Release Mechanism Research Articles

Rapid Fabrication of Large-Grain Opal Films and Photonic Crystal Hydrogel Sensors by a Filter Paper-Enhanced Evaporation Chip.

Developing a rapid fabrication method for crack-free opal films is a significant challenge with broad applications. We developed a microfluidic platform known as the "filter paper-enhanced evaporation microfluidic chip" (FPEE-chip) for the fabrication of photonic crystal and inverse opal hydrogel (IOPH) films. The chip featured a thin channel formed by bonding double-sided adhesive poly(ethylene terephthalate) with a polymethyl methacrylate cover and a glass substrate. This channel was then filled with nanosphere colloids. The water was guided to evaporate rapidly at the surface of the filter paper, allowing the nanospheres to self-assemble and accumulate within the channel under capillary forces. Experimental results confirmed that the self-assembly method based on the FPEE-chip was a rapid platform for producing high-quality opal, with centimeter-sized opal films achievable in less than an hour. Furthermore, the filter paper altered the stress release mechanism of the opal films during drying, resulting in fewer cracks. This platform was proven capable of producing large-grain, crack-free opal films of up to 30 mm2 in size. We also fabricated crack-free IOPH pH sensors that exhibited color and size responsiveness to pH changes. The coefficient of variation of the gray color distribution for crack-free IOPH ranged from 0.03 to 0.07, which was lower than that of cracked IOPH (ranging from 0.07 to 0.14). Additionally, the grayscale peak value in 1 mm2 of the crack-free IOPH was more than twice that of the cracked IOPH at the same pH. The FPEE-chip demonstrated potential as a candidate for developing vision sensors.

Dynamic characteristics and evolution laws of underground brine in Mahai salt lake of Qaidam Basin during mining process

In the late stage of underground brine mining in salt lakes, the method of injecting fresh water is often used to extract the salt from the brine storage medium. This method of freshwater displacement breaks the original water–rock equilibrium and changes the evolution process of the original underground brine. To explore the mechanism of salt release in saline water-bearing media under conditions of relatively fresh lake water dissolution, this paper analyzes the changes in the chemical parameters of brine from 168 sampling points in the Mahai salt lake in the Qaidam Basin at three stages (before exploitation, during exploitation, and late exploitation) by correlation analysis, ion ratio analysis, and other methods and investigate the variations in porosity and the evolution laws of brine. The results show that the changes in the main ion content and brine mineralization during the exploitation process are small. The changes in Ca2+ content are significant due to the low solubility of calcium minerals, the precipitation of gypsum during the mixing process, and the adsorption of cations by alternating with Ca2+. Primary intergranular pore skeletons are easily corroded to form secondary pores, which increase the geological porosity. Na+ and Cl- are the dominant ions in the brine in the study area, but the concentration of Ca2 + decreased significantly under the influence of mining, by 41.7% in the middle period and 24.5% in the late period. The correlation between Ca2+ and salinity changes significantly in different mining stages, and the reason for the decrease of Ca2+ may be due to the influence of mineral dissolution, mixing, and anion-cation exchange. The porosity of the layer in the study area showed the opposite trend of Ca2+, and the porosity increased first and then decreased. The innovation of this paper lies in analyzing the reasons and mechanisms of the disturbance of artificial dissolution mining on stratum structure by comparing the hydrochemical characteristics and porosity of underground brine storage media in three different mining stages. The research in this paper provides a theoretical basis for the calculation of brine resource reserves and the sustainable development of underground brine in salt lake areas.

Human iPSC-derived neurons with reliable synapses and large presynaptic action potentials

