Cancer Cell Membrane-Biomimetic Nanoparticles Based on Gelatin and Mitoxantrone for Synergetic Chemo-Photothermal Therapy of Metastatic Breast Cancer.

The purpose of this paper is to develop a cancer cell membrane biomimetic nanodrug delivery system (NDDS) to achieve an enhanced chemo-photothermal synergistic antitumor effect. The biomimetic NDDSs are composed of mitoxantrone (MIT)-loaded gelatin nanoparticles and IR820-encapsulated 4T1 cancer cell membrane-derived vesicles. The biomimetic NDDS displayed excellent stability and photothermal conversion efficiency. Compared to naked nanoparticles, the cell membrane-coated nanoparticles improved 4T1 cell uptake through homologous targeting and effectively reduced internalization of macrophages. In vivo photothermal imaging results further showed that the NDDS could be enriched at the tumor site for 48 h and could raise the temperature of the tumor area to 60 °C within 5 min under 808 nm laser irradiation. Finally, NDDS successfully inhibited primary tumor growth (over 89% inhibition) and significantly inhibited lung metastasis. This study may provide a new strategy for personalized chemotherapy-photothermal combination therapy of metastatic breast cancer using tumor cell membranes from cancer patients as drug carriers.

Dynamic carboxymethyl chitosan prodrug hydrogel precisely mediates robust therapy on wound infection.

Dynamic antibacterial polysaccharide prodrug hydrogels are in great demand for treatment of wound infection owing to their unique advantages such as excellent biocompatibility, superior antimicrobial property as well as favorable wound healing capacity. Herein, this work highlights the successful development of a dynamic carboxymethyl chitosan (CMC) prodrug hydrogel, which is facilely constructed through Schiffer base reaction between antibacterial components (amikacin and CMC) and crosslinker (dialdehyde PEG). Moderate dynamic imine linkages endow the hydrogel with excellent injectable and self-healing capability as well as targeted on-demand drug release in slightly alkaline condition at infected wound. All ingredients and their strong intermolecular interactions endow the hydrogel with favorable swelling and moisture retention capability. Moreover, the covalent and non-covalent interactions also endow the hydrogel with superior adhesion and mechanical property. These attractive characteristics enable hydrogel to effectively kill pathogens, promote wound healing and reduce side effects of amikacin. Thereby, such a dynamic CMC prodrug hydrogel may open a new avenue for a robust therapy on wound infection, greatly advancing their use in clinics.

Bioinformatics analyses of gene expression profile to identify pathogenic mechanisms for COVID-19 infection and cutaneous lupus erythematosus.

Objective: The global mortality rates have surged due to the ongoing coronavirus disease 2019 (COVID-19), leading to a worldwide catastrophe. Increasing incidents of patients suffering from cutaneous lupus erythematosus (CLE) exacerbations after either contracting COVID-19 or getting immunized against it, have been observed in recent research. However, the precise intricacies that prompt this unexpected complication are yet to be fully elucidated. This investigation seeks to probe into the molecular events inciting this adverse outcome. Method: Gene expression patterns from the Gene Expression Omnibus (GEO) database, specifically GSE171110 and GSE109248, were extracted. We then discovered common differentially expressed genes (DEGs) in both COVID-19 and CLE. This led to the creation of functional annotations, formation of a protein-protein interaction (PPI) network, and identification of key genes. Furthermore, regulatory networks relating to these shared DEGs and significant genes were constructed. Result: We identified 214 overlapping DEGs in both COVID-19 and CLE datasets. The following functional enrichment analysis of these DEGs highlighted a significant enrichment in pathways related to virus response and infectious disease in both conditions. Next, a PPI network was constructed using bioinformatics tools, resulting in the identification of 5 hub genes. Finally, essential regulatory networks including transcription factor-gene and miRNA-gene interactions were determined. Conclusion: Our findings demonstrate shared pathogenesis between COVID-19 and CLE, offering potential insights for future mechanistic investigations. And the identification of common pathways and key genes in these conditions may provide novel avenues for research.

