Semipermeable Research Articles

Interaction of Ionic Solution with Permeable Membranes: a Variational Approach

Interaction of Ionic Solution with Permeable Membranes: a Variational Approach

Development of single layer osmotic controlled release tablet for low soluble drug: Single Core Osmotic Pump (SCOP)

A novel Single Core Osmotic Pump (SCOP) pill has been created to administer high doses of the low solubility medication Rifaximin using osmosis. The formulations were evaluated using six comparative parameters: Q24 (total release after 24 hours), Q12 (total release after 12 hours), TL (lag time), RSQzero12 (R square of the zero-order equation for drug release in 12 hours), RR12 (in vitro release rate for 12 hours), and T80% (time required to deliver 80% of the drug). The drug release profile from osmotic devices shows that the choice of polymer and its concentration in the core formulation can significantly impact the release of the drug. Augmenting the osmogent quantity to an optimal level resulted in a substantial enhancement of Q12 and a notable improvement in the zero-order release pattern of rifaximin. In order to improve the bioavailability of the core formulation, an additive called citric acid was included. Citric acid has several properties that contribute to this enhancement, such as increased solubility of the active ingredient, the creation of a difference in osmotic pressure, regulation of the flow of the active ingredient, and making the composition containing the active ingredient more water-loving. Consequently, TL and T80% experienced a decline, whereas Q12 and RR12 saw a rise. The concentration of PEG 4000 in the semipermeable membrane of the SCOP was found to have a significant impact on TL, T80%, Q12, Q24, and RR12. Specifically, increasing the concentration of PEG 4000 led to a decrease in TL and T80%, while increasing Q12, Q24, and RR12. The optimal aperture diameter for achieving a zero-order release pattern was found to be 850 μm. This study also demonstrated that optimizing the thickness of SPM is crucial for achieving zero order kinetics. The invented SCOP technology has the potential to create a single layer osmotic controlled release tablet of a water insoluble medication with a high dosage.

Dissipative particle dynamics simulation of proposed artificial filament contraction mechanism using variable external force inspired by nature

ABSTRACT In this numerical research, the proposed mechanism of contraction of an artificial muscle filament with regard to the performance of a natural filament and the possibility of industrial production is presented using the Dissipative Particle Dynamics (DPD) method. First, an artificial myosin component has been simulated, which includes a micro-nozzle with a thin fixed two-end polymer membrane in the middle. The swelling of the limited permeable membrane from one side results from moving the DPD fluid and, consequently, the fluid force will be transferred. Also, by changing the direction of the movement of the fluid, the swelling of the polymer membrane is reversed. It has been shown that the amount of swelling is directly dependent on the amount and direction of external force implementation ( F e = ± 0.001, ± 0.003, ± 0.005 and ± 0.007) and there is a delay (almost one DPD unit) in the amount of displacement when the direction of the flow is changed due to the inertia force effect. The proposed mechanism includes six double artificial myosins, whose myosin movement causes that actin to take contraction in a wave motion considering both forward and backward movements of the limited permeable thin membrane. Also, more artificial myosins may provide smoother contraction.

Increased Absorption of Thyroxine in a Murine Model of Hypothyroidism Using Water/CO2 Nanobubbles

Thyroxine (T4) is a drug extensively utilized for the treatment of hypothyroidism. However, the oral absorption of T4 presents certain limitations. This research investigates the efficacy of CO2 nanobubbles in water as a potential oral carrier for T4 administration to C57BL/6 hypothyroid mice. Following 18 h of fasting, the formulation was administered to the mice, demonstrating that the combination of CO2 nanobubbles and T4 enhanced the drug’s absorption in blood serum by approximately 40%. To comprehend this observation at a molecular level, we explored the interaction mechanism through which T4 engages with the CO2 nanobubbles, employing molecular simulations, semi-empirical quantum mechanics, and PMF calculations. Our simulations revealed a high affinity of T4 for the water–gas interface, driven by additive interactions between the hydrophobic region of T4 and the gas phase and electrostatic interactions of the polar groups of T4 with water at the water–gas interface. Concurrently, we observed that at the water–gas interface, the cluster of T4 formed in the water region disassembles, contributing to the drug’s bioavailability. Furthermore, we examined how the gas within the nanobubbles aids in facilitating the drug’s translocation through cell membranes. This research contributes to a deeper understanding of the role of CO2 nanobubbles in drug absorption and subsequent release into the bloodstream. The findings suggest that utilizing CO2 nanobubbles could enhance T4 bioavailability and cell permeability, leading to more efficient transport into cells. Additional research opens the possibility of employing lower concentrations of this class of drugs, thereby potentially reducing the associated side effects due to poor absorption.