Understanding the function of the human brain requires determining basic properties of synaptic transmission in human neurons. One of the most fundamental parameters controlling neurotransmitter release is the presynaptic action potential, but its amplitude and duration remain controversial. Presynaptic action potentials have so far been measured with high temporal resolution only in a limited number of vertebrate but not in human neurons. To uncover properties of human presynaptic action potentials, we exploited recently developed tools to generate human glutamatergic neurons by transient expression of Neurogenin 2 (Ngn2) in pluripotent stem cells. During maturation for 3 to 9 weeks of culturing in different established media, the proportion of cells with multiple axon initial segments decreased, while the amount of axonal tau protein and neuronal excitability increased. Super-resolution microscopy revealed the alignment of the pre- and postsynaptic proteins, Bassoon and Homer. Synaptic transmission was surprisingly reliable at frequencies of 20, 50, and 100 Hz. The synchronicity of synaptic transmission during high-frequency transmission increased during 9 weeks of neuronal maturation. To analyze the mechanisms of synchronous high-frequency glutamate release, we developed direct presynaptic patch-clamp recordings from human neurons. The presynaptic action potentials had large overshoots to ∼25 mV and short durations of ∼0.5 ms. Our findings show that Ngn2-induced neurons represent an elegant model system allowing for functional, structural, and molecular analyses of glutamatergic synaptic transmission with high spatio-temporal resolution in human neurons. Furthermore, our data predict that glutamatergic transmission is mediated by large and rapid presynaptic action potentials in the human brain.Significance statementPresynaptic physiology remains poorly understood despite its relevance to neurological and psychiatric diseases. Studying presynaptic functions in human iPSC-derived neurons offers the important advantage of characterizing molecular mechanisms of neurotransmitter release in neurons derived from diseased patients. As a first step towards this goal, we established direct presynaptic whole-cell patch-clamp recordings from human glutamatergic neurons induced by transient Neurogenin 2 overexpression. We furthermore analyzed the structure of the synapses with super-resolution light microscopy and the synaptic short-term plasticity during high-frequency transmission. Our findings show that synchronous high-frequency transmission is mediated by rapid and large presynaptic action potentials in human neurons, similar to small conventional nerve terminals of rodent neurons.

New Hydrophilic Matrix Tablets for the Controlled Released of Chlorzoxazone

The modified release of active substances such as chlorzoxazone from matrix tablets, based on Kollidon®SR and chitosan, depends both on the drug solubility in the dissolution medium and on the matrix composition. The aim of this study is to obtain some new oral matrix tablet formulations, based on Kollidon®SR and chitosan, in order to optimize the low-dose oral bioavailability of chlorzoxazone, a non-steroidal anti-inflammatory drug of class II Biopharmaceutical Classification System. Nine types of chlorzoxazone matrix tablets were obtained using the direct compression method by varying the components ratio as 1:1, 1:2, and 1:3 chlorzoxazone/excipients, 20–40 w/w % Kollidon®SR, 3–7 w/w % chitosan while the auxiliary substances: Aerosil® 1 w/w %, magnesium stearate 0.5 w/w % and Avicel® up to 100 w/w % were kept in constant concentrations. Pharmaco-technical characterization of the tablets included the analysis of flowability and compressibility properties (flow time, friction coefficient, angle of repose, Hausner ratio, and Carr index), and pharmaco-chemical characteristics (such as mass and dose uniformity, thickness, diameter, mechanical strength, friability, softening degree, and in vitro release profiles). Based on the obtained results, only three matrix tablet formulations (F1b, F2b, and F3b, containing 30 w/w % KOL and 5 w/w % CHT, were selected and further tested. These formulations were studied in detail by Fourier-transform infrared spectrometry, X-ray diffraction, thermogravimetry, and differential scanning calorimetry. The three formulations were comparatively studied regarding the release kinetics of active substances using in vitro release testing. The results were analyzed by fitting into four representative mathematical models for the modified-release oral formulations. In vitro kinetic study revealed a complex mechanism of release occurring in two steps of drug release, the first step (0–2 h) and the second (2–36 h). Two factors were calculated to assess the release profile of chlorzoxazone: f1—the similarity factor, and f2—the factor difference. The results have shown that both Kollidon®SR and chitosan may be used as matrix-forming agents when combined with chlorzoxazone. The three formulations showed optima pharmaco-technical properties and in vitro kinetic behavior; therefore, they have tremendous potential to be used in oral pharmaceutical products for the controlled delivery of chlorzoxazone. In vitro dissolution tests revealed a faster drug release for the F2b sample.

Fluorescent Chiral Quantum Dots to Unveil Origin-Dependent Exosome Uptake and Cargo Release.

