Search Results (3,714)

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile. Full article

Omniphobic membranes have gained extensive attention for mitigating membrane wetting in robust membrane separation owing to the super-repulsion toward water and oil. In this study, a Teflon/PAI composite membrane with omniphobic characteristics was prepared by a vacuum-assisted dip-coating strategy on the PAI hollow fiber membrane. A series of characterizations on morphological structure, surface chemical composition, wettability, permeability, mechanical properties, and stability were systematically investigated for pristine PAI and Teflon/PAI composite membranes. Subsequently, the experiment was conducted to explore the oil–gas separation performance of membranes, with standard transformer oil containing dissolved gas as the feed. The results showed that the Teflon AF2400 functional layer was modified, and C-F covalent bonds were introduced on the composite membrane surface. The Teflon/PAI composite membrane exhibited excellent contact angles of 156.3 ± 1.8° and 123.0 ± 2.5° toward DI water and mineral insulating oil, respectively, indicating omniphobicity. After modification, the membrane tensile stress at break increased by 23.0% and the mechanical performance of the composite membrane was significantly improved. In addition, the Teflon/PAI composite membrane presented satisfactory thermal and ultrasonic stability. Compared to the previous membranes, the Teflon/PAI composite membrane presented a thinner Teflon AF2400 separation layer. Furthermore, the omniphobic membrane demonstrated anti-wetting performance by reaching the dynamic equilibrium within 2 h for the dissolved gases separated from the insulating oil. This suggests an omniphobic membrane as a promising alternative for oil–gas separation in monitoring the operating condition of oil-filled electrical equipment online. Full article

Background/Objectives: Predicting whether a compound is subject to active transport is crucial in drug development. We propose a simple threshold for passive membrane permeability (P_m), derived from the cell’s energy limitation, to identify compounds unlikely to be actively effluxed. Results: By considering fundamental cellular energy constraints, our approach provides a mechanistic rationale for why compounds with very high passive permeability in combination with low applied concentration will not undergo active efflux. This moves beyond the empirical observation (such as in previous systems that associate fast-permeating, poorly soluble compounds with low transporter activity) by grounding the prediction in the cell’s energetic limitations. For MDCK (Madin–Darby canine kidney) cells, this threshold—normalized to the applied compound concentration (C_ext)—was determined to be P_m×C_ext = 10^−1.7 cm/s×µM. Methods: To derive this threshold, we conducted an extensive analysis of literature-reported efflux ratios (ERs) in MDCKII cells overexpressing efflux transporters (MDR1, BCRP, MRP2; 294 datapoints across 136 unique compounds). Concentration-dependent measurements for Amprenavir, Eletriptan, Loperamide, and Quinidine—chosen because these borderline compounds exhibited the highest P_m×C_ext while still being actively effluxed—enabled the most accurate determination of the threshold. Literature ER values were re-evaluated through the experimental determination of reliable P_m values, as well as newly measured ER values with MDCK efflux assays. Conclusions: The results of these assays and the re-evaluation allowed us to reclassify all but three outliers (compounds with ER > 2.5 and log(P_m×C_ext) > −1.7). In contrast, more than 60% of the compounds analyzed without significant ER values (123 compounds) fell above the threshold, in strong agreement with our theory of an energy limitation to active transport. This permeability threshold thus provides a simple and broadly applicable criterion to identify compounds for which active efflux is energetically not feasible and may serve as a practical tool for early drug discovery and optimization, pending further validation in practical applications. Full article