Characterization of endoplasmic reticulum stress unveils ZNF703 as a promising target for colorectal cancer immunotherapy.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors globally, with high morbidity and mortality. Endoplasmic reticulum is a major organelle responsible for protein synthesis, processing, and transport. Endoplasmic reticulum stress (ERS) refers to the abnormal accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, which are involved in tumorigenesis and cancer immunity. Nevertheless, the clinical significance of ERS remains largely unexplored in CRC. METHODS: In present study, we performed an unsupervised clustering to identify two types of ERS-related subtypes [ERS clusters, and ERS-related genes (ERSGs) clusters] in multiple large-scale CRC cohorts. Through the utilization of machine learning techniques, we have successfully developed an uncomplicated yet robust gene scoring system (ERSGs signature). Furthermore, a series of analyses, including GO, KEGG, Tumor Immune Dysfunction and Exclusion (TIDE), the Consensus Molecular Subtypes (CMS), were used to explore the underlying biological differences and clinical significance between these groups. And immunohistochemical and bioinformatics analyses were performed to explore ZNF703, a gene of ERSGs scoring system. RESULTS: We observed significant differences in prognosis and tumor immune status between the ERS clusters as well as ERSGs clusters. And the ERSGs scoring system was an independent risk factor for overall survival; and exhibited distinct tumor immune status in multicenter CRC cohorts. Besides, analyses of TNM stages, CMS groups demonstrated that patients in advanced stage and CMS4 had higher ERSGs scores. In addition, the ERSGs scores inversely correlated with positive ICB response predictors (such as, CD8A, CD274 (PD-L1), and TIS), and directly correlated with negative ICB response predictors (such as, TIDE, T cell Exclusion, COX-IS). Notably, immunohistochemical staining and bioinformatics analyses revealed that ZNF70 correlated with CD3 + and CD8 + T cells infiltration. CONCLUSION: Based on large-scale and multicenter transcriptomic data, our study comprehensively revealed the essential role of ERS in CRC; and constructed a novel ERSGs scoring system to predict the prognosis of patients and the efficacy of ICB treatment. Furthermore, we identified ZNF703 as a potentially promising target for ICB therapy in CRC.

Development of an amoxicillin-radix scutellaria extract formulation and evaluation of its pharmacokinetics in pigs.

BACKGROUND: A new antibacterial compound powder of amoxicillin (AMO)/Radix Scutellaria extract (RSE) was developed, and its pharmacokinetics were determined in pigs following oral administration. RESULTS: The MIC ranges of AMO against Escherichia coli, Staphylococcus aureus and Streptococcus were 1-8 µg/mL, 0.5-4 µg/mL and 0.5-64 µg/mL, respectively. The MIC ranges of RSE against E. coli, S. aureus, and Streptococcus were greater than 2.5 mg/mL, 0.156-2.5 mg/mL, and greater than 2.5 mg/mL, respectively. For S. aureus, the combined drug susceptibility test showed that AMO and RSE had an additive or synergistic effect. The results of compatibility test, the excipient screening test and the drug quality control test showed that the formulation had stable quality and uniform properties under the test conditions. Two studies were conducted to investigate the pharmacokinetics of the compound product in pigs. First, the pharmacokinetics of the AMO-RSE powder were compared with those of their respective single products. The results showed no significant change in the main pharmacokinetic parameters when either component was removed from the compound formulation; thus, AMO and RSE have no pharmacokinetic interaction in pigs. Second, pigs were orally administered three different doses of AMO-RSE powder. The Cmax and AUC increased proportionally with increasing p.o. dose; thus, the λz, t1/2λ, MRT, and Tmax were unchanged for the doses of 10, 20, and 30 mg/kg AMO and the doses of 5, 10, and 15 mg/kg BCL, showing that AMO/baicalin in AMO-RSE powder showed linear pharmacokinetic characteristics in pigs. CONCLUSIONS: The combined drug sensitivity test of AMO and RSE against S. aureus showed that the combination was additive or synergistic. Pharmacokinetic studies indicated that AMO and BCL do not interfere with each other in pigs when used in a compound formulation. The pharmacokinetic parameters remained unchanged regardless of the dose for p.o. administration, indicating linear pharmacokinetic properties over the tested dose range. The quality of the AMO-RSE powder was good and stable, providing a foundation for its clinical application in veterinary medicine. Further bioavailability, PK/PD and clinical trials are still needed to determine the final dosage regimen.

pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy.