Exosomes are promising nanocarriers for drug delivery. Yet, it is challenging to apply exosomes in clinical use due to the limited understanding of their physiological functions. While cellular uptake of exosomes is generally known through endocytosis and/or membrane fusion, the mechanisms of origin-dependent cellular uptake and subsequent cargo release of exosomes into recipient cells are still unclear. Herein, we investigated the intricate mechanisms of exosome entry into recipient cells and intracellular cargo release. In this study, we utilized chiral graphene quantum dots (GQDs) as representatives of exosomal cargo, taking advantage of the superior permeability of chiral GQDs into lipid membranes as well as their excellent optical properties for tracking analysis. We observed that the preferential cellular uptake of exosomes derived from the same cell-of-origin (intraspecies exosomes) is higher than that of exosomes derived from different cell-of-origin (cross-species exosomes). This uptake enhancement was attributed to receptor-ligand interaction-mediated endocytosis, as we identified the expression of specific ligands on exosomes that favorably interact with their parental cells and confirmed the higher lysosomal entrapment of intraspecies exosomes (intraspecies endocytic uptake). On the other hand, we found that the uptake of cross-species exosomes primarily occurred through membrane fusion, followed by direct cargo release into the cytosol (cross-species direct fusion uptake). We revealed the underlying mechanisms involved in the cellular uptake and subsequent cargo release of exosomes depending on their cell-of-origin and recipient cell types. Overall, this study envisions valuable insights into further advancements in effective drug delivery using exosomes, as well as a comprehensive understanding of cellular communication, including disease pathogenesis.

Cerebrospinal fluid synaptic biomarker changes in bipolar disorder – A longitudinal case-control study

BackgroundThis exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections. MethodsFifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14–3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes. ResultsThe synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up. LimitationIt is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect. ConclusionThis first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.

Residual stress relief strategy in thick steel weldments via local induction heat treatment: Simulation and neutron diffraction experiment

This study investigated the effect of local induction post-weld heat treatment (PWHT) on residual stress relief in thick submerged arc welded steel plates. A combination of numerical and neutron diffraction methods was used to examine the effect of various PWHT parameters, such as annealing temperature and holding time, on the relief of residual stress in welded plates with various thicknesses. A sequentially coupled thermal–mechanical finite element model was used to calculate the residual stress distribution in welded AH36 steel plates before and after PWHT. The model was validated by comparing its predictions with the experimental measurements, and the results showed good agreement. The residual stress of the thick welded plates was effectively reduced via PWHT with local induction. The primary mechanism for this stress release was identified as stress relaxation caused by creep strain. Furthermore, a process map was established considering the PWHT conditions and plate geometry. This map provides a means of determining the optimal PWHT conditions to achieve desired stress reduction levels.

Alternative Approaches for the Treatment of Chagas Disease

AbstractChagas disease (CD), or American trypanosomiasis, caused by the parasitic protozoa Trypanosoma cruzi, is a substantial global health burden. This comprehensive review explored the multifaceted landscape of CD treatment, providing a historical perspective on the development and discontinuation of benznidazole (BNZ) and nifurtimox (NF), the primary medications. Efforts towards a pediatric version of BZN in Brazil address demographic‐specific treatments, while concerns over drug resistance prompt the exploration of alternative medications like Amiodarone, Allopurinol, Posaconazole, Ravuconazole, and Fexinidazole, which were clinically tested as antichagasic drugs. In recent years, some of the synthesized derivative (1,3‐thiazoles, 4‐thiazolidinones, 2‐styrylquinolines, imidazole‐containing nitrophthalazine, and some others) were found to better activity as compared to standard drug. Traditional herbal alternatives (Resveratrol, curcumin, 1,8‐cineole, β‐pinene, and some others) rooted in traditional practices show promise, with various plant extracts exhibiting anti‐parasitic properties. The frontier of nanomedicine unfolds with studies on solid nanomedicines, PLA‐nanoparticles, ZIF‐8, BNZ carriers, and PLGA nanoparticles, showcasing improved drug delivery systems and controlled release mechanisms. The absence of a definitive vaccine accentuates ongoing research in recombinant antigens, peptide‐based vaccines, and nanoparticle formulations, with notable candidates like TcG1, TcG2, TcG4, MASPpep‐KLH, adenovirus vectors, Tc24 protein, and integrin activators. A novel strategy combining a recombinant protein vaccine with low dose BZN treatment presents promising results in a mouse model, emphasizing the urgency for further research and potential advancements in CD therapeutics.