Consisting of phospholipids, sperm membranes surround the head and tail, playing essential roles in maintaining cellular structural integrity and functions. Their characteristics directly influence sperm fertility and cryopreservation outcomes. This minireview provides a summary of how sperm fertility and freezability are affected by the characteristics of its cell membranes. The primary emphasis is on the molecular and cellular anatomy as well as the physiology of sperm membranes and their attributes associated with fertility determinants or biomarkers for fertility and freezability. It also explores how this knowledge can guide the development of extenders to improve sperm freezability and enhance reproductive technologies in mammals. By providing integrity, fluidity, and selective permeability, the membranes play vitally important roles in sperm motility, which is required for successful fertilization. Cryopreservation, which involves freezing and thawing of sperm for storage or ART, alters the integrity and functionality of the sperm membranes. Sperm freezability, its viability following freezing and thawing, is influenced by several properties of the sperm cell membranes, such as lipid composition, cholesterol content, and structures and functions of the membrane proteins. This review provides concise information about the nature of sperm membranes. It highlights the importance of understanding specific biophysical and biochemical features, including lipid composition, protein distribution, and membrane phase behavior. Particular attention is given to parameters such as the cholesterol–phospholipid ratio and membrane phase transition temperature (Tm). A deeper understanding of these factors can contribute to the identification of reliable fertility biomarkers and the optimization of cryopreservation techniques used in ART and animal breeding programs. Furthermore, this review underscores the need for comprehensive investigations into the molecular and cellular architecture of sperm cells. Such studies are essential for advancing both fundamental and applied aspects of reproductive biology in food-producing animals, endangered species, and humans. Full article

Background/Objectives: Breast cancer remains the most prevalent malignancy among women worldwide, with letrozole (LZ) serving as a critical aromatase inhibitor for hormone receptor–positive cases. However, long-term oral administration of LZ is often associated with systemic adverse effects and poor patient compliance. To overcome these limitations, new non-aqueous nanoemulgels (NEMGs) were developed for transdermal delivery of LZ. Methods: The NEMGs were formulated using glyceryl monooleate (GMO), Sepineo P600^®, Transcutol, propylene glycol, and penetration enhancers propylene glycol laurate (PGL), propylene glycol monocaprylate (PGMC), and Captex^®. Physicochemical characterization, solubility, stability, and in vitro permeation studies were conducted using Strat-M^® membranes, while in vivo pharmacokinetics were evaluated in rat models. Results: The optimized GMO/PGMC-based NEMG demonstrated significantly enhanced drug flux, higher permeability coefficients, and shorter lag times compared with other NEMGs and suspension emulgels. In vivo, transdermal application of the GMO/PGMC-based NEMG over an area of 2.55 cm² produced dual plasma absorption peaks, with 57% of the LZ dose absorbed relative to oral administration over 12 days. Shelf-life and accelerated stability assessments confirmed excellent physicochemical stability with negligible crystallization. Conclusions: The developed LZ NEMG formulations offer a stable, effective, and patient-friendly transdermal drug delivery platform for breast cancer therapy. This system demonstrates potential to improve patient compliance and reduce systemic toxicity compared to conventional oral administration. Full article

The widespread use of plastics has caused severe environmental pollution, driving interest in biodegradable alternatives like polylactic acid (PLA). However, incomplete degradation of biodegradable plastics under natural conditions may generate micro/nanoplastics that could exacerbate ecological risks. This study investigated the combined effects of UV-aged microplastics from biodegradable PLA and conventional PET, along with sulfamethoxazole (SMX), on the conjugative transfer of antibiotic resistance genes (ARGs) between bacteria. Using UV aging to simulate environmental weathering, the microplastic morphology, adsorption behavior, and interaction with SMX were characterized. The study further evaluated the bacterial viability, ROS level, membrane permeability, and the expression of conjugative transfer-related genes to elucidate the underlying mechanisms. Results showed that aged PLA released significantly more nanoplastics and exhibited higher adsorption affinity for SMX than PET. Combined exposure to aged PLA and SMX significantly enhanced ARG transfer frequency by approximately 14.5-fold compared to the control. Mechanistic studies revealed that this promotion was associated with increased intracellular ROS levels, elevated membrane permeability, and upregulation of conjugative related genes. These findings underscore that biodegradable plastics, after environmental aging, may pose greater ecological risks than conventional plastics, and highlight the importance of considering environmental aging in the risk assessment of plastics. Full article

