responses and virus-host interactions. Relatively high expression of ORF3a in diseased individuals and implication with inflammasome activation, apoptosis and autophagy inhibition, ratifies as an effective target for developing vaccines and therapeutics. Herein, we present the elusive dynamics of ORF3a-dimeric state using all-atoms molecular dynamics (MD) simulations at μ-seconds scale in a heterogeneous lipid-mimetic system in multiple replicates. Additionally, we also explore the effect of non-synonymous pathogenic mutations on ORF3a ion channel activity and viral pathogenicity in different SARS-CoV-2 variants using various structure-based protein stability (ΔΔG) tools and computational saturation mutagenesis. Our study ascertains the role of phosphatidylcholines and cholesterol in modulating the structure of ORF3a, which perturbs the size and flexibility of the polar cavity that allows permeation of large cations. Discrete trend in ion channel pore radius and area per lipid arises the premise that presence of lipids might also affect the overall conformation of ORF3a. MD structural-ensembles, in some replicates rationalize the crucial role of TM2 in maintaining the native structure of ORF3a. We also infer that loss of structural stability primarily grounds for pathogenicity in more than half of the pathogenic variants of ORF3a. Overall, the effect of mutation on alteration of ion permeability of ORF3a, proposed in this study brings mechanistic insights into variant consequences on viral membrane proteins of SARS-CoV-2, which can be utilized for the development of novel therapeutics to treat COVID-19 and other coronavirus diseases.

Enhancement in proton conductivity and vanadium resistance of SPEEK-based hybrid membrane induced by incorporating amphoteric GO-DA nanofillers for vanadium flow battery

Sulfonated poly(ether ether ketone)-based hybrid membranes (S/GO-DA) have been fabricated through the solution-mixing method, and the introduced graphene oxide (GO) nanofillers functionalized by 2, 4-diaminobenesulfonic acid (DA) afford outstanding physicochemical properties and excellent battery performance for the S/GO-DA membranes. At low loading 1 wt% GO-DA nanofillers, the S/GO-DA-1 membrane gives the highest ion selectivity (45.4 × 103 S min cm−3) and the lowest vanadium ion permeability (7.38 × 10−7 cm2 min−1), which is superior to Nafion 212 (3.0 × 103 S min cm−3, 42.5 × 10−7 cm2 min−1) and SPEEK (3.85 × 103 S min cm−3, 94.4 × 10−7 cm2 min−1), respectively. Moreover, the better energy efficiency (81.1–68.6 %) and longer self-discharge time (78.3 h) of S/GO-DA-1 at 100–200 mA cm−2 current density further prove its good structure stability and durability, elucidating the balanced proton conductivity and vanadium resistance is helpful to enhance the membrane performance. In addition, after cycling at 150 mA cm−2 current density for at least 200 cycles, 76.3 % energy efficiency and 26.9 % charge retention rate are given, illustrating the combined physical barrier of GO-DA nanofillers and the acid-base interaction contribute a synergistic promoting effect on enhancing the battery efficiency of the S/GO-DA hybrid membranes. Therefore, the present work provides a facile method to construct a high-performance proton exchange membrane by developing 2D nanostructured nanofillers containing various chemical covalent-bonded functional amphoteric molecular chains.

Surface diffusion enhanced ion transport through two-dimensional nanochannels

Fast ion permeation in nanofluidic channels has been intensively investigated in the past few decades because of their potential uses in separation technologies and osmotic energy harvesting. Mechanisms governing ion transport at this ultimately small spatial regime remain to be understood, which can only be achieved in nanochannels that are controllably fabricated. Here, we report the fabrication of two-dimensional nanochannels with their top and bottom walls consisting of atomically flat graphite and mica crystals, respectively. The distinct wall structures and properties enable us to investigate interactions between ions and interior surfaces. We find an enhanced ion transport within the channels that is orders of magnitude faster than that in the bulk solutions. The result is attributed to the highly dense packing of adsorbed cations at mica surfaces, where they diffuse in-plane. Our work provides insights into surface effects on ion transport at the nanoscale.

