Search Results (12,228)

Transdermal drug delivery systems (TDDS) offer an alternative to conventional oral and injectable drug administration by bypassing the gastrointestinal tract and liver metabolism, improving bioavailability, and minimizing systemic side effects. However, widespread adoption of TDDS is limited by challenges such as the skin’s permeability barrier, particularly the stratum corneum, and the need for optimized formulations. Factors like skin type, hydration levels, and age further complicate the development of universally effective solutions. Advances in artificial intelligence (AI) address these challenges through predictive modeling and personalized medicine approaches. Machine learning models trained on extensive molecular datasets predict skin permeability and accelerate the selection of suitable drug candidates. AI-driven algorithms optimize formulations, including penetration enhancers and advanced delivery technologies like microneedles and liposomes, while ensuring safety and efficacy. Personalized TDDS design tailors drug delivery to individual patient profiles, enhancing therapeutic precision. Innovative systems, such as sensor-integrated patches, dynamically adjust drug release based on real-time feedback, ensuring optimal outcomes. AI also streamlines the pharmaceutical process, from disease diagnosis to the prediction of drug distribution in skin layers, enabling efficient formulation development. This review highlights AI’s transformative role in TDDS, including applications of models such as Deep Neural Networks (DNN), Artificial Neural Networks (ANN), BioSIM, COMSOL, K-Nearest Neighbors (KNN), and Set Covering Machine (SVM). These technologies revolutionize TDDS for both skin and non-skin diseases, demonstrating AI’s potential to overcome existing barriers and improve patient care through innovative drug delivery solutions. Full article

Garlic (Allium sativum L.), a vital global crop, suffers significant losses from soil-borne fungal pathogens such as Fusarium proliferatum, responsible for Fusarium bulb rot, and Stromatinia cepivora, the causal agent of white rot. In May 2023, garlic fields near Makó City, Hungary, showed simultaneous yellowing and wilting symptoms of unknown fungal infestations, which appeared sporadically. The causal pathogens were later confirmed as F. proliferatum and S. cepivora through sampling of symptomatic garlic plants, incubation in humid chambers to stimulate fungal growth, and culturing on Potato Dextrose Agar (PDA) under sterile conditions. This was followed by hyphal tip isolation and purification. Molecular identification was performed using ITS1-2 sequencing, supported with morphological identification based on colony and microscopic features. This research aimed to elucidate pathogen interaction dynamics and assess the resistance of eleven garlic cultivars to both single and simultaneous inoculations by these pathogens, under in vitro and in planta tests. Dual culture assays of F. proliferatum and S. cepivora were studied at two time points: Day 8, marking the cessation of growth along the interacting fronts due to competitive coexistence, and Day 14, when single cultures reached full radial growth. On Day 8, inhibition percentages were 8.47% for F. proliferatum and 6.40% for S. cepivora, reflecting the initial effects of competitive interactions at the point of contact. By Day 14, inhibition rates increased to 25.39% and 28.61%, respectively, highlighting the cumulative effects of sustained competition and the growing difference between single and dual culture growth. Inoculation trials, involving placing fungal disks onto the basal areas of wounded garlic cloves, revealed considerable variability in disease incidence and severity. Cultivars such as ‘Aulxito’, ‘Sabadrome’, ‘Arno’, ‘Garcua’, and ‘Makói Tavaszi’ were highly susceptible to both pathogens, while ‘Flavor’ and ‘Sabagold’ exhibited only mild symptoms when inoculated with F. proliferatum and S. cepivora, respectively. Simultaneous inoculation resulted in more rapid and severe infections, exhibiting disease incidences above 96.00% across all cultivars. Remarkably, the cultivar ‘Elephant’ exhibited complete resistance to both pathogens, even under simultaneous inoculation, highlighting its potential for future garlic resistance breeding programs. Full article