Exploiting Hydrophobic Amino Acid Scanning to Develop Cyclic Peptide Inhibitors of the SARS-CoV-2 Main Protease with Antiviral Activity.

The development of novel antivirals is crucial not only for managing current COVID-19 infections but for addressing potential future zoonotic outbreaks. SARS-CoV-2 main protease (Mpro) is vital for viral replication and viability and therefore serves as an attractive target for antiviral intervention. Herein, we report the optimization of a cyclic peptide inhibitor that emerged from an mRNA display selection against the SARS-CoV-2 Mpro to enhance its cell permeability and in vitro antiviral activity. By identifying mutation-tolerant amino acid residues within the peptide sequence, we describe the development of a second-generation Mpro inhibitor bearing five cyclohexylalanine residues. This cyclic peptide analogue exhibited significantly improved cell permeability and antiviral activity compared to the parent peptide. This approach highlights the importance of optimizing cyclic peptide hits for activity against intracellular targets such as the SARS-CoV-2 Mpro.

Recent Progress of Electrolyte Materials for Solid‐State Lithium–Oxygen (Air) Batteries

AbstractSolid‐state lithium–air batteries (SSLABs) have become the focus of next‐generation advanced batteries due to their safety and high energy densities. Current research on SSLABs is mainly centered on solid‐state electrolytes (SSEs). Although SSEs exhibit excellent properties, such as good stability, high safety, and great mechanical strength, they also display several distinct weaknesses of low ionic conductivities, poor stabilities in air, and high interfacial impedances, which will require sustained attentions for further investigations. This review first overviews the development history of SSEs achieved in terms of Li–air batteries. Subsequently, the fundamental properties, preparation methods, merits and drawbacks of different SSEs, along with their use in SSLABs, and the optimization strategy, especially for the inorganic solid electrolytes, polymer electrolytes, and hybrid electrolytes are comprehensively summarized. Finally, the research progresses made with SSEs are outlined, and critical insights and approaches for the remaining challenges of electrolytes and commercial application of SSLABs are proposed, which include advanced characterization, combining experiments and artificial intelligence such as theoretical calculations, and constructing selective permeability membranes. It is expected that this timely review will provide researchers with an integrated, systematic, and in‐depth understanding of SSEs and guidelines for future research, thus further promoting the commercial application of SSLABs.

Aptamer-RIBOTAC Strategy Enabling Tumor-Specific Targeted Degradation of MicroRNA for Precise Cancer Therapy.

MicroRNA (miRNA) molecules play crucial roles in a variety of diseases, making miRNA targeting a burgeoning field in medicinal chemistry. Ribonuclease targeting chimeras (RIBOTACs) present a compelling approach for RNA degradation. However, small molecule-based RIBOTAC requires an expensive and time-consuming screening process, and is difficult to directly target miRNA due to its short length lacking secondary structure. Antisense oligonucleotide (ASO)-based RIBOTAC is easy to design but with poor cell permeability. While both of them lack the specificity for tumor targeting. In this study, the first Aptamer-RIBOTAC (ARIBOTAC) chimera is designed based on ASO to achieve precise degradation of miRNA in a tumor cell-specific manner for precise cancer therapy. This chimera exhibits a remarkable ability to specifically identify and enter cancer cells, trigger localized activation of endogenous RNase L, and selectively cleave miRNAs that are complementary to ASO. The efficacy and universality of the ARIBOTAC strategy both in vitro and in vivo by degrading oncogenic miR-210-3p and miR-155-5p are validated. These findings underscore the potential of the ARIBOTAC strategy as a promising avenue for cancer therapy by precisely targeting cancer-associated miRNAs.

Exogenous Methyl Jasmonate (MeJA) Improves ‘Ruixue’ Apple Fruit Quality by Regulating Cell Wall Metabolism

‘Ruixue’ apples were used as the test material to study the effect of 10 μM methyl jasmonate (MeJA) on the quality and cell wall metabolism of apples after 18 d of storage. The results showed that MeJA significantly decreased the respiratory rate, reduced the titratable acid content and maintained a high soluble solids content. MeJA has been shown to suppress the activities and gene expressions of WSP, CSP, ISP, and cellulose in contrast to the control group, thereby maintaining a lower cell permeability and higher exocarp firmness. MeJA significantly decreased the expression of MdACS, MdACO, MdPL, Mdgal, and MdPG genes in the apple exocarp when compared to the control group. In addition, the overexpression of MdPL18 increased the content of cell wall polysaccharides such as WSP and CSP, enhanced cell wall-degrading enzyme activities, and accelerated fruit ripening and softening, whereas silencing MdPL18 did the opposite. Together, these results demonstrate that exogenous MeJA maintains the Ruixue apple fruit quality by regulating the metabolism of cell wall substances.