Effect of the electron irradiation on the ion permeation through the GO membrane

Effect of the electron irradiation on the ion permeation through the GO membrane

Investigation of the Effect of Fracturing Fluids on Shale Pore Structure by Nuclear Magnetic Resonance

Hydraulic fracturing technology significantly enhances the productivity of shale oil and gas reservoirs. Nonetheless, the infiltration of fracturing fluid into shale formations can detrimentally affect the microscopic pore structure, thereby impairing the efficacy of hydraulic stimulation. In this study, nuclear magnetic resonance (NMR) technology was utilized to conduct high-pressure soaking tests on shale specimens treated with EM30+ + guar gum mixed water and CNI nano variable-viscosity slickwater, where various concentrations of a drag reducer were utilized. Additionally, the differences in porosity, permeability, mineral composition, and iron ion concentration before and after the measurements were compared, which were used to analyze the influence on the shale’s microscopic pore structure. It features a reduction in the total pore volume after the interaction with the fracturing fluid, with the pore-throat damage degree, porosity damage degree, and permeability damage degree ranging from 0.63% to 5.62%, 1.51% to 6.84%, and 4.17% to 19.61%, respectively. Notably, EM30+ + guar gum mixed water exhibits heightened adsorption retention, alkaline dissolution, and precipitation compared to CNI nano variable-viscosity slickwater, rendering it more deleterious to shale. Moreover, higher concentrations of drag reducers, such as EM30+ or CNI-B, predominantly result in damage to the shale’s micropores. Shale compositions characterized by lower content of quartz and elevated proportions of clay minerals and iron-bearing minerals showcase augmented mineral dissolution and precipitation, consequently intensifying the shale damage. The hydration expansion of mixed-layer illite/smectite profoundly diminishes the core permeability. Consequently, the mechanisms underpinning the damage inflicted on shale’s microscopic pore structure primarily involve fracturing fluid adsorption and retention, mineral dissolution, and precipitation, such as clay minerals and iron-containing minerals.

Pharmacological Activity and Mechanisms of Action of Terpenoids from Laurus nobilis L.

Abstract: Native to the Southern Mediterranean region, Laurus nobilis L. (Family Lauraceae) is an evergreen shrub or tree found in warm climate regions with high rainfall. The leaves and essential oil of this plant have been widely used as condiments, spices, and flavoring agents in the culinary and food industries. The whole plant is also used for the traditional treatment of various diseases, including cough, asthma, hemorrhoids, rheumatic pain, diarrhea, intestinal, and cardiac diseases. Previous phytochemical investigation of this plant demonstrated the presence of a variety of secondary metabolites, especially terpenoids. The present study aims to critically analyze comprehensive literature on the pharmacological activity and mechanisms of action of terpenoids from Laurus nobilis L. The available information on the pharmacological activity of terpenoids from L. nobilis L. was obtained from textbooks, theses, as well as published articles through a variety of libraries and electronic databases. The present study demonstrated that L. nobilis is rich in terpenoids, with more than 200 entities identified in reported studies. Terpenoids from L. nobilis have shown a wide range of pharmacological activities, including anti-inflammatory, antidiabetic, antifungal, antibacterial, immunomodulatory, anticonvulsant, antioxidant and cytotoxic activities. The mechanisms of action of most of these terpenoids included the imbalance of the ionic permeability of the cell membrane (anti- inflammatory and antimicrobial activities), modulation of the effects of gamma-aminobutyric acid (GABA) nergic neurotransmission (anticonvulsant activity), and the inhibition of inflammatory responses, prevention of metastasis, and induction of apoptosis (cytotoxic effect), among others. Referring to in vitro studies, terpenoids of L. nobilis L. have shown a variety of biological activities. However, more cytotoxic and in vivo studies and detailed mechanisms of action of the bioactive terpenoids are recommended.