Currently, the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy, owing to its precise structure, high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract, blood circulation and tumor tissues compared to other oral nanomedicines. Herein, this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes, which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters. The precise nano-prodrugs exhibit extraordinarily high drug loading (68.16%), electric neutrality, strong hydrophobicity, and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH. These favorable physicochemical properties can effectively facilitate gastrointestinal absorption, blood circulation stability, tumor accumulation, cellular uptake, and cytotoxicity, therefore achieving high oral relative bioavailability (358.72%) and significant tumor growth inhibition while decreasing side effects. Thus, this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

Preparation and Application of a NaCl-KCl-CsCl-Cs2ZrCl6 Composite Electrolyte.

Using ternary molten salt with a molar ratio of NaCl:KCl:CsCl = 30:24.5:45.5 and ZrCl4 as raw materials to prepare a NaCl-KCl-CsCl-Cs2ZrCl6 composite electrolyte. Characterizing by XRD, ICP-AES, optical microscopy and SEM-EDS, the results showed that when the molar ratio of CsCl:ZrCl4 ≥ 2:1, Cs2ZrCl6 was generated according to the stoichiometric reaction; when the molar ratio of CsCl:ZrCl4 < 2:1, CsCl in molten salt was almost completely converted to Cs2ZrCl6, and there was a ZrCl4 phase. When the molar ratio of CsCl:ZrCl4 = 2:1, with the increase of the reaction temperature and reaction time, the concentration of zirconium ions first increased and then decreased. The optimized preparation process conditions are: the 2:1 molar ratio of CsCl to ZrCl4 in NaCl-KCl-CsCl, 500 °C of reaction temperature of and 3 h of reaction time. Under this condition, 99.68% conversion rate from ZrCl4 to Cs2ZrCl6 was obtained. Taking the prepared NaCl-KCl-CsCl-Cs2ZrCl6 composite electrolyte as a raw material, a preliminary study of molten salt electrolytic refining zirconium was carried out, and a refined zirconium product with a dendrite of 10.61 mm was obtained under the conditions of a zirconium ions concentration of 5%, an electrolysis temperature of 750 °C, a current density of 0.1 A/cm2, and an electrolysis time of 9 h, indicating that the composite electrolyte can be used for the electrolytic refining of zirconium.

Study on the mechanism of Wumei San in treating piglet diarrhea using network pharmacology and molecular docking.

Wumei San (WMS) is a traditional Chinese medicine that has been widely applied in the treatment of piglet diarrhea (PD). However, the mechanism of WMS in PD has not been investigated. In this study, the main active compounds of WMS and the target proteins were obtained from the Traditional Chinese Medicine Systematic Pharmacology, PubChem, and SwissTargetPrediction databases. The molecular targets of PD were identified using GeneCards, OMIM, and NCBI databases. The common targets of WMS and PD were screened out and converted into UniProt gene symbols. PD-related target genes were constructed into a protein-protein interaction network, which was further analyzed by the STRING online database. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to construct the component-target gene-disease network. Molecular docking was then used to examine the relationship between the core compounds and proteins. As a result, a total of 32 active compounds and 638 target genes of WMS were identified, and a WMS-compound-target network was successfully constructed. Through network pharmacology analysis, 14 core compounds in WMS that showed an effect on PD were identified. The targets revealed by GO and KEGG enrichment analysis were associated with the AGE-RAGE signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, IL-17 signaling pathway, and other pathways and physiological processes. Molecular docking analysis revealed that the active compounds in WMS spontaneously bind to their targets. The results indicated that WMS may regulate the local immune response and inflammatory factors mainly through the TNF signaling pathway, IL-17 signaling pathway, and other pathways. WMS is a promising treatment strategy for PD. This study provides new insights into the potential mechanism of WMS in PD.

Coacervation-Mediated Cytocompatible Formation of Supramolecular Hydrogels with Self-Evolving Macropores for 3D Multicellular Spheroid Culture.

