Soluble Polymer Microneedles Loaded with Interferon Alpha 1b for Treatment of Hyperplastic Scar.

To achieve the painless administration of interferon alpha 1b (rhIFNα-1b), a double-layered soluble polymer microneedle (MN) patch loaded with rhIFNα-1b was used to deliver rhIFNα-1b transdermally. The solution containing rhIFNα-1b was concentrated in the MN tips under negative pressure. The MNs punctured the skin and delivered rhIFNα-1b to the epidermis and dermis. The MN tips implanted in the skin dissolved within 30 min and gradually released rhIFNα-1b. The rhIFNα-1b had a significant inhibitory effect on the abnormal proliferation of fibroblasts and excessive deposition of collagen fibers in the scar tissue. The color and thickness of the scar tissue treated using the MN patches loaded with rhIFNα-1b were effectively reduced. The relative expressions of type I collagen (Collagen I), type III collagen (Collagen III), transforming growth factor beta 1 (TGF-ß1), and α-smooth muscle actin (α-SMA) were significantly downregulated in scar tissues. In summary, the MN patch loaded with rhIFNα-1b provided an effective method for the transdermal delivery of rhIFNα-1b.

Aspirin microcrystals deposited on high-density microneedle tips for the preparation of soluble polymer microneedles.

To reduce mucosal damage in the gastrointestinal tract caused by aspirin, aspirin microcrystals were loaded in soluble polymeric microneedle (MN) tips. Aspirin was prepared into aspirin microcrystals by jet milling. Aspirin microcrystals with particle sizes of 0.5-5 µm were loaded on MN tips with a height of 250 µm or 300 µm. The aspirin microcrystals suspended in a polymer solution were concentrated in the MN tips under negative pressure. The aspirin microcrystals had high stability in the MNs since they were not dissolved in solution during the fabrication process. The MN patch packaged in an aluminum-plastic bag containing silica gel desiccant can be stored at 4 °C. The MN tips implanted in the skin of Institute of Cancer Research (ICR) mice dissolved within 30 min. Isolated porcine ear skin was punctured by MNs with heights of 300 µm and 250 µm to depths of 130 µm and 90 µm, respectively. The fluorescent red (FR) release from MNs reached 98.59% within 24 h. The MNs delivered aspirin microcrystals to the epidermis and dermis, providing a smooth plasma concentration in rats. The MNs loaded with aspirin microcrystals did not evoke primary irritation on the dorsal skin of Japanese white rabbits. In summary, MNs loaded with aspirin microcrystals provide a new approach to improve the stability of aspirin in MN patches.

Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein.

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.

Thermal stability of exenatide encapsulated in stratified dissolving microneedles during storage.

As low-temperature storage and transportation of peptides require high costs, improving the dosage form of peptides can reduce costs. We developed a thermostable and fast-releasing stratified dissolving microneedle (SDMN) system for delivering exenatide (EXT) to patients with type 2 diabetes. Among the tested polymers, dextran and polyvinyl alcohol (PVA) were the best at stabilizing EXT under high-temperature storage for 9 weeks. The two polymers possess a relatively high glass transition temperature (Tg) and weak hydrogen bonding between PVA and EXT. Additionally, zinc sulfate (ZnSO4) had a stabilizing effect on EXT among the selected stabilizers, suggesting that EXT formed a dimer after coordination with zinc ions (Zn2+). In addition, the denaturation temperature (Tm) of EXT was increased by adding ZnSO4, thus stabilizing EXT. Accordingly, SDMNs consisting of a tip layer (dextran encapsulating the Zn2+-EXT complex) and a base layer (PVA) were fabricated. Within 2 min of implantation, the EXT loaded on the patch was quickly released into the skin. Transdermal pharmacokinetics studies showed that manufactured SDMNs generated comparable efficacy to subcutaneous injection. Significantly, the remaining EXT amount was not significantly different under storage at 40 °C and -20 °C for 3 months, supporting that the SDMN system had excellent delivery efficiency and stability, thus reducing the dependence on the cold chain.