Background: Fusarium solani (Fs), a drug-resistant phytopathogenic fungus, is a major cause of severe infections in both plants and humans. Artemisia annua and its derivatives exhibit antimicrobial, antiviral and anticholesterolemic activities, yet their clinical use has been dominated by potent antimalarial and anticancer effects. Artemisinin (ART), a sesquiterpene lactone isolated from A. annua, is well recognized for its antimalarial efficacy but remains underexplored as an antifungal agent. Methods: Conidia of Fs were treated with increasing concentrations of ART (75–500 μM) for 0 and 24 h. Fungal viability was assessed using viability assays. Membrane permeability was examined using confocal laser scanning microscopy with propidium iodide (PI) staining. Protein carbonylation assays were performed to quantify oxidative damage induced by ART. Results: A 24 h, ART exposure reduced Fs viability in a dose-dependent manner, with an IC₅₀ of 147.5 μM. At 500 μM, ART achieved fungicidal activity with 99% growth inhibition. Confocal microscopy confirmed extensive membrane disruption in ART-treated conidia, while carbonylation assays demonstrated marked protein oxidation, supporting a mechanism involving free radical generation from the peroxide bridge of ART. ART exhibits potent antifungal activity against Fs, mediated by oxidative stress, membrane disruption and protein carbonylation. Conclusions: These findings highlight ART as a promising candidate for antifungal drug development against resistant Fusarium species. Full article

Ischemic stroke remains one of the most catastrophic diseases in neurology, in which, due to a disturbance in the cerebral blood flow, the brain is acutely deprived of its oxygen and glucose oligomer, which in turn rapidly leads to energetic collapse and progressive cellular death. There is now increasing evidence that this type of stroke is not simply a type of ‘oxidative stress’ but rather a programmable loss-of-redox homeostasis, within which electron flow and the balance of oxidants/reductants are cumulatively displaced at the level of the single molecule and at the level of the cellular area. The advances being made in cryo-electron microscopy, lipidomics, and spatial omics are coupled with the introduction of a redox code produced by the interaction of the couples NADH/NAD⁺, NADPH/NADP⁺, GSH/GSSG, BH₄/BH₂, and NO/SNO, which determine the end results of the fates of the neurons, glia, endothelium, and pericytes. Within the mitochondria, pathophysiological events, including reverse electron transport, succinate overflow, and permeability transition, are found to be the first events after reperfusion, while signals intercommunicating via ER–mitochondria contact, peroxisomes, and nanotunnels control injury propagation. At the level of the tissue, events such as the constriction of the pericytes, the degradation of the glycocalyx, and the formation of neutrophil extracellular traps underlie microvascular failure (at least), despite the effective recanalization of the vessels. Systemic influences such as microbiome products, oxidized lipids, and free mitochondrial DNA in cells determine the redox imbalance, but this generally occurs outside the brain. We aim to synthesize how the progressive stages of ischemic injury evolve from the cessation of flow to the collapse of the cell structure. Within seconds of injury, there is reverse electron transport (RET) through mitochondrial complex I, with bursts of superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂) being produced, which depletes the stores of superoxide dismutase, catalase, and glutathione peroxidase. Accumulated succinate and iron-induced lipid peroxidation trigger ferroptosis, while xanthine oxidase and NOX2/NOX4, as well as uncoupled eNOS/nNOS, lead to oxidative and nitrosative stress. These cascades compromise the function of neuronal mitochondria, the glial antioxidant capacity, and endothelial–pericyte integrity, leading to the degradation of the glycocalyx with microvascular constriction. Stroke, therefore, represents a continuum of redox disequilibrium, a coordinated biochemical failure linking the mitochondrial metabolism with membrane integrity and vascular homeostasis. Full article

Field emission scanning electron microscopy (FE-SEM) may be used to visualize the surface morphology of samples that are permeable to electron beams, including biological samples. Probiotics attenuate host physiological functions and are characterized by their three-dimensional surface structures. In this study, we determined the effect of critical point drying (CPD) on FE-SEM observations of the surface of Lacticaseibacillus paracasei strain Shirota (LcS). We also assessed ionic liquid (IL), a non-volatile liquid salt that retains moisture, and NanoSuit^®, which forms a protective polymer membrane around the sample, through FE-SEM observation of these probiotics. The results indicate that dehydration during CPD leads to reticular structures on the probiotic surface, potentially affecting the characteristics observed by FE-SEM. In addition, we examined IL and NanoSuit^®, which do not involve dehydration. The initial examination involving optimal dilution using silica particles revealed that 5–10% IL and 5–20% NanoSuit^® solutions maintained particle size consistency. We examined LcS specimens under these conditions and observed smooth surfaces, not reticulate structures. These results indicate that CPD affects LcS surface morphology, whereas the IL and NanoSuit^® methods preserved it. This suggests their applicability for probiotic preparation before FE-SEM observations. Full article