Development of Novel Phosphonodifluoromethyl-Containing Phosphotyrosine Mimetics and a First-In-Class, Potent, Selective, and Bioavailable Inhibitor of Human CDC14 Phosphatases.

Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) control protein tyrosine phosphorylation and regulate numerous cellular functions. Dysregulated PTP activity is associated with the onset of multiple human diseases. Nevertheless, understanding of the physiological function and disease biology of most PTPs remains limited, largely due to the lack of PTP-specific chemical probes. In this study, starting from a well-known nonhydrolyzable phosphotyrosine (pTyr) mimetic, phosphonodifluoromethyl phenylalanine (F2Pmp), we synthesized 7 novel phosphonodifluoromethyl-containing bicyclic/tricyclic aryl derivatives with improved cell permeability and potency toward various PTPs. Furthermore, with fragment- and structure-based design strategies, we advanced compound 9 to compound 15, a first-in-class, potent, selective, and bioavailable inhibitor of human CDC14A and B phosphatases. This study demonstrates the applicability of the fragment-based design strategy in creating potent, selective, and bioavailable PTP inhibitors and provides a valuable probe for interrogating the biological roles of hCDC14 phosphatases and assessing their potential for therapeutic interventions.

Biocatalytic Strategy for the Highly Stereoselective Synthesis of Fluorinated Cyclopropanes

Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigidity nature of the cyclopropane ring and the beneficial effects of C–F bonds on the pharmacokinetic properties, cell permeability, and metabolic stability of drug molecules. Herein a biocatalytic strategy for the stereoselective synthesis of mono‐fluorinated and gem‐difluoro cyclopropanes is reported though the use of engineered myoglobin‐based catalysts. In particular, this system allows for a broad range of gem‐difluoro alkenes to be cyclopropanated in the presence of diazoacetonitrile with excellent diastereo and enantiocontrol (up to 200:1 d.r. and 99% e.e.), thereby enabling a transformation not currently accessible with chemocatalytic methods. The synthetic utility of the present approach is further exemplified through the gram‐scale synthesis of a key gem‐difluorinated cyclopropane intermediate useful for the preparation of fluorinated bioactive molecules.

Biocatalytic Strategy for the Highly Stereoselective Synthesis of Fluorinated Cyclopropanes.

Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigidity nature of the cyclopropane ring and the beneficial effects of C-F bonds on the pharmacokinetic properties, cell permeability, and metabolic stability of drug molecules. Herein a biocatalytic strategy for the stereoselective synthesis of mono-fluorinated and gem-difluoro cyclopropanes is reported though the use of engineered myoglobin-based catalysts. In particular, this system allows for a broad range of gem-difluoro alkenes to be cyclopropanated in the presence of diazoacetonitrile with excellent diastereo and enantiocontrol (up to 200:1 d.r. and 99% e.e.), thereby enabling a transformation not currently accessible with chemocatalytic methods. The synthetic utility of the present approach is further exemplified through the gram-scale synthesis of a key gem-difluorinated cyclopropane intermediate useful for the preparation of fluorinated bioactive molecules.

Novel highly permeable ultrathin polyamide composite membrane with interfacial polymerization of 4,6-diaminoresorcinol for molecular separation

Developing ultrathin polyamide thin-film composite (PA TFC) membrane with ultrahigh performance to overcome the perm-selectivity upper bound of molecular separation is still the major challenge for practical applications. Herein, we first designed an ultrahigh performance PA TFC membrane fabricated by interfacial polymerization of 4,6-diaminoresorcinol dihydrochloride (DAR) and trimethyl chloride (TMC) on the substrate. The structural morphology of the PA active layer and the separation performance of the resultant membrane were tuned by DAR dosage. This ultrathin PA TFC membrane breaks the trade-off between water permeance and dye (NOM) selectivity. Accordingly, the optimal membrane had a water flux of 212.5 LHM/bar with superior rejection of 98.6 % and 100 % for BBR and CR, respectively, surpassing the upper-bound limit of most reported polymeric membranes thus far. The membranes also exhibited a high salt passage (>95 %), achieving an impressive screening capacity for the dye/salt mixture as well as excellent antifouling and operation stability performance. This work sheds light on the regulation of the PA selective layer via new amine monomer featuring ultrahigh performance.