Th2/Th1 cytokine imbalance is associated with higher recurrent intussusception incidence in children: A 10-year retrospective study of 1657 patients.

Recurrent intussusception is one of the common acute abdominal diseases in infants, which seriously affects the physical and mental health of infants, but its risk factors have not been fully clarified. The objective of this study was to evaluate the relationship between Th2/Th1 cytokine imbalance and recurrent intussusception, so as to provide a theoretical basis for making a more comprehensive treatment strategy for patients with recurrent intussusception. A retrospective study was conducted between July 2012 and September 2022, enrolling patients with intussusception in Children's Hospital of Hebei Province. The patients were divided into recurrent group and non-recurrent group according to whether they suffered from recurrent intussusception. We summarized the clinical characteristics of recurrent intussusception and explored the role of T helper 2 (Th2)/T helper 1 (Th1) cytokine imbalance in it. A total of 2008 patients were initially enrolled and finally 1657 patients qualified for the study. The results showed that the incidence of recurrent intussusception was 18.41% and the Th2/Th1 cytokine imbalance was closely related to the incidence of recurrent intussusception. Th2/Th1 cytokine imbalance is a potential risk factor of recurrent intussusception and more likely to occur in children between the ages of 2 and 3. Future studies are needed to preemptively target the Th2/Th1 cytokine imbalance to formulate a reasonable treatment plan for children with intussusception to avoid recurrence.

Dissolvable polymeric microneedles loaded with aspirin for antiplatelet aggregation.

To reduce mucosal damage in the gastrointestinal tract caused by aspirin, we developed a dissolvable polymeric microneedle (MN) patch loaded with aspirin. Biodegradable polymers provide mechanical strength to the MNs. The MN tips punctured the cuticle of the skin and dissolved when in contact with the subcutaneous tissue. The aspirin in the MN patch is delivered continuously through an array of micropores created by the punctures, providing a stable plasma concentration of aspirin. The factors affecting the stability of aspirin during MNs fabrication were comprehensively analyzed, and the hydrolysis rate of aspirin in the MNs was less than 2%. Compared to oral administration, MN administration not only had a smoother plasma concentration curve but also resulted in a lower effective dose of antiplatelet aggregation. Aspirin-loaded MNs were mildly irritating to the skin, causing only slight erythema on the skin and recovery within 24 h. In summary, aspirin-loaded MNs provide a new method to reduce gastrointestinal adverse effects in patients requiring aspirin regularly.

Prediction model of combustion characteristics of methane-air using hyperspectral imaging.

Hyperspectral imaging can obtain considerable flame information, which can improve the prediction accuracy of combustion characteristics. This paper studies the hyperspectral characteristics of methane flames and proposes several prediction models. The experimental results show that the radiation intensity and radiation types of free radicals are related to the equivalent ratio, and the radiation region of free radicals becomes larger with the increase of the Reynolds number. The polynomial regression prediction models include the linear model and quadratic model. It takes C2∗/CH∗ as input parameters, and results can be available immediately. The three-dimensional convolutional neural network (3D-CNN) prediction model takes all spectral and spatial information in the flame hyperspectral image as input parameters. By improving the structural parameters of the convolution network, the final prediction errors of the equivalent ratio and Reynolds number are 2.84% and 3.11%, respectively. The method of combining the 3D-CNN model with hyperspectral imaging significantly improves the prediction accuracy, and it can be used to predict other combustion characteristics such as pollutant emissions and combustion efficiency.

Preparation, characterization, and in vivo evaluation of levonorgestrel-loaded thermostable microneedles.