The molten salt chlorination method is one of the two main methods for producing titanium tetrachloride, an important intermediate product in the titanium industry. To effectively improve chlorination efficiency and reduce unnecessary waste salt generation, it is necessary to understand the mechanism of the molten salt chlorination reaction, and consequently this paper conducted studies on the carbon chlorination reaction mechanism in molten salts by combining ab initio molecular dynamics (AIMD) and deep potential molecular dynamics (DeePMD) methods. The use of DeePMD allowed for simulations on a larger spatial and longer time scale, overcoming the limitations of AIMD in fully observing complex reaction processes. The results comprehensively revealed the mechanism of titanium dioxide transforming into titanium tetrachloride. In addition, the presence form and conversion pathways of chlorine in the system were elucidated, and it was observed that chloride ions derived from NaCl can chlorinate titanium dioxide to yield titanium tetrachloride, which was validated through experimental studies. Self-diffusion coefficients of chloride ions in pure NaCl which were acquired by DeePMD showed good agreement with the experimental data. Full article

Graphene-based materials, including graphene oxide (GO) and functionalized derivatives, have demonstrated exceptional potential in addressing environmental challenges related to heavy metal detection and wastewater treatment. This review presents the latest advancements in graphene-based electrochemical and fluorescence sensors, emphasizing their superior sensitivity and selectivity in detecting metal ions, such as Pb²⁺, Cd²⁺, and Hg²⁺, even in complex matrices. The key focus of this review is on the use of molecular dynamics (MD) simulations to understand and predict ion transport through graphene membranes, offering insights into their mechanisms and efficiency in removing contaminants. Particularly, this article reviews the effects of external conditions, pore radius, functionalization, and multilayers on water purification to provide comprehensive insights into filtration membrane design. Functionalized graphene membranes exhibit enhanced ion rejection through tailored electrostatic interactions and size exclusion effects, achieving up to 100% rejection rates for selected heavy metals. Multilayered and hybrid graphene composites further improve filtration performance and structural stability, enabling sustainable, large-scale water purification. However, challenges related to fabrication scalability, environmental impact, and cost remain. This review also highlights the importance of computational approaches and innovative material designs in overcoming these barriers, paving the way for future breakthroughs in graphene-based filtration technologies. Full article

Alzheimer’s disease is a chronic neurodegenerative disorder characterized by progressive memory loss and a significant impact on quality of life. The APOE ε4 allele is a major genetic contributor to AD pathogenesis, with synaptic dysfunction being a central hallmark in its pathophysiology. While the role of APOE4 in reducing SNARE protein levels has been established, the underlying molecular mechanisms of this interaction remain obscure. Our research employs molecular dynamics simulations to analyze interactions between APOE4 and APOE3 isoforms and the synaptic proteins VAMP2, SNAP25, and SYNTAXIN1, which play crucial roles in the presynaptic membrane. Our findings reveal that APOE4 significantly destabilizes the SNARE complex, suppresses its structural dynamics, and reduces hydrogen bonding, consequently partially hindering neurotransmitter release—a very likely discovery for elucidating synaptic dysfunction in Alzheimer’s disease. We identified that APOE4 exhibits a diminished affinity for the SNARE complex in comparison to APOE3. This observation suggests that APOE4 may play a role in modulating the stability of the SNARE complex, potentially impacting the progression and occurrence of Alzheimer’s disease through free energy analysis. This work highlights the perturbations in synaptic function mediated by APOE4, which may offer novel insights into the molecular underpinnings of AD. By elucidating the molecular interplay between APOE4 and the SNARE complex, our study not only enhances our comprehension of AD’s synaptic pathology but also paves the way for devising innovative therapeutic interventions, such as targeting the APOE4–SNARE complex interaction or to restore neurotransmitter release. Full article

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) is a key regulator in cellular signaling pathways because its dysregulation has been implicated in various pathological conditions, including cancers and developmental disorders. Despite its importance, the molecular basis of SHP2’s regulatory mechanism remains poorly understood, hindering the development of effective targeted therapies. In this study, we utilized the high-specificity monobody Mb11 to investigate its interaction with the SHP2 phosphatase domain (PTP) using multiple replica molecular dynamics simulations. Our analyses elucidate the precise mechanisms through which Mb11 achieves selective recognition and stabilization of the SHP2-PTP domain, identifying key residues and interaction networks essential for its high binding specificity and regulatory dynamics. Furthermore, the study highlights the pivotal role of residue C459 in preserving the structural integrity and functional coherence of the complex, acting as a central node within the interaction network and underpinning its stability and efficiency. These findings have significantly advanced the understanding of the mechanisms underlying SHP2’s involvement in disease-related signaling and pathology while simultaneously paving the way for the rational design of targeted inhibitors, offering significant implications for therapeutic strategies in SHP2-associated diseases and contributing to the broader scope of precision medicine. Full article