Coacervation driven liquid-liquid phase separation of biopolymers has aroused considerable attention for diverse applications, especially for the construction of microstructured polymeric materials. Herein, a coacervate-to-hydrogel transition strategy is developed to create macroporous hydrogels (MPH), which are formed via the coacervation process of supramolecular assemblies (SA) built by the host-guest complexation between γ-cyclodextrin and anthracene dimer. The weak and reversible supramolecular crosslinks endow the SA with liquid-like rheological properties, which facilitate the formation of SA-derived macroporous coacervates and the subsequent transition to MPH (pore size ≈ 100 µm). The excellent structural dynamics (derived from SA) and the cytocompatible void-forming process of MPH can better accommodate the dramatic volumetric expansion associated with colony growth of encapsulated multicellular spheroids compared with the non-porous static hydrogel with similar initial mechanical properties. The findings of this work not only provide valuable guidance to the design of biomaterials with self-evolving structures but also present a promising strategy for 3D multicellular spheroid culture and other diverse biomedical applications.

Microstructure and Mechanical Properties of Ni-20Cr-Eu2O3 Composites Prepared by Vacuum Hot Pressing.

Ni-20Cr-Eu2O3 composites were designed as new control rod materials and were synthesized from Ni, Cr, and Eu2O3 mixture powders via ball milling and vacuum hot pressing. During ball milling, Eu2O3 was fined, nano-crystallized, amorphized, and then dissolved into matrix. The effect of Eu2O3 content on the microstructure and mechanics was researched, and the corresponding mechanism was discussed. The relative densities, grain sizes, and microhardness increased when Eu2O3 content increased. According to the TEM observations, Eu2O3 particles showed a semi-coherent relationship with the matrix. The results of mechanical property testing showed that the ultimate tensile strength, yield strength, and elongation decreased with the Eu2O3 content increased. The maximum ultimate tensile strength, yield strength, and elongation were 741 MPa, 662 MPa, and 4%, respectively, with a 5 wt.% Eu2O3 addition. The experimental strengths were well matched with the theoretical values calculated by the strengthening mechanisms indicating that this method was highly effective for predicting the mechanical properties of Ni-20Cr-Eu2O3 composites.

Fluorinated carboxymethyl chitosan-based nano-prodrugs for precisely synergistic chemotherapy.

The clinical transformation of polysaccharide-based nano-prodrugs remains a long way off, due to the shackles on easy metabolic clearance, dilemma of dose-dependent toxicity and immunogenicity, and poor tumor selectivity. To address these challenges, the fluorinated dual-crosslinked carboxymethyl chitosan (CMCS)-based nano-prodrugs with precise structure were facilely developed through the reaction of CMCS with water-soluble stimuli-responsive synergistic small molecule prodrug (Pt(IV)-1), glutaraldehyde and heptafluorobutyric anhydride successively. The fluorination enabled the nano-prodrugs to display metabolic stability and improve tumoral cellular uptake. The pH/glutathione (GSH)-sensitive dual-crosslinked structure enabled the nano-prodrugs to show physicochemical stability at physiological pH, selective drug release and synergistic cytotoxicity at tumoral intracellular pH/GSH, and circumventing the dilemma of dose-dependent toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. These superior performances promoted stability in long-term storage and circulation, normal blood routine and aminotransferase, fantastic hemocompatibility, selective tumor accumulation and precisely synergistic chemotherapy, therefore achieving significant tumor growth inhibition while minimizing side effects. Thus, the precise fluorinated dual-crosslinked CMCS-based nano-prodrugs have great potential for selective clinical cancer treatment.

Associations of intermuscular adipose tissue and total muscle wasting score in PG-SGA with low muscle radiodensity and mass in nonmetastatic colorectal cancer: A two-center cohort study.