Mechanical, Chloride Permeation, and Freeze–Thaw Resistance of Recycled Micronized Powder Polypropylene-Fiber-Engineered Cementitious Composites

Research on engineered cementitious composites was carried out using recycled micronized powder from waste construction waste as a substitute for cement. Consequently, this paper focuses on the investigation of recycled micronized powder (RMP) as the subject of study. Using RMP-PP-ECCA0 as the control group, we explored the impact of polypropylene fiber content (0.5%, 1%, 1.5%, 2%) and the substitution rate of RMP (10%, 20%, 30%, 40%) on the mechanical properties, resistance to chloride ion penetration, and freeze–thaw durability of recycled micronized powder polypropylene-fiber-engineered cementitious composites (RMP-PP-ECCs). It was found that, with the increase in RMP substitution rate and fiber content, the mechanical, chloride ion permeation, and freeze–thaw resistance of recycled micronized powder polypropylene-fiber-engineered cementitious composites showed a trend of increasing and then decreasing when the RMP substitution rate was 10%, and the fiber content was 1.5%; the compressive, tensile, chloride ion permeation, and freeze–thaw resistance of recycled micronized powder polypropylene-fiber-engineered cementitious composites were most obviously improved. Compressive strength performance increased by 18.8%, tensile strength performance increased by 80.8%, maximum tensile strain increased by 314%, and electrical flux decreased by 56.3%. Meanwhile, when the recycled micronized powder substitution rate was 10%, the fiber content was 1%, with the most obvious improvement in flexural and freeze–thaw cycle resistance, compared with the control group 28 d flexural strength increased by 22%, after 150 freeze–thaw cycles, the mass-loss rate was reduced by 26%, and the relative dynamic elastic modulus was improved by 4%. In addition, the chemical composition of the regenerated microfractions and the defects in the matrix of the fracture surface of the tensile specimens, the distribution of polypropylene fibers, the surface morphology, and the failure mode were analyzed by X-ray diffraction and scanning electron microscopy.

AtFH5-labeled secretory vesicles-dependent calcium oscillation drives exocytosis and stepwise bulge during pollen germination

Pollen germination is an essential step for delivering sperm cells to the embryo sac for double fertilization inflowering plants. The cytosolic Ca2+ concentration ([Ca2+]cyt) and vesicle dynamics are critical for pollengermination, but their potential correlation in pollen grains is not fully understood. Here, we report that [Ca2+]cyt oscillates periodically at the prospective germination sites during pollen germination. The [Ca2+]cyt is mainly from extracellular Ca2+ ([Ca2+]ext) influx, which implicates the Ca2+-permeable ion channel cyclic nucleotide-gated channel 18 (CNGC18). The [Ca2+]cyt oscillations spatiotemporally correlate with the accumulation of secretory vesicles labeled by a formin protein AtFH5, and disruption of vesicle accumulation inhibits the [Ca2+]cyt oscillations. In turn, the [Ca2+]cyt oscillations promote exocytosis, which leads to stepwise cell extension during pollen germination. Together, these data provide a timeline of vesicle dynamics, calcium oscillation, and exocytosis during pollen germination and highlight the importance of the correlation of these events for pollen germination.

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.

N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.

Acetylated lignin as a biocomponent for epoxy coating — Anticorrosive performance analysis by accelerated corrosion tests