As a part of our ongoing search for bioactive constituents of Artemisia capillaris, we isolated 4-O-caffeoyl-2-C-methyl-d-threonic acid (PPT-14). This is a rare caffeic acid ester derivative that is reported here for the first time in the Artemisia species, which is the third occurrence in any plant species worldwide. In this study, we evaluated the anti-diabetic potential of PPT-14 using in vitro and in silico approaches. PPT-14 demonstrated significant inhibitory activity against two crucial enzymes linked to diabetes progression and complications: protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR). These had IC₅₀ values of 64.92 and 19.50 µM, respectively. Additionally, PPT-14 exhibited free radical scavenging activity with 2,2-diphenyl-2-picrylhydrazyl (IC₅₀ 14.46 µM). Molecular docking and 200 ns molecular dynamics simulations confirmed that there were stable binding interactions with the key residues of PTP1B and AR, highlighting strong affinity and dynamic stability. Pharmacokinetic analyses revealed favorable water solubility, adherence to Lipinski’s Rule of Five, and minimal interactions with cytochrome P450 enzymes, indicating the drug-like potential of PPT-14. Toxicity studies confirmed its safety profile, showing no genotoxicity, hepatotoxicity, or significant toxicity risks, with an acceptable oral LD₅₀ value of 2.984 mol/kg. These findings suggest that PPT-14 could be a promising multitarget lead compound for ameliorating diabetes and its associated complications. Full article

This study aimed to provide an inclusive in silico investigation for the identification of novel drug targets that can be exploited to develop drug candidates for treating oral infections caused by S. sputigena. By coupling subtractive genomics with an in silico drug discovery approach, we identified dTDP-4-dehydrorhamnose 3,5-epimerase (UniProt ID: C9LUR0), UTP-glucose-1-phosphate uridyltransferase (UniProt ID: C9LRH1), and imidazole glycerol phosphate synthase (UniProt ID: C9LTU7) as three unique proteins crucial for the S. sputigena life cycle with no substantial similarity to human proteins. These potential drug targets served as the starting point for screening bioactive phytochemicals (1090 compounds) from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Among the screened natural products, cubebin (IMPHY001912) showed a higher affinity for two of the three selected targets, as evidenced by molecular docking and molecular dynamics studies. Given its favorable drug-like profile and possible multitargeting behavior, cubebin could be further exploited as an antibacterial agent for treating S. sputigena-mediated oral infections. It is worth nothing that cubebin could be the active ingredient of appropriate formulations such as mouthwash and/or toothpaste to treat S. sputigena-induced periodontitis, with the advantage of limiting the adverse effects that could affect the use of current drugs. Full article

Using 3D-printed (3DPd) polymers and their composites as shape memory materials in various smart engineering applications has raised the demand for such functionally graded sustainable materials. This study aims to investigate the viscoelastic, shape memory, and fracture toughness properties of the epoxy-based ultraviolet (UV)-curable resin. A UV-based DLP (Digital Light Processing) printer was employed for the 3D printing (3DPg) epoxy-based structures. The effect of the hydrothermal accelerated ageing on the various properties of the 3DPd components was examined. The viscoelastic performance in terms of glass transition temperature (T_g), storage modulus, and loss modulus was evaluated. The shape memory polymer (SMP) performance with respect to shape recovery and shape fixity (programming the shape) were calculated through dynamic mechanical thermal analysis (DMTA). DMTA is used to reveal the molecular mobility performance through three different regions, i.e., glass region, glass transition region, and rubbery region. The shape-changing region (within the glass transition region) between the T_g value from the loss modulus and the T_g value from the tan(δ) was analysed. The temperature memory behaviour was investigated for flat and circular 3DPd structures to achieve sequential deployment. The critical stress intensity factor values of the single-edge notch bending (SENB) specimens have been explored for different crack inclination angles to investigate mode I (opening) and mixed-mode I/III (opening and tearing) fracture toughness. This study can contribute to the development of highly complex shape memory 3DPd structures that can be reshaped several times with large deformation. Full article