StMAPKK5 responds to heat stress by regulating potato growth, photosynthesis, and antioxidant defenses

BackgroundsAs a conserved signaling pathway, mitogen-activated protein kinase (MAPK) cascade regulates cellular signaling in response to abiotic stress. High temperature may contribute to a significant decrease in economic yield. However, research into the expression patterns of StMAPKK family genes under high temperature is limited and lacks experimental validation regarding their role in supporting potato plant growth.MethodsTo trigger heat stress responses, potato plants were grown at 35°C. qRT-PCR was conducted to analyze the expression pattern of StMAPKK family genes in potato plants. Plant with StMAPKK5 loss-of-function and gain-of-function were developed. Potato growth and morphological features were assessed through measures of plant height, dry weight, and fresh weight. The antioxidant ability of StMAPKK5 was indicated by antioxidant enzyme activity and H2O2 content. Cell membrane integrity and permeability were suggested by relative electrical conductivity (REC), and contents of MDA and proline. Photosynthetic capacity was next determined. Further, mRNA expression of heat stress-responsive genes and antioxidant enzyme genes was examined.ResultsIn reaction to heat stress, the expression profiles of StMAPKK family genes were changed. The StMAPKK5 protein is located to the nucleus, cytoplasm and cytomembrane, playing a role in controlling the height and weight of potato plants under heat stress conditions. StMAPKK5 over-expression promoted photosynthesis and maintained cell membrane integrity, while inhibited transpiration and stomatal conductance under heat stress. Overexpression of StMAPKK5 triggered biochemical defenses in potato plant against heat stress, modulating the levels of H2O2, MDA and proline, as well as the antioxidant activities of CAT, SOD and POD. Overexpression of StMAPKK5 elicited genetic responses in potato plants to heat stress, affecting heat stress-responsive genes and genes encoding antioxidant enzymes.ConclusionStMAPKK5 can improve the resilience of potato plants to heat stress-induced damage, offering a promising approach for engineering potatoes with enhanced adaptability to challenging heat stress conditions.

Synthesis of Membrane-Permeable Macrocyclic Peptides via Imidazopyridinium Grafting.

Macrocyclic peptides (MPs) are a class of compounds that have been shown to be particularly well suited for engaging difficult protein targets. However, their utility is limited by their generally poor cell permeability and bioavailability. Here, we report an efficient solid-phase synthesis of novel MPs by trapping a reversible intramolecular imine linkage with a 2-formyl- or 2-keto-pyridine to create an imidazopyridinium (IP+)-linked ring. This chemistry is useful for the creation of macrocycles of different sizes and geometries, including head-to-side and side-to-side chain configurations. Many of the IP+-linked MPs exhibit far better passive membrane permeability than expected for "beyond Rule of 5" molecules, in some cases exceeding that of much lower molecular weight, traditional drug molecules. We demonstrate that this chemistry is suitable for the creation of libraries of IP+-linked MPs and show that these libraries can be mined for protein ligands.

Antibacterial Activity and Mechanism of Action of Osthole against Listeria monocytogenes.

The purpose of this study was to investigate the antibacterial activity and mechanism of action of osthole against Listeria monocytogenes. The antibacterial activity of osthole was evaluated by determining the minimum inhibitory concentration (MIC) and growth curve. Cell morphology, membrane permeability, membrane integrity, bacterial physiology, and metabolism were explored using different methods to elucidate the mechanism of action of osthole. It was shown that the MIC of osthole against L. monocytogenes was 62.5 μg/mL and it inhibited the growth of L. monocytogenes effectively in a concentration-dependent manner. Scanning electron microscopy (SEM) images demonstrated morphology changes of L. monocytogenes, including rough surface, cell shrinkage, and rupture. It was found that extracellular conductivity and macromolecule content were increased significantly in the presence of osthole, indicating the disruption of cell membrane integrity and permeability. Laser confocal microscopy results supported the conclusion that osthole caused severe damage to the cell membrane. It was also noticed that osthole depleted intracellular adenosine triphosphate (ATP), inhibited Na+-K+-ATPase and Ca2+-Mg2+-ATPase activity, and promoted the accumulation of intracellular reactive oxygen species (ROS), leading to cell death. This study suggests that osthole is a promising antibacterial agent candidate against L. monocytogenes, and it shows potential in the prevention and control of foodborne pathogens.

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody.