Backgrounds: The patient-generated subjective global assessment (PG-SGA) is one of the screening criteria for malnutrition, the skeletal muscle radiodensity (SMD) and skeletal muscle mass index (SMI) are associated with survival in colorectal cancer patients. Body composition parameters can be easily assessed; however, few studies have examined the association between total muscle wasting scores in PG-SGA and body composition parameters and two muscle abnormalities. Methods: This cohort study included 1,637 stage I-III CRC patients from 2 clinical centers in China, who were enrolled in the training cohort (n = 1,005) and validation cohort (n = 632). Baseline data were collected prospectively from patients including age, BMI, staging, gait speed, hand grip strength (HGS), peak expiratory flow (PEF), neutrophil-lymphocyte ratio (NLR), intermuscular adipose tissue (IMAT), visceral fat area (VFA) and total muscle wasting score in PG-SGA. Relevant risk factors were subjected to logistic regression analysis and Cox regression analysis to identify characteristics associated with muscle abnormalities and survival. Based on the logistic model results, normograms were established to predict muscle abnormalities, and its discrimination and calibration were assessed using the receiver operating characteristic (ROC) curve and calibration curve. The Kaplan-Meier curves were used to assess the survival of colorectal cancer patients with malnutrition or sarcopenia in an inflammatory state (assessed by NLR). Results: The mean age of all participants was 57.7 ± 10.6 years (56.9% males) and the prevalence of low SMD and low SMI was 32.2 and 39.5%, respectively. Low SMD rate was significantly associated with age, TNM stage, BMI, IMAT, walking speed, total muscle wasting score and NRS2002 score by logistic regression analysis (p < 0.05). Low SMI rate was significantly correlated with age, NLR, BMI, PEF, handgrip strength, calf circumference, walking speed, total muscle wasting score and NRS2002 score (p < 0.05). The AUCs of the diagnostic nomograms were 0.859 (95% CI, 0.831-0.886) for low SMD and 0.843 (95% CI, 0.813-0.871) for low SMI in the validation cohort. We also found that patients with colorectal cancer with malnutrition or sarcopenia had a worse prognosis when NLR ≥3.5. Conclusion: Muscle abnormalities and malnutrition are strongly associated with mortality in patients with non-metastatic colorectal cancer. Early identification and intervention of the associated risk factors may offer new ways to improve patient prognosis.

Dynamic carboxymethyl chitosan-based nano-prodrugs precisely mediate robust synergistic chemotherapy.

Currently, the polysaccharide-based nano-prodrug crosslinked by stimuli-responsive synergetic prodrug is of great demand, owing to its excellent stability, synergetic effect and tumor selectivity, and circumventing the dilemma of dose-limiting toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. Herein, the dynamic carboxymethyl chitosan (CMCS)-based nano-prodrugs with precise structure were facilely fabricated, via crosslinking reaction between CMCS and water-soluble synergistic small molecule prodrug (cisplatin-demethylcantharidin conjugate) and further stabilization by glutaraldehyde. The pH/glutathione (GSH)-responsive double-crosslinked structure endowed the nano-prodrugs with long-term storge and circulation stability at physiological pH, and dynamic transitions at tumor sites including extracellular surface amino protonation and intracellular efficient drug release, which promoted selective tumor accumulation and synergistic cytotoxicity, therefore achieving robust tumor suppression while decreasing side effects. Thus, the dynamic precise CMCS-based nano-prodrugs crosslinked by water-soluble synergistic prodrug have great potential for highly selective robust chemotherapy attractive for clinical translation.

Linear Skeletal Muscle Index and Muscle Attenuation May Be New Prognostic Factors in Colorectal Carcinoma Treated by Radical Resection.

Objective: This study evaluated the association between body composition and clinical parameters and prognosis in patients with colorectal cancer (CRC) treated by radical resection. Methods: Baseline data on patient age, body mass index (BMI), bowel obstruction and tumor-related factors were collected retrospectively. Body composition parameters such as visceral fat area (VFA), total abdominal muscle area (TAMA), muscle attenuation (MA), posterior renal fat thickness (PPNF) and intermuscular fat area (IMF) are measured using Computed tomography (CT) scans. We also propose a new predictor of linear skeletal muscle index (LSMI) that can be easily measured clinically at CT. Follow-up endpoints were disease-free survival and all-cause death. We follow up with patients in hospital or by telephone. Univariate and multifactorial Cox proportional hazards analyses were performed to identify risk factors associated with prognosis. Survival analysis was performed using the Kaplan-Meier method and a nomogram was established to predict survival. Results: A total of 1761 patients (median age 62 years) with CRC were enrolled in our study, of whom 201 had intestinal obstruction and 673 had a BMI > 24.0. Among all patients, the 3- and 5-year disease-free survival rates were 84.55% and 68.60% respectively, and the overall survival rates were 88.87% and 76.38%. Overall survival was significantly correlated with MA, LSMI, SMI, Tumor size, N stage, metastasis and adjuvant therapy by Cox regression analysis (p < 0.05). The risk of tumor progression was significantly associated with MA, VFA, LSMI, SMI, Male, N stage, metastasis and adjuvant therapy (p < 0.05). In addition, based on the Chinese population, we found that female patients with MA < 30.0 HU, LSMI < 18.2, and SMI < 38.0 had a worse prognosis, male patients with MA < 37.6 HU, LSMI < 21.9, and SMI < 40.3 had a poorer prognosis. Conclusion: Our findings suggest that linear skeletal muscle index and MA can be used as new independent predictors for colorectal cancer patients treated with radical surgery, and that baseline data such as body composition parameters, LSMI and tumor-related factors can collectively predict patient prognosis. These results could help us to optimize the management and treatment of patients after surgery.