Clinical emergent bacterial pathogens are a great threat to the global health system, chiefly Gram-negative carbapenem-resistant Enterobacterales and the Klebsiella pneumoniae species complex. Here, we present the molecular and phenotypic characterization of Klebsiella quasipneumoniae subs. similipneumoniae IEC57090 strain, belonging to ST138 and showing a multidrug resistance phenotype. The bla_NDM-7 present in one of the two resistance plasmids carried by the isolate, the antibiotic resistance genes fosA, oqxAB, and acrR, and gene mutations on porins ompK36 and ompK37, both associated with cephalosporin and carbapenem resistance, were detected. Virulence factors such as the clusters of type I and III fimbria, type IV pili genes, and genes associated with the K1 capsule, siderophore production, and multiple mobile genetic elements (MGE) were predicted. The emergence of silent pathogens in clinical environments highlights the importance of active research on new threads that may compromise the last resources of antimicrobials, such as carbapenems, specifically on mobile genetic elements containing carbapenemases in emergent pathogens, which can spread these antimicrobial resistance elements. This study reinforces that molecular biology vigilance can prevent outbreaks and help to better understand antimicrobial resistance and pathogens in clinical environment dynamics. Full article

Long COVID-19, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), involves symptoms or effects that persist for more than 4 weeks after the initial SARS-CoV-2 infection. One contributing factor to this condition is the disruption in the expression of the antioxidant enzyme Nuclear Factor Erythroid-2 (Nrf2) induced by the COVID-19 infection. Apigenin and related flavonoids, known for their diverse pharmacological activities, including potent antioxidant properties, have emerged as promising candidates for Long COVID-19 therapy. These compounds, particularly apigenin, are recognized for their ability to modulate oxidative stress and inflammation, making them potential activators of the Nrf2 pathway. This study aims to predict the activity of apigenin and its related flavonoids as Nrf2 activators using molecular modeling and molecular dynamics (MD) techniques, providing insights into their therapeutic potential in managing Long COVID-19. The findings from the molecular modeling analysis indicate that apigenin has a favorable affinity, with a free energy value (ΔG) of −6.40 kcal/mol. Additionally, MD simulation results demonstrate the strong stability of the Keap1-apigenin complex, with an average Root Mean Square Deviation (RMSD) value below 0.20 nm and the lowest average Root Mean Square Fluctuation (RMSF) value of 0.86 nm. Using the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculation method, the binding affinity of the Keap1-apigenin complex yields a lower free energy value (ΔG) of −67.039 kJ/mol, consistent with the molecular modeling results. Apigenin also exhibits the ability to inhibit the binding of Nrf2 to the hydrophobic surface of Keap1, with a total energy value of 993.266 kcal/mol and binding affinity value of −1.162 kJ/mol through peptide−receptor docking. In conclusion, the comprehensive results suggest that apigenin has the potential to be a lead compound for developing Nrf2 activators specifically designed for Long COVID-19 therapy. Full article

Naturally available antioxidants offer remarkable medicinal applications in wound healing. However, the encapsulation of these phytoactive moieties into suitable nano-scale drug delivery systems has always been challenging due to their inherent characteristics, such as low molecular weight, poor aqueous solubility, and inadequate skin permeability. Here, we provide a systematic review focusing on the major obstacles hindering the development of various lipid and polymer-based drug transporters to carry these cargos to the targeted site. Additionally, this review covers the possibility of combining the effects of a polymer and a lipid within one system, which could increase the skin permeability threshold. Moreover, the lack of suitable physical characterization techniques and the challenges associated with scaling up the progression of these nano-carriers limit their utility in biomedical applications. In this context, consistent progressive approaches for addressing these shortcomings are introduced, and their prospects are discussed in detail. Full article