Carbon steel is one of the main metallic materials used in the manufacture of products in various sectors of society. The high susceptibility of this material to the corrosive process makes it necessary to use mechanisms to protect it from corrosion, with the use of epoxy coatings being one of the main methods. However, in harsh environments, the anticorrosive ability of epoxy coatings weakens. Therefore, there is a growing number of studies of compounds to be used as additives in the development of anticorrosive coatings. This work uses Kraft lignin, a waste from the pulp and paper industry, as a bio-additive for epoxy resins to be used in the corrosion protection of carbon steel when exposed to severe corrosion environments. For this, accelerated corrosion tests of salt spray, ultraviolet weathering, and saturated humidity were carried out. The epoxy-lignin coatings were obtained by incorporating acetylated lignin (AKL) in the diglycidyl ether of bisphenol-A resin (DGEBA). The curing agent for the coatings was isophorone diamine (IPDA). Two types of epoxy-lignin coatings were prepared, namely: DGEBA/7.5% AKL, and DGEBA/15%AKL. The structural characterization of the coatings was evaluated by Fourier transform infrared spectroscopy (FTIR). The physicochemical properties of the coatings were analyzed by testing contact angle, gel content, water vapor transmission, and ion permeation. The anticorrosive properties of the coatings were evaluated by electrochemical impedance spectroscopy (EIS). The performance of coatings with acetylated lignin was compared with the epoxy coating without acetylated lignin and the corrosion protection mechanism of epoxy-lignin coatings was proposed. The results indicate that the addition of acetylated lignin improves the resistance of the coatings against corrosion, as demonstrated by higher impedance values and capacitive behavior in the accelerated corrosion tests. Additionally, the coatings with acetylated lignin exhibit better performance in blocking the migration of Na+ and Cl− ions, further slowing down the corrosion process.

Enhancement of K+ channel permeation by selective terahertz excitation

The optical excitation effects offer an opportunity to gain insights into the structure and the function of K+ channel, contributing to the prediction of possible targets for drug design and precision therapy. Although there has been increasing research attention on the modulation of ion permeation in K+ channel by terahertz electromagnetic (THz-EM) stimuli, little exploration has been conducted regarding the dependence of ion permeation on frequencies. By using two-dimensional (2D) infrared excitation spectrum calculation for the K+ channel, we have discovered that the frequency of 53.60 THz serves as an optimal excitation modulation mode. This mode leads to an almost twofold enhancement in the rate of K+ ion permeation and a tenfold increase in selectivity efficiency. These improvements can be attributed to the coupling mode matching of the excited properties of CO groups in the K+ channel. Our findings propose a promising application of terahertz technology to improve the performance of ion channels, nanomembrane sieves, nanodevices, as well as neural therapy.

Strategies for simultaneous improvement of reaction rate and caustic efficiency of brine electrolyzer

Brine electrolyzers can produce HCl and NaOH concurrently using NaCl-concentrated wastewater discharged from various desalination processes. However, the electrolyzers still have poor performance, and thus commercialization is retarded. The main factor affecting the performance of this technology is the trade-off between reaction rate and caustic efficiency. This study aims to improve the reaction rate and caustic efficiency simultaneously by optimizing the operating conditions of the electrolyzer. Through various experiments, we have found that increasing the applied voltage and operating temperature can effectively enhance the reaction rate and caustic efficiency. This is because the relative permeation rate of sodium ions over protons through the Nafion membrane increases with temperature and applied voltage. Under the optimal conditions, the reaction rate is significantly enhanced by 2.1 times (from 86.5 mA cm−2 to 179.2 mA cm−2) and the caustic efficiency by 1.6 times (from 56% to 90%) compared to the standard conditions. The mechanism for the improved performance is revealed by investigating the permeation behavior of ions through the membrane. It is found that protons hinder the permeation of sodium ions, but increasing the temperature and/or applied voltage overcomes this interference. A long-term test for 1600 h confirms the stability and feasibility of the electrolyzer. Overall, this study is expected to contribute to commercializing brine electrolyzers for HCl and NaOH production.