Hydrogen Permeation Behavior of Zirconium Nitride Film on Zirconium Hydride.

Hydrogen permeation barrier plays an important role in reducing hydrogen loss from zirconium hydride matrix when used as neutron moderator. Here, a composite nitride film was prepared on zirconium hydride by in situ reaction method in nitrogen atmosphere. The phase structure, morphology, element distribution, and valence states of the composite film were investigated by XRD, SEM, AES, and XPS analysis. It was found that the composite nitride film was continuous and dense with about 1.6 µm thickness; the major phase of the film was ZrN, with coexistence of ZrO2, ZrO, and ZrN0.36H0.8; and Zr-C, Zr-O, Zr-N, O-H, and N-H bonds were detected in the film. The existence of ZrN0.36H0.8 phase and the bonds of O-H and N-H revealed that the nitrogen and oxygen in the film could capture hydrogen from the zirconium hydride matrix. The hydrogen permeation performance of nitride film was compared with oxide film by permeation reduction factor (PRF), vacuum thermal dehydrogenation (VTD), and hydrogen permeation rate (HPR) methods, and the results showed that the hydrogen permeation barrier effects of nitride film were better than that of oxide film. The zirconium nitride film would be a potential candidate for hydrogen permeation barrier on the surface of zirconium hydride.

Dynamic crosslinked polymeric nano-prodrugs for highly selective synergistic chemotherapy.

To achieve highly selective synergistic chemotherapy attractive for clinical translation, the precise polymeric nano-prodrugs (PPD-NPs) were successfully constructed via the facile crosslinking reaction between pH-sensitive poly(ortho ester)s and reduction-sensitive small molecule synergistic prodrug (Pt(IV)-1). PPD-NPs endowed the defined structure and high drug loading of cisplatin and demethylcantharidin (DMC). Moreover, PPD-NPs exhibited steady long-term storage and circulation via the crosslinked structure, suitable negative potentials and low critical micelle concentration (CMC), improved selective tumour accumulation and cellular internalization via dynamic size transition and surficial amino protonation at tumoural extracellular pH, promoted efficient disintegration and drug release at tumoural intracellular pH/glutathione, and enhanced cytotoxicity via the synergistic effect between cisplatin and DMC with the feed ratio of 1:2, achieving significant tumour suppression while decreasing the side effects. Thus, the dynamic crosslinked polymeric nano-prodrugs exhibit tremendous potential for clinically targeted synergistic cancer therapy.

Mechanisms of Growth and Hydrogen Permeation of Zirconium Nitride Film on Zirconium Hydride.

Nitride film as a hydrogen permeation barrier on zirconium hydride has seldom been studied. In this work, the zirconium nitride films were prepared on zirconium hydride in an atmosphere of N2 and N2 + H2 at 500~800 °C, with a holding time of 5 h and 20 h, and the mechanisms of film growth and hydrogen permeation were analyzed. The results showed that the film growth was mostly influenced by the temperature, followed by the reaction atmosphere and the holding time. The hydrogen could increase the nitrogen diffusivity during the formation of zirconium nitride films. The in situ nitriding conditions were optimized as 800 °C, N2 + H2 atmosphere, and 5~20 h. The chemical composition of ZrN-based films was mainly comprised of Zr and N, with a minor content of O. In addition, the film exhibited a major phase of ZrN, accompanied by the coexistence of ZrO2, ZrO, ZrN(NH2), and ZrN0.36H0.8, as well as O-H and N-H bonds based on the XPS analysis. The as-prepared ZrN base films in the present study exhibited superior hydrogen permeation resistance to other ZrO2 films previously reported. The hydrogen permeation resistance of the films could be attributed to the following mechanisms, including the chemical capture of hydrogen by the above-mentioned compounds and bonds; the physical barrier of continuous and dense film incurred from the volume effect of different compounds based on Pilling-Bedworth model and the different nitrogen diffusion coefficients at different temperatures.