To facilitate the storage and use of poly (lactic-co-glycolic acid) (PLGA)-based microneedles (MNs) in hot seasons and regions, thermally stable MNs loaded with levonorgestrel (LNG) were developed. Due to its good biocompatibility and high glass transition temperature (Tg), Hydroxypropyl methylcellulose (HPMC) was added to the PLGA-based MNs to increase thermal stability. MNs with HPMC exhibited excellent thermal stability at high temperatures. After the MNs has been applied to the skin for 10 min, the backing layer of the MNs was dissolved by contact with the interstitial fluid of skin, which resulted in the separation of the MN tips from the backing layer. The MN tips were implanted intradermally and sustained-release LNG. Biodegradable polymers were used to encapsulate the LNG, providing long-acting contraception. The in vitro release rate of LNG from the MNs reached 72.78%-83.76% within 21 days. In rats, the MNs maintained plasma concentrations of LNG above the human contraceptive level for 8-12 days. In mice, the time required for complete degradation of the MN tips was 12-16 days. MNs have excellent medication adherence due to the advantages of painlessness, minimally invasive, and self-administered. MNs can make long-acting contraceptives more readily available to humans.

The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8.

Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.

Novel dissolving microneedles preparation for synergistic melasma therapy: Combined effects of tranexamic acid and licorice extract.

The aim of this study was to prepare dissolving microneedles (DMNs) patches containing tranexamic acid (TA) for the treatment of melasma. Polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) were preferred as matrix materials through the compatibility experiment. In the in vitro permeation study, the transdermal amount of TA was significantly promoted through dissolving microneedles with the cumulative release was 44.43 ± 6.55%. By comparison, the release of TA solution assisted with solid microneedles (SMNs) was merely 11.31 ± 2.30% (p < 0.05). Pharmacokinetics study indicated the bioavailability of dissolving microneedles was more than 1.3 times compared with oral administration. In pharmacodynamics investigation, TA dissolving microneedles obviously reduced melanin deposition in the skin of melasma guinea pigs after 8 consecutive administrations. In particular, the combination of tranexamic acid and licorice extract (LIC) dissolving microneedles worked better than tranexamic acid alone. Accelerated stress conditions including high temperature, high humidity, as well as photostability were designed to prove that TA microneedles maintained good pharmaceutical stability. In conclusion, tranexamic acid dissolving microneedles showed reliable quality and remarkable effect. Moreover, the combination of tranexamic acid and licorice extract had a synergistic therapy in melasma.

The deposition of VWOx on the CuCeOy microflower for the selective catalytic reduction of NOx with NH3 at low temperatures.

NOx emissions are a major environmental problem, and the selective catalytic reduction (SCR) is the most effective method to convert NOx in flue gas into harmless N2 and H2O. In this work, a new carrier, CuCeOy microflower assembled from a large number of copper-cerium mixed oxide nanosheets, is firstly developed to load vanadium-tungsten mixed oxides (VWOx) for the SCR of NOx with NH3. The resultant optimal VWOx/CuCeOy catalyst exhibits significantly enhanced low-temperature de-NOx performance with the NOx conversion of 60% at 180 °C, over 90% from 240 °C to 390 °C under the gas hourly space velocity (GHSV) of 36,000 h-1. The reason can be mainly attributed the fact that the transfer of electrons among Ce, Cu and V ions is very easy to occur via the following equations Ce3++Cu2+ â†” Ce4++Cu+, V5+ + Cu+ â†” V4+ + Cu2+, V4+ + Ce4+ â†” V5+ + Ce3+, which effectively decreases the apparent activation energy (Ea = 16.59 kJ/mol) of NH3-SCR de-NOx reaction. In addition, the enhanced reducibility and a large number of Brønsted acid sites also contribute the low-temperature de-NOx performance. Both Eley-Rideal and Langmuir-Hinshelwood mechanisms are included in the NH3-SCR de-NOx reaction over the VWOx/CuCeOy catalyst.

Synthesis and structure-activity relationship of N-(piperidin-4-yl)benzamide derivatives as activators of hypoxia-inducible factor 1 pathways.

Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13 µM, respectively). Compounds 10b and 10j induced the expression of HIF-1α protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis.

KDP Aqueous Solution-in-Oil Microemulsion for Ultra-Precision Chemical-Mechanical Polishing of KDP Crystal.