Preparation and evaluation of TA/APTES-HDTMS hydrophobic nanocomposite coating for enhancing corrosion resistance of concrete

Coating anticorrosive technology has been widely used in marine concrete structures, but there are some problems such as poor adhesion, lack of durability or environmental pollution. Tannic acid (TA) -aminopropyl triethoxysilane (APTES) coating has good adhesion, corrosion resistance and secondary reactivity, and has been widely used in biomedicine etc. fields. However, the feasibility of applying TA-APTES to concrete surface treatment remains to be studied. In this study, hydrophobic nanocomposite coating TA/APTES- hexadecyltrimethoxysilane (HDTMS) was prepared by coupling HDTMS with TA-APTES, and applied to concrete surface treatment. By water contact angle measurement (WCA), Coulomb charge experiment and scanning electron microscopy test, the effects of TA-APTES mixture content, mass ratio of TA to APTES and HDTMS concentration on the hydrophobic property and ionic permeability of coated concrete were investigated. The results indicated that TA/APTES-HDTMS coating prepared with 4.0 mg/mL TA-APTES mixture content, 2:1 mass ratio of TA to APTES and 7.0 % HDTMS solution concentration showed optimal improvement efficiency. In this case, the chloride transport properties and sulfate resistance of coated concrete were studied by chloride and sulfate natural diffusion tests, respectively. The results indicated that compared with uncoated concrete, coated concrete showed better and stable resistance to chloride ion and sulfate. In addition, the chloride transport models of both coated and uncoated concrete were established based on Fick’s Second Law. It was found that the chloride diffusion coefficient of coated concrete was similar to that of uncoated concrete, but the surface chloride content was significantly lower. Meanwhile, the lifetime of TA/APTES-HDTMS coating was evaluated based on the change of surface chloride content and compared with other research literature. Furthermore, by WCA and Coulomb charge experiment, it was concluded that the anti-abrasion property and acid-alkaline resistance of coated concrete were significantly improved. Finally, the cost-benefit analysis of TA/APTES-HDTMS coating and existing commercial coatings also illustrated the advantages of TA/APTES-HDTMS coating.

An approach for environment protection by regression and cluster analysis of GGBS-based geopolymer composite at different proportion of brick dust

The study focused on the significance of ground granulated blast furnace slag (GGBS) as replacement of brick dust. Compression, tension, rapid chloride permeability test (RCPT) and water absorption test (WA) is analyzed. Study revealed that the produced geopolymer concrete showed better properties over normal concrete. Up to 10% GGBS replacement with calcined clay, exhibits enhanced compressive strength. Chloride ion permeability tests showed that GPC is superior to normal concrete of all ages in its resistance to chloride ion penetration. On increasing brick dust proportion, mass loss minimized due to sulfate attack. Compressive strength has low relationship with water absorption (0.6618).

The metal organic framework of UiO-66-NH2 reinforced nanofiltration membrane for highly efficient ion sieving

Metal organic framework (MOF) with fine pore structures, ultra-high porosity and large specific surface area can provide more water transport channels while achieving precise sieving of different sizes of ions, which is a promising material for high efficiency desalination. However, particle agglomeration, interface incompatibilities and interface defects severely restrict the performance of MOF-based membranes. It is still a challenge to construct MOF-based desalination membranes with both high water permeability and high ion sieving. Herein, the UiO-66-NH2 based nanofiltration membrane was fabricated by in-situ growth of UiO-66-NH2 on Nylon membrane and composed with polyamide (PA) layer by interfacial polymerization (IP). With 12 h solvothermal reaction, the UiO-66-NH2 nanoparticles are found uniformly loaded on the Nylon substrate. Therefore, the water molecule transport channels provided by UiO-66-NH2 nanoparticles reduce the transport resistance, which can improve the water permeability. More importantly, UiO-66-NH2 nanoparticles are found to be involved in the IP process, which can reduce the interfacial defects and thus enhance the bonding force between the PA layer and base film. The synergistic effect of the UiO-66-NH2 and PA layer improves the nanofiltration performance of the membrane with rejection rate of 92.97% for Na2SO4 and the pure water permeance (PWP) of 11.55 L m−2 h−1 bar−1. The N-UN12 @PA membrane also has excellent antifouling performance (flux recovery ratio (FRR) of 95.86%, reversible fouling ratio (Rr) of 33.93%, irreversible fouling ratio (Rir) of 4.14%). Unlike the mixed-matrix membrane (MMM) and polycrystalline MOF membrane, this strategy provides a promising method to prepare high-performance nanofiltration membrane for desalination.