Complexation of alkaline earth metal cations with fluorescent tertiary-amide lower-rim calix[⁴]arene derivative bearing two phenanthridine moieties was studied experimentally (UV spectrophotometry, fluorimetry, isothermal microcalorimetry, NMR spectroscopy) and computationally (classical molecular dynamics and DFT calculations) at 25 °C. The complexation reactions were studied in acetonitrile, methanol, and ethanol, whereby the solvent effect on cation-binding processes was particularly addressed. The complex stability constants and standard reaction thermodynamic quantities (Gibbs energies, enthalpies, and entropies) were determined. The receptor exhibited particularly high affinity towards alkaline earth metal cations in acetonitrile, with peak affinity for Ca²⁺. The stability of all complexes was significantly lower in ethanol and methanol, where the most stable complex was formed with Sr²⁺. The decrease in cation-binding abilities was a consequence of the differences in solvation of the reactants and products of the complexation reactions (involving inclusion of the solvent molecule in the calixarene cone), cation charge density, as well as the cation–ligand binding site compatibility. The reactions were enthalpically controlled in acetonitrile, whereas in methanol and ethanol, the binding processes were endothermic and thus entropy driven. The results of ¹H NMR measurements, MD simulations, and DFT calculations provided an insight into the structure of the complexes and the corresponding adducts with solvent molecules, as well as the structural aspects behind the differences in complexation thermodynamics. Due to the significant increase in its fluorescence upon cation binding, the studied calixarene derivative was proven to be a promising luminescent sensor for alkaline earth metal cations. Full article

The Kunlun, Arjin, and Qilian mountain ranges mark the northern edge of the Qinghai–Tibet Plateau (QTP), where rapid uplift and Quaternary glacial cycles have shaped a unique cold desert ecosystem and species distribution. Despite sampling challenges, phylogeographic studies are crucial for understanding reptile populations such as the Qinghai toad-headed agama (Phrynocephalus vlangalii), a viviparous lizard with limited dispersal and multiple subspecies in the northeastern QTP. Our fieldwork identified populations of P. vlangalii on the northern slope of the Kunlun–Arjin Mountains, similar to the controversial subspecies P. v. lidskii. We analyzed 130 individuals from the northern slope of the Kunlun–Arjin–Qilian Mountains and 253 individuals from GenBank, using three mitochondrial genes and two nuclear genes to assess intraspecific differentiation and demographic history. We found high haplotype diversity and low nucleotide diversity in P. vlangalii, with phylogenetic analyses revealing six distinct clades. Clade VI, confirmed as P. v. lidskii, and Clade IV, a new genetic lineage, were identified alongside three recognized subspecies. Genetic variation was largely attributed to clade splitting, indicating significant divergence. The Mantel test indicated that geographical and environmental factors drove population differentiation. Bayesian molecular clock analysis suggested that the most recent common ancestor of P. vlangalii lived 2.55 million years ago, influenced by the Qinghai–Tibet Movement and glacial cycles. Demographic history and ecological niche modeling (ENM) indicated no population decline during the Last Glacial Maximum, supporting the glacial maximum expansion model, with ENM predicting future habitat expansion for P. vlangalii. In addition, morphological data from 13 meristic and 15 metric characters confirmed clade differences. Our findings significantly advance our understanding of P. vlangalii diversification, population dynamics and response to geological and climatic changes in the QTP. Full article

Antibiotic contamination constitutes a serious environmental and public health risk. In order to fill the gap in the study of plasma degradation of erythromycin (ERY), this paper systematically investigated the mechanism of ERY degradation by dielectric barrier discharge (DBD) plasma. The underlying reaction mechanisms were investigated by experiments and molecular dynamics simulations. Plasma emission spectra revealed active hydroxyl radicals (·OH) and argon (Ar) spectral lines. The degradation efficiency of plasma treatment for ERY was found to be strongly influenced by treatment parameters, including applied voltage, treatment duration, and gas flow rate. In particular, a maximum degradation of 90% was achieved for a 250 mg/L ERY solution under conditions of 18 kV voltage, 850 sccm gas flow rate, and 60 min of treatment. The presence of ·OH and hydrogen peroxide (H₂O₂) in the reaction and their important role in the degradation were proved experimentally. Fracture of the ERY lactone ring induced by hydrogen abstraction reactions with reactive oxygen species (ROS) was observed by molecular dynamics simulations. In the in vitro antimicrobial assays targeting Staphylococcus aureus, the treated solutions demonstrated low toxicity, underscoring the practical applicability of dielectric barrier discharge (DBD) plasma technology in addressing antibiotic contamination in aquatic environments. Full article