Integrated Janus nanofibers enabled by a co-shell solvent for enhancing icariin delivery efficiency

During the past several decades, nanostructures have played their increasing influences on the developments of novel nano drug delivery systems, among which, double-chamber Janus nanostructure is a popular one. In this study, a new tri-channel spinneret was developed, in which two parallel metal capillaries were nested into another metal capillary in a core–shell manner. A tri-fluid electrospinning was conducted with a solvent mixture as the shell working fluid for ensuring the formation of an integrated Janus nanostructure. The scanning electronic microscopic results demonstrated that the resultant nanofibers had a linear morphology and two distinct compartments within them, as indicated by the image of a cross-section. Fourier Transformation Infra-Red spectra and X-Ray Diffraction patterns verified that the loaded poorly water-soluble drug, i.e. icariin, presented in the Janus medicated nanofibers in an amorphous state, which should be attributed to the favorable secondary interactions between icariin and the two soluble polymeric matrices, i.e. hydroxypropyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP). The in vitro dissolution tests revealed that icariin, when encapsulated within the Janus nanofibers, exhibited complete release within a duration of 5 min, which was over 11 times faster compared to the raw drug particles. Furthermore, the ex vivo permeation tests demonstrated that the permeation rate of icariin was 16.2 times higher than that of the drug powders. This improvement was attributed to both the rapid dissolution of the drug and the pre-release of the trans-membrane enhancer sodium lauryl sulfate from the PVP side of the nanofibers. Mechanisms for microformation, drug release, and permeation were proposed. Based on the methodologies outlined in this study, numerous novel Janus nanostructure-based nano drug delivery systems can be developed for poorly water-soluble drugs in the future.

Design of SBS molecular structure and contribution mechanism from its soft and hard segments to modify asphalt

ABSTRACT The excellent performance of SBS-modified asphalt is attributed to the release of the SBS soft segment (PB segment) and hard segment (PS segment) in the asphalt. The release mechanism of the SBS soft and hard segments was studied using MD simulation and laboratory experiments, and the optimal molecular structure of SBS for asphalt modification was determined. MD simulation results revealed that SBS with a higher PS content exhibited better compatibility with asphalt. The larger and stronger molecular aggregates of the PS segment improved the high-temperature shear resistance of the asphalt but reduced the molecular mobility of the system. Additionally, radial distribution function analysis showed varying degrees of aggregation behaviour of asphaltenes with different segment ratios of polymer modifiers. Laboratory experiments were conducted using synthetically prepared SBS modifiers with specific segment ratios, as well as PB and PS monomer modifiers. Conventional tests and rheological experiments indicated that the PB segment improved the low-temperature performance of the asphalt, while the PS segment enhanced its high-temperature performance. The experimental results of the Cole–Cole plots are consistent with the solubility parameter results. Morphological studies revealed a two-phase continuous structure formed between SBS and asphalt when the SBS segment ratio was approximately 30/70.

Superoxide anions inhibit intracellular calcium response in porcine airway smooth muscle cells.

BACKGROUND: Superoxide anions (O2-) have multiple effects on pulmonary parenchyma altering cell proliferation, cellular metabolism, and airway smooth muscle (ASM) contraction. Intracellular Ca2+ concentration ([Ca2+]i) plays a significant role in the regulation of ASM contraction, relaxation, proliferation, and gene expression. OBJECTIVE: We investigated the effects of O2- on agonist-stimulated changes in [Ca2+]i in ASM cells. DESIGN/METHODS: Fura-2 AM-loaded, freshly isolated porcine ASM (PASM) cells were used to examine [Ca2+]i release in response to acetylcholine (ACh), histamine, endothelin, caffeine, and thapsigargin in the presence or absence of extracellular calcium. RESULTS: Exposure of PASM cells to xanthine and xanthine oxidase (X+XO) resulted in a time-dependent generation of O2-, inhibited by superoxide dismutase (SOD). Pre-incubating PASM cells with X+XO for 15- or 45-min inhibited net [Ca2+]i responses to ACh, Histamine, Caffeine, and Thapsigargin compared to control cells. Pretreating PASM cells with SOD for 30 min mitigated the inhibitory effect of X+XO treatment on ACh-induced Ca2+ elevation suggesting role of O2-. X+XO treatment also inhibited caffeine-and thapsigargin-induced Ca2+ elevation suggesting effect of O2- on intracellular calcium release and reuptake mechanisms. CONCLUSIONS: Superoxide attenuates [Ca2+]i release, reuptake and may interfere with physiological functions of ASM cells.