A novel functional KH2PO4 (KDP) aqueous solution-in-oil (KDP aq/O) microemulsion system for KDP crystal ultra-precision chemical-mechanical polishing (CMP) was prepared. The system, which consisted of decanol, Triton X-100, and KH2PO4 aqueous solution, was available at room temperature. The functional KDP aq/O microemulsion system was systematically studied and applied as polishing solution to KDP CMP technology. In this study, a controlled deliquescent mechanism was proposed for KDP polishing with the KDP aq/O microemulsion. KDP aqueous solution, the chemical etchant in the polishing process, was caged into the micelles in the microemulsion, leading to a limitation of the reaction between the KDP crystal and KDP aqueous solution only if the microemulsion was deformed under the effect of the external force. Based on the interface reaction dynamics, KDP aqueous solutions with different concentrations (cKDP) were applied to replace water in the traditional water-in-oil (W/O) microemulsion. The practicability of the controlled deliquescent mechanism was proved by the decreasing material removal rate (MRR) with the increasing of the cKDP. As a result, the corrosion pits on the KDP surface were avoided to some degree. Moreover, the roughnesses of KDP with KDP aq/O microemulsion (cKDP was changed from 10 mM to 100 mM) as polishing solutions were smaller than that with the W/O microemulsion. The smallest surface root-mean-square roughness of 1.5 nm was obtained at a 30 mmol/L KDP aq solution, because of the most appropriate deliquescent rate and MRR.

Rationally Designed Porous MnOx-FeOx Nanoneedles for Low-Temperature Selective Catalytic Reduction of NOx by NH3.

In this work, a novel porous nanoneedlelike MnOx-FeOx catalyst (MnOx-FeOx nanoneedles) was developed for the first time by rationally heat-treating metal-organic frameworks including MnFe precursor synthesized by hydrothermal method. A counterpart catalyst (MnOx-FeOx nanoparticles) without porous nanoneedle structure was also prepared by a similar procedure for comparison. The two catalysts were systematically characterized by scanning and transmission electron microscopy, X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, hydrogen temperature-programmed reduction, ammonia temperature-programmed desorption, and in situ diffuse reflectance infrared Fourier transform spectroscopy (in situ DRIFT), and their catalytic activities were evaluated by selective catalytic reduction (SCR) of NOx by NH3. The results showed that the rationally designed MnOx-FeOx nanoneedles presented outstanding low-temperature NH3-SCR activity (100% NOx conversion in a wide temperature window from 120 to 240 °C), high selectivity for N2 (nearly 100% N2 selectivity from 60 to 240 °C), and excellent water resistance and stability in comparison with the counterpart MnOx-FeOx nanoparticles. The reasons can be attributed not only to the unique porous nanoneedle structure but also to the uniform distribution of MnOx and FeOx. More importantly, the desired Mn4+/Mnn+ and Oα/(Oα + Oß) ratios, as well as rich redox sites and abundant strong acid sites on the surface of the porous MnOx-FeOx nanoneedles, also contribute to these excellent performances. In situ DRIFT suggested that the NH3-SCR of NO over MnOx-FeOx nanoneedles follows both Eley-Rideal and Langmuir-Hinshelwood mechanisms.

The Magnetorheological Finishing (MRF) of Potassium Dihydrogen Phosphate (KDP) Crystal with Fe3O4 Nanoparticles.

The cubic Fe3O4 nanoparticles with sharp horns that display the size distribution between 100 and 200 nm are utilized to substitute the magnetic sensitive medium (carbonyl iron powders, CIPs) and abrasives (CeO2/diamond) simultaneously which are widely employed in conventional magnetorheological finishing fluid. The removal rate of this novel fluid is extremely low compared with the value of conventional one even though the spot of the former is much bigger. This surprising phenomenon is generated due to the small size and low saturation magnetization (M s) of Fe3O4 and corresponding weak shear stress under external magnetic field according to material removal rate model of magnetorheological finishing (MRF). Different from conventional D-shaped finishing spot, the low M s also results in a shuttle-like spot because the magnetic controllability is weak and particles in the fringe of spot are loose. The surface texture as well as figure accuracy and PSD1 (power spectrum density) of potassium dihydrogen phosphate (KDP) is greatly improved after MRF, which clearly prove the feasibility of substituting CIP and abrasive with Fe3O4 in our novel MRF design.