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Ultramicroporous cardo-pendant polyamide nanofilms for enhanced organic solvent nanofiltration

Permeable, selective, and stable polymeric membranes are essential for efficient molecular separation in organic solvents. Polymers of intrinsic microporosity (PIMs) with rigid and twisted chain structures offer abundant pores for high solvent permeability and are emerging as an ideal membrane material. However, guaranteeing high separation selectivity and stability is challenging owing to the wide pore size distribution and low swelling resistance in organic solvents. In this work, we developed intrinsically ultramicroporous polyamides (PAs) with cardo-pendant groups to create crosslinking, ultrathin, and defect-free nanofilms for organic solvent nanofiltration. The molecular simulation confirmed the pivotal role of cardo-pendant group structures in the amine monomers and exhibited their effect in creating pore channel structures within the PAs. Distinctive rigid fluorenyl-based cardo-pendant groups were introduced in amine monomers to finely tailor the packing of PA chains for high ultramicroporosity and a finely tuned pore size. We further achieved the growth of such PAs using a cyclic deposition strategy, in-situ generating highly crosslinking nanofilms with an ultralow thickness of 23–36 nm without structure relaxation. As such, the typically-designed PA membranes demonstrated high and stable solvent permeance (e.g., 18 L m−2 h−1 bar−1 for methanol) and high solute rejection (up to 95 % rejection of 306 Da Azure I), which is superior to its counterparts and current PIM membranes, presenting a new perspective for efficient organic solvent nanofiltration.

Interplay of hypoxia and host cells in the translocation, invasion and dissemination of Taenia solium in neurocysticercosis

Neurocysticercosis, caused by the invasion of the central nervous system (CNS) by Taenia solium larvae, poses a significant global health burden. Despite its prevalence and severe neurological consequences, understanding of the molecular and signalling pathways facilitating parasite dissemination and CNS invasion is limited. The lack of comprehensive knowledge of host-parasite interactions and associated proteins involved in T. solium infection hinders the development of targeted interventions to mitigate its ability to cross the epithelia barrier. This is complicated by reduced oxygen availability in the intestine, a phenomenon called hypoxia. Hypoxia can result in epithelial barrier disruption and cell damage, thereby promoting the translocation and dissemination of T. solium. This study aims to establish the role of hypoxia in T. solium invasion and disseminated infections. The effect of hypoxia on the migration, viability and morphological characteristics of T. solium would be determined using transwell invasion assays, flow cytometry and microscopy. T. solium oncosphere development and dissemination under hypoxic and normoxic conditions will be monitored using animal models. Also, host-parasite transcriptome and proteome profiling will be performed to determine pathways triggered under hypoxic conditions. It is expected that hypoxia would promote the invasion and dissemination of T. solium by enhancing epithelial and endothelial cell permeability. , hypoxia will induce the expression of binding and adhesion proteins and other virulence markers such as enolase, serpin, and glutathione transferases that are involved in host invasion. Understanding the role of hypoxia in the translocation mechanism of T. solium can be leveraged to provide insights into host tissues dissemination and the development of appropriate interventions.

Osmosis: A Natural Approach for Treating Constipation

Osmosis is a natural process that occurs in living organisms and plays a vital role in maintaining their health. This abstract investigates the effectiveness of treating constipation with salt water after getting out of bed in the morning using the process of osmosis. Constipation is a common bowel problem caused by diet, lifestyle, medications, or other factors that make stool hard or impede the ability to pass it comfortably, affecting people of all ages worldwide. By conducting osmosis, where solute molecules move through a semi permeable membrane from low solute concentration to high solute concentration, salt water treatment softens stool and facilitates bowel movements. This paper presents an overview of treatment protocols, including materials, methods and observational results. Preliminary findings indicate promising results, with participants experiencing increased frequency and ease of bowel movements after consuming salt water. This paper explores the benefits of osmosis in treating constipation and how it works. We discuss the osmosis and their mechanisms of action, as well as their safety and efficacy. Overall, we conclude that osmosis is a safe and effective way to treat constipation and has the potential to change the life style of millions of people across the Globe.

Highly permeable membrane based on permax and PEG for air dehumidification

In this work, polyethylene glycol (PEG) with varying molecular weights was incorporated into the water-based polyurethane matrix (Permax232) to prepare Permax/PEG blend membranes for air dehumidification. The physical properties of the prepared membranes were characterized by FTIR, SEM, XRD and DSC. Furthermore, the influence of PEG molecular weight on the water vapor adsorption and permeability properties of the Permax/PEG blend membranes was investigated. The experimental results showed that blending PEG600 into the Permax232 matrix obtained optimal performance for air dehumidification. The water vapor sorption enthalpy and the permeation activation energy in the membranes were determined. Furthermore, Permax/20PEG600/PAN thin film composite membrane was developed via dip-coating method. The composite membrane showed superior water vapor permeance of 6578 GPU and water vapor/N2 selectivity of 4909 and a satisfactory long-term stability, which had potential industrial application for energy efficient dehumidification.