Influence of lithium ion doping and mitoxantrone hydrochloride loading on the structure and in vitro biological properties of mesoporous bioactive glass microspheres in the treatment of multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell hematologic tumor in which bone pain is a typical symptom. The current main treatment methods not only easily cause multidrug resistance but also cause bacterial infections. Therefore, improving multidrug resistance and bacterial infection during MM therapy and repairing bone defects caused by bone pain are necessary. In this work, we propose a drug delivery platform of lithium-doped mesoporous bioactive glass microspheres (7Li-MBGs) with a mesoporous structure (2-5nm) and a high specific surface area (636 m2/g) to achieve these functions. Interestingly, lithium ions are network modifier doped into the silicon-oxygen network. This in turn affects the dissolution and release behavior of silicon ions in the MBGs network. Thus, the bioactive response as well as drug release of the MBGs were enhanced. During this process, hydroxyapatite easily forms on the surface, which has a therapeutic effect on bone defects caused by MM. The drug (mitoxantrone hydrochloride, MTO) release mechanism is diffusion-driven, suggesting that drug/platform interactions are key determinants of release kinetics and depend on the release medium environment and platform structure. In vitro antibacterial and cytotoxicity experiments proved that the synergistic effect of Li ions and the MTO improved the antibacterial ability of the MBGs (> 98%) and the ability to treat MM. Therefore, the proposed 7Li-MBGs drug delivery platform can effectively release drugs in the long-term, repair bone defects, inhibit bacterial growth and tumor cell activity, and provide new ideas for the treatment of MM.

Membrane/electrolyte interplay on ammonia motion inside a flow-cell for electrochemical nitrogen and nitrate reduction

Electrochemical ammonia production from molecular nitrogen and nitrate reduction reactions at ambient conditions has gained a lot of attention in recent years, making this topic more and more appealing. The race towards good and quick results in terms of Faradaic efficiency and productivity is not always focused on the possible source of ammonia contamination. In particular, Nafion membrane is the most commonly used in this field as cell separator, discarding the possible known disadvantages coming from ammonium ions absorption and release. The wettable microporous Celgard membrane has been proposed as a substitute for Nafion membranes, despite the separation mechanism, in this case, is only dimension-driven, so it does not assure ammonium ions retention. This paper reveals that the mechanism of ammonium ions absorption and release by Nafion 117 is strongly related to the cations present in the electrolyte and to a lesser extent by its pH value. On the other hand, Celgard membrane does not show any relevant ammonium ions absorption. Moreover, the different trend of ammonium ions motion from catholyte to anolyte solution inside a flow-cell reactor shows that none of the membranes is able to avoid ammonium ions crossover and that there is a correlation between the applied potential and the motion trend. Electrochemical nitrogen and nitrate reduction tests confirm how Nafion membrane can have a big impact on the final result of ammonium ions production, especially when dealing with low production quantities, leading to mistakes in the real quantity of ammonium ions coming from the reduction reaction.

Rapid and robust hydrogen generation from sodium borohydride in optimum mixture of methanol and ethylene glycol using phosphorus-doped chitosan polymer matrix dispersed on alumina nanoparticles

Here, the highly efficient hydrogen (H2) generation by sodium borohydride (NaBH4) in a novel synergistic mixture of methanol and ethylene glycol using phosphorus-doped chitosan polymer matrix incorporated on alumina particles was investigated. The efficiency of P-doped chitosan-alumina hybride catalyst for H2 generation from NaBH4(NaBH4-HGR) in methanol, ethylene glycol, and methanol + ethylene glycol mixture showed significant differences. In particular, there is a very effective performance for NaBH4-HGR in a methanol + ethylene glycol mixture. The HGR values by mixture of methanol, ethylene glycol and methanol/ethylene glycol were 2342, 7364 and 13548 ml min-1g−1, respectively. Moreover, the H2 generation rate (HGR) value by NaBH4 using P-doped chitosan-alumina with the combination of methanol (8 ml) + ethylene glycol (2 ml) was 25,964 ml min-1g−1. Also, activation energy (Ea) was 30.62 kJmol−1. Additionally, the mechanism of H2 release by NaBH4 solvolysis reactions in the methanol + ethylene glycol mixture using P-doped chitosan-alumina was evaluated. In the methanol + ethylene glycol mixture, both the low viscosity of methanol and the high acidity of ethylene glycol are likely to have a positive synergistic effect on H2 production at the same time. Moreover, both the positivity of the P atoms and the increased acidity of the alumina become attractive to the negatively charged ions present in the reaction medium.