This review reappraises the anti-inflammatory potential of the contact activation system (CAS) in intensive care through an evolutionary lens. The authors propose that coagulation factor XII (FXII) and related components evolved in terrestrial animals as a “foreign-surface sensing–immunothrombosis” module, helping to explain the minimal bleeding phenotype of FXII deficiency and the secondary loss of F12 in marine mammals. CAS shares components with the kallikrein–kinin system (KKS): alpha-coagulation factor XIIa (α-FXIIa) drives coagulation factor XI (FXI) activation to amplify coagulation, whereas betacoagulation factor XIIa (β-FXIIa) activates the KKS to generate bradykinin, promoting vasodilation and vascular leak. Beyond proteolysis, zymogen FXII signals via urokinase-type plasminogen activator receptor (uPAR) to induce neutrophil extracellular trap formation (NETosis), thereby amplifying immunothrombosis. Clinically, the relevance spans sepsis and extracorporeal organ support: pathogens can hijack CAS/KKS to facilitate invasion, and artificial surfaces such as extracorporeal membrane oxygenation (ECMO) circuits chronically trigger contact activation. In animal models, selective inhibition of FXII/FXI prolongs circuit life and attenuates pulmonary edema and inflammation without materially increasing bleeding. The review also catalogs “non-coagulation” roles of CAS members: Activated coagulation factor XI (FXIa) modulates endothelial permeability and smooth-muscle migration, and the FXII heavy chain exhibits direct antimicrobial activity—underscoring CAS as a nexus for coagulation, inflammation, and host defense. Overall, CAS inhibitors may couple “safe anticoagulation” with “cascade-level anti-inflammation,” offering a testable translational path for organ protection in the ICU alongside infection control and informing combined, precision strategies for anticoagulation and anti-inflammatory therapy. Full article

Layered graphene oxide (GO) has emerged as an ideal membrane structure for water desalination. In GO-stacked structures, the slit gaps between GO nanosheets can serve as critical pathways for molecule permeation. Exploring the permeation mechanisms of functionalized GO nanoslits is critical for improving the separation performance. Herein, molecular simulations were performed to investigate the water permeation and ion rejection for six types of ionic solutions by considering edge-amino functionalized GO (NGO) slit membranes. The NGO slit exhibits higher ion retention while maintaining reasonable water permeability. Edge amine groups can interact strongly with water molecules and immobilize ions, thus enhancing ion rejection. The thermodynamic free energy for ion passing was simulated to explain the unique ion rejection mechanism of amine-functionalized GO slits. The thermodynamic barrier for ion rejection can be considered as the delicate combination of the ion dehydration effect and the slit-generated attraction. The ion dehydration accounts for a repulsive contribution, which is the controlling portion in governing the free-energy profile. Overall, our work is important and valuable for the development and design of new-type layered GO membranes. Full article

Pseudomonas aeruginosa is a Gram-negative bacterium that poses a serious threat to patients with weakened immunity, cystic fibrosis, severe burns, or those in hospitals. Its ability to resist antibiotics comes largely from its outer membrane, which blocks drug entry. This means higher doses are often needed, raising the risk of side effects. To design new treatments, researchers need drugs that not only bind strongly to bacterial targets but also cross this tough membrane. Unfortunately, there are few reliable methods to directly measure how easily drugs pass through the Pseudomonas aeruginosa cell envelope. Recent advances, such as electrophysiology-based flux studies, have started to reveal how different antibiotics particularly β-lactams move through porin channels. These studies show large differences in permeability, but the findings remain scattered. What is missing is a unified dataset that captures permeability under varied conditions. Such a resource would clarify how porin structures influence drug entry and help chemists design better compounds. This review brings together current knowledge on drug permeability in Pseudomonas aeruginosa, with a focus on electrophysiological and related methods. This review highlights the need for standardized approaches that generate consistent and comparable data. A comprehensive “permeability atlas” could guide the development of new antibiotics by fine-tuning molecular properties like size, charge, and lipophilicity, ultimately improving porin passage and restoring treatment effectiveness against this challenging pathogen. Full article