Experimental study on the high water pressure erosion mechanism and its influence on the submarine shield tunnel concrete segments

This study investigated a high water pressure erosion mechanism and its influence on the mechanical performance deterioration of submarine shield tunnel concrete segments using a series of tests. First, a chloride ion pressure penetration test was conducted to reveal the impermeability performance and chloride ion permeability of the tunnel lining concrete. Then, given the environmental and mechanical characteristics of the lining segment structure of a submarine shield tunnel, a cofferdam-type electrochemically accelerated corrosion method was proposed to simulate the simultaneous application of unilateral water pressure and compression-bending loads on the segment. The effects of water pressure on the strain, deformation, crack propagation, and failure mode of the segment components were investigated. In addition, the damage caused by high water pressure on the segment components was explored using acoustic emission. This study lays the foundation for further research on the durability of shield tunnel structures under high water pressures.

Increase in Paracellular Leakage of Amino Acids Mediated by Aging-Induced Reduction of Claudin-4 Expression

BackgroundClaudins (CLDNs), major components of tight junctions, control paracellular permeabilities of mineral ions and wastes. The absorption of nutrients including glucose and amino acids (AAs) is regulated by intestinal epithelial cells. However, the role of CLDNs is not fully understood. ObjectivesThe purpose of this study was to clarify the effect of AA deprivation on the expression of AA transporters and CLDNs, as well as the role of CLDNs in the regulation of paracellular AA fluxes. MethodsThe messenger RNA and protein expression of various CLDNs were examined by real-time quantitative polymerase chain reaction and Western blot analyses, respectively. The AA selectivity of CLDNs was estimated using liquid chromatography-tandem mass spectrometry (LC-MS) analysis. ResultsThe expression levels of some AA transporters, CLDN4, and CLDN15 were increased by AA deprivation in normal mouse colon-derived MCE301 cells. The expression of AA transporters and CLDN15 in the mouse colon was positively correlated with aging but the expression of CLDN4 was not. The AA deprivation-induced elevation of CLDN4 expression was inhibited by MHY1485, a mammalian target of rapamycin (mTOR) activator. Furthermore, CLDN4 expression was increased by rapamycin, an mTOR inhibitor. mTOR may be involved in the transcriptional activation of CLDN4. The fluxes of AAs from the basal to apical compartments were decreased and increased by CLDN4 overexpression and silencing, respectively. LC-MS analysis showed that the fluxes of all AAs, especially Lys, His, and Arg, were enhanced by CLDN4 silencing. ConclusionsCLDN4 is suggested to form a paracellular barrier to AAs, especially alkaline AAs, which is attenuated with aging.

Claudin-23 reshapes epithelial tight junction architecture to regulate barrier function

Claudin family tight junction proteins form charge- and size-selective paracellular channels that regulate epithelial barrier function. In the gastrointestinal tract, barrier heterogeneity is attributed to differential claudin expression. Here, we show that claudin-23 (CLDN23) is enriched in luminal intestinal epithelial cells where it strengthens the epithelial barrier. Complementary approaches reveal that CLDN23 regulates paracellular ion and macromolecule permeability by associating with CLDN3 and CLDN4 and regulating their distribution in tight junctions. Computational modeling suggests that CLDN23 forms heteromeric and heterotypic complexes with CLDN3 and CLDN4 that have unique pore architecture and overall net charge. These computational simulation analyses further suggest that pore properties are interaction-dependent, since differently organized complexes with the same claudin stoichiometry form pores with unique architecture. Our findings provide insight into tight junction organization and propose a model whereby different claudins combine to form multiple distinct complexes that modify epithelial barrier function by altering tight junction structure.

β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure-Activity Relationships and Antiallodynic Activity.

The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N'-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure-activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N'-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).