Preparation and drug release performance of different gelation type polysaccharide/β-lactoglobulin fiber composite gels

Self-assembled protein fibers have attracted much attention in the fields of medicine and food because of their high aspect ratio, polymorphic structure and strong surface hydrophobicity. In this study, three different gelation types of polysaccharides/β-lactoglobulin fiber (Fblg) composite gels, including ionic alginate-Fblg gels, synergistic xanthan-Fblg gels, and double network agar-Fblg gels, were first prepared. The interactions between the polysaccharides and the Fblgs, the microstructure and mechanical properties of the composite gels were investigated using the light scattering, scanning electron microscopy, rheology and texture analysis in order to reveal their formation mechanisms. Then the loading and release properties of the water-soluble drug 5-fluorouracil (5-FU) and the hydrophobic drug curcumin (Cur) through these composite gels were further studied with release mechanisms determined by fitting different release models. It was found that the mechanical properties of the composite gels were determined by the mesh density of the three-dimensional networks formed inside the gels. The network structure and mechanical strength of the alginate-Fblg gels became weaker with the increase of Fblg content at pH 4 due to their attractive interaction which hindered the binding of Ca2+ to ALG, while the network and the strength of the alginate-Fblg gels didn't change much at pH 7 due to the repulsion between Alg and Fblg. The xanthan-Fblg gels formed lamellar structures with enhanced gel network and mechanical strength due to the hydrogen bonding and the electrostatic interaction with Fblg. The Agar-Fblg composite gel formed at 60 °C (above the gelation temperature of agar of 40 °C) had a denser double network structure and higher mechanical strength than that formed at 0 °C due to inhibition of diffusion of Ca2+ as salt bridges for Fblg. The hydrophilic drugs were loaded in the meshes of the composite gels and their release was determined by the structure of the composite gel networks, whereas the hydrophobic drugs were loaded by attaching to the Fblgs in the composite gels and their release was determined by the loading ability and strength of the gels. The study not only provided a new idea for the preparation and application of polysaccharide-protein fiber composite hydrogels, but also provided insights for improving the efficiency of drug carriers.

Role of cyclodextrin inclusion complexes assembled in the fast-dissolving structures of electrospun gelatin mats to extend the release of menthol

In this study, inclusion complexes (ICs) of menthol with various cyclodextrins (CDs) [α-CD, β-CD, γ-CD, (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), and methyl-β-cyclodextrin (M-β-CD)] were prepared first, and then the ICs with the highest encapsulation efficiency were applied in electrospun gelatin mats to extend release of menthol. Electrospinning feed solutions in terms of surface tension, zeta potential, electrical conductivity, and rheological properties were evaluated. The diameter and morphology of the pure gelatin and the CDs-loaded gelatin mats were analyzed using microscopy (FESEM and AFM), which confirms that CDs loading leads to a decrease in the diameter of the nanofibers. The longest disintegration time belonged to the gelatin mat containing the β-CD complex. Comparison of the FTIR spectrum and XRD patterns of gelatin mats containing menthol-loaded CD complexes with the pure compounds confirmed the successful encapsulation of menthol inside the cavity of the CD, and also the disappearance of the crystalline state of electrospun gelatin mats. Applying the electrospun gelatin mats as a fast-dissolving structure for the menthol-loaded inclusion complexes increased its thermal stability. In the bioadhesieve test, the lowest force required to separate the gelatin mat from the skin model was obtained in the menthol-containing β-CD gelatin mat (6.21± 1.01 g). The menthol release from the pure gelatin mats was much faster than the electrospun mats containing CDs complexes, however the menthol-loaded β-CD gelatin mat showed the slowest release into the simulated saliva. Peppas-Sahlin and Fickian diffusion (Case-I) were the best-fitted model and menthol release mechanism, respectively.