Treating bacterial infections has become increasingly difficult due to the rise in antibiotic-resistant bacterial strains. Strategies involving the targeted delivery of antibiotics have been proposed to minimize the administered antibiotic doses. This study aims to develop the first double-modified nanovehicle capable of increasing bacterial membranes’ permeability while specifically targeting Staphylococcus aureus, one of the foremost pathogens responsible for global mortality rates. Thus, polymeric NPs composed of poly(lactic-co-glycolic acid) (PLGA) were produced, and their surface was modified with TAT peptide to increase the membranes’ permeability and folic acid (FA) to direct the NPs to S. aureus. The nanosystem showed spherical morphology with sizes of 174 ± 4 nm, a monodisperse population (polydispersity index of 0.08 ± 0.02), and a zeta potential of −2.5 ± 0.1 mV. The NPs remained stable for up to four months during storage. Fluorescence-based flow cytometry analysis proved that the double modification of PLGA NPs increased the interaction of the NPs with S. aureus, with fluorescence increasing from 71 ± 3% to 87 ± 1%. The nanosystem slightly affected the growth curve of S. aureus by extending both the lag time (from 2.5 ± 0.2 to 2.88 ± 0.4 h) and the exponential phase, as evidenced by an increase in the half-maximum growth time (from 3.9 ± 0.2 to 4.4 ± 0.1 h). Furthermore, the nanocarrier showed no toxicity for human dermal fibroblast cells, maintaining a 100% cell viability at the highest concentration tested (100 µM). Therefore, the proposed FA/TAT-functionalized nanocarrier presented promising features to be successfully used as a delivery vehicle of antimicrobials to fight S. aureus. Full article

Conventional thermoplastic polyurethane (TPU) films are commonly used in the field of waterproof and moisture-permeable textiles because of their excellent mechanical properties and flexibility. However, the high water absorption of TPU films limits their application in sophisticated waterproof and moisture-permeable products, particularly in extremely humid environments, where it may compromise the waterproof performance of textiles and negatively affect the wearing comfort. Therefore, to enhance the durability of these films, TPU was hydrophobically modified with end-hydroxy polydimethylsiloxane (PDMS). Because of its unique low-surface-energy properties and excellent hydrophobicity, PDMS substantially reduces the surface energy of the films and provides them with excellent water repellency, effectively addressing the excessive water absorption issue of TPU films. On this basis, a microporous film featuring waterproof and moisture-permeable properties is produced using phase conversion technology. Compared with that of the unmodified sample, the surface energy of silicone-modified TPU (Si-TPU) decreased by 10.56 mJ/m². Furthermore, the water contact angle increased from 83° to 105°, whereas the water absorption rate considerably reduced after the modification. Moreover, Si-TPU was employed for the fabrication of a microporous membrane, which displayed exceptional moisture permeability (8651.34 g/(m²⸱24 h)). Full article

The Salmonella enterica serovar Typhimurium (ST) mutant lacking the msbB gene (ΔmsbB) has been widely studied as a candidate for attenuated bacterial vectors in therapeutic applications. Deletion of msbB results in LPS with under-acylated lipid A, which lowers endotoxicity while maintaining structural integrity. This attenuation has traditionally been attributed to reduced TLR4 activation due to weaker interaction between the modified lipid A and TLR4. In our study, we confirmed that ΔmsbB ST was less lethal than wild-type (WT) ST in a mouse sepsis model. However, this difference persisted even in TLR4- and caspase-11-deficient mice, suggesting that LPS signaling is not the primary determinant of virulence. In vitro, bone marrow–derived macrophages (BMDMs) from TLR4- or caspase-11-deficient mice showed only modest reductions in ST-induced cell death and cytokine production. Importantly, ΔmsbB ST behaved similarly to WT ST in these assays, further indicating that LPS-mediated signaling is not central to the observed attenuation. Our previous studies showed that ST-induced mortality in mice is primarily mediated through NLRC4 activation. Using qPCR and immunoblotting, we found that expression of NLRC4 activators was diminished in the ΔmsbB strain. Additionally, the mutant exhibited increased outer membrane permeability—likely contributing to its heightened antibiotic sensitivity—and reduced motility due to lower flagellin protein levels. In summary, the attenuation of virulence observed in the ΔmsbB strain is not directly due to altered LPS–TLR4 interactions, but rather an indirect effect of diminished expression of virulence factors that activate the NLRC4 inflammasome. Full article