Bioinformatics analyses of gene expression profile identify key genes and functional pathways involved in cutaneous lupus erythematosus.

BACKGROUND: Lupus erythematosus is an autoimmune disease that causes damage to multiple organs ranging from skin lesions to systemic manifestations. Cutaneous lupus erythematosus (CLE) is a common type of lupus erythematosus (LE), but its molecular mechanisms are currently unknown. The study aimed to explore changes in the gene expression profiles and identify key genes involved in CLE, hoping to uncover its molecular mechanism and identify new targets for CLE. METHOD: We analyzed the microarray dataset (GSE109248) derived from the Gene Expression Omnibus (GEO) database, which was a transcriptome profiling of CLE cutaneous lesions. The differentially expressed genes (DEGs) were identified, and the functional annotation of DEGs was performed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein-protein interaction (PPI) network was also constructed to identify hub genes involved in CLE. RESULT: A total of 755 up-regulated DEGs and 405 down-regulated DEGs were identified. GO enrichment analysis showed that defense response to virus, immune response, and type I interferon signaling pathway were the most significant enrichment items in DEGs. The KEGG pathway analysis identified 51 significant enrichment pathways, which mainly included systemic lupus erythematosus, osteoclast differentiation, cytokine-cytokine receptor interaction, and primary immunodeficiency. Based on the PPI network, the study identified the top 10 hub genes involved in CLE, which were CXCL10, CCR7, FPR3, PPARGC1A, MMP9, IRF7, IL2RG, SOCS1, ISG15, and GSTM3. By comparison between subtypes, the results showed that ACLE had the least DEGs, while CCLE showed the most gene and functional changes. CONCLUSION: The identified hub genes and functional pathways found in this study may expand our understanding on the underlying pathogenesis of CLE and provide new insights into potential biomarkers or targets for the diagnosis and treatment of CLE. Key Points • The bioinformatics analysis based on CLE patients and healthy controls was performed and 1160 DEGs were identified • The 1160 DEGs were mainly enriched in biological processes related to immune responses, including innate immune response, type I interferon signaling pathway, interferon-γ-mediated signaling pathway, positive regulation of T cell proliferation, regulation of immune response, antigen processing, and presentation via MHC class Ib and so on • KEGG pathway enrichment analysis indicated that DEGs were mainly enriched in several immune-related diseases and virus infection, including systemic lupus erythematosus, primary immunodeficiency, herpes simplex infection, measles, influenza A, and so on • The hub genes such as CXCL10, IRF7, MMP9, CCR7, and SOCS1 may become new markers or targets for the diagnosis and treatment of CLE.

Preparation, evaluation, and pharmacokinetics in beagle dogs of a taste-masked flunixin meglumine orally disintegrating tablet prepared using hot-melt extrusion technology and D-optimal mixture design.

Flunixin meglumine (FM) is a nonsteroidal anti-inflammatory drug limited by irritation of the respiratory tract and mucosa in veterinary tissue. This study aimed to develop a taste-masked FM solid dispersion (SD) by hot-melt extrusion (HME) and formulate an orally disintegrating tablet (ODT) with selected excipients by direct compression. Eudragit® E PO was chosen as the matrix, and HME parameters were optimized: extrusion temperature, 135℃; screw speed, 100 rpm; and drug loading, 20%. Characterization techniques proved that FM was rendered amorphous in the HME extrudate. In vitro dissolution studies showed that FM SD released significantly slower than the corresponding physical mixture in artificial saliva. Excipients were selected based on compression formability, disintegration, and solubility. A D-optimal mixture design was used to optimize the composition: 25% FM SD, 18.75% microcrystalline cellulose, 52.5% mannitol, 3.75% low-substituted hydroxypropyl cellulose, and 1% magnesium stearate. Taste-masked FM ODT had a tensile strength of 0.7 ± 0.01 MPa and a disintegration time of 17.6 ± 0.1 s. E-tongue and E-nose analysis showed that FM ODT had a better taste-masked effect than commercial granules. Finally, a pharmacokinetic study proved that the main pharmacokinetic parameters of FM ODT were not significantly different from those of commercial granules, which indicated that these formulations had similar pharmacokinetic behaviours in beagles.