In Vitro Release from Polymeric Core/Shell Nanoparticles through the Lens of Multiscale Modeling.

The large number of studies involving nanoparticles for cancer therapy is due to their peculiar features: they protect loaded active molecules while extending circulation time and can extravasate from the blood flow to the tumor to deliver drugs directly in the target area. Mathematical modeling can provide a preliminary in silico exploration of design space to optimize an experimental activity that often relies on a trial-and-error approach. However, because of the characteristic size of these vectors (10-1000 nm), numerous phenomena of interest occur at different time and length scales, making a single modeling technique insufficient to fully characterize the system of interest. In this work we employed a multiscale modeling approach, which bridges the phenomena of interest across different scales, to study the in vitro release from polymeric core/shell nanoparticles for cancer therapy loaded with an active compound assembled as a hydrophobic ion pair. The "computational microscope" provided by molecular dynamics simulations was used to track drug molecules through the release process at an atomic scale. The outcomes suggested that the drug is mainly partitioned in the polymer and released as hydrophobic ion pair rather than a free molecule, and that the hydrophobic ion pair is preferentially partitioned in Tween 20 micelles in the release media. A model at macroscale, aimed at describing the release rate and elucidating the release mechanism, was developed according to the results from molecular simulations and validated against experimental data. The outcomes provided insights that are challenging to be obtained experimentally and which supported the development and validation of a release model at macroscale. Overall, the adopted multiscale approach corroborated the experimental findings and provided significant insights into the mechanisms of release.

Progress in extracellular vesicle homeostasis as it relates to cardiovascular diseases.

Extracellular vesicles (EVs) are involved in both physiological and pathological processes in many organ systems and are essential in mediating intercellular communication and maintaining organismal homeostasis. It is helpful to propose new strategies for disease treatment by elucidating the mechanisms of EV release and sorting. An increasing number of studies have shown that there is specific homeostasis in EVs, which is helpful for the human body to carry out physiological activities. In contrast, an EV homeostasis im-balance promotes or accelerates disease onset and development. Alternatively, regulating the quality of EVs can maintain homeostasis and even achieve the purpose of treating conditions. An analysis of the role of EV homeostasis in the onset and development of cardiovascular disease is presented in this review. This article also summarizes the methods that regulate EV homeostasis and their application in cardiovascular diseases. In particular, this study focuses on the connection between EV steady states and the cardiovascular system and the potential value of EVs in treating cardiovascular diseases.

The Effect of Self-Myofascial Release Method on the Suboccipital Muscle Group in the Treatment of Cervicogenic Headache

The primary objective of this study is to investigate the short-term and long-term effects of the Self-Myofascial Release Method (SMFR) on the suboccipital muscle group in the improvement of cervicogenic headache. Additionally, the study aims to compare the therapeutic mechanism of Self-fascial Release and acupuncture in the treatment of cervicogenic headache

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation

Fixed-dose combination (FDC) products represent a novel, safe, and cost-effective formulation. Combined use of anticoagulant and antiplatelet medications is common among comorbid cardiovascular patients. This study aimed to formulate FDC tablets for Apixaban and Clopidogrel, as prophylaxis and treatment of thrombo-embolic events. FDC tablets were developed by combining small tablets of Immediate-Release Clopidogrel 75 mg and Extend-Release Apixaban 5 mg through direct compression and wet granulation. Particularly, Apixaban tablets were developed using design expert software, and various types and concentrations of polymers were entered. For Clopidogrel tablets, various diluents were used to develop the formulation. Then, the dissolution profile for each formula was studied. Finally, the optimized formulations were encapsulated within hard gelatin capsules. Apixaban formulation followed zero-order with super case Ⅱ transport mechanism as the dominant mechanism of drug release. The Apixaban drug release rate was affected by the type and concentration of the polymers in the formulation (P < 0.05). As the HPMC concentration was increased, Apixaban release was retarded. For, Clopidogrel, the formulated tablets with spray-dried lactose filler and sodium stearyl fumarate lubricant were found to be stable with good properties. In conclusion, the optimum formulation yielded Clopidogrel and extended-release Apixaban for 24 h with the desired in vitro drug dissolution.