Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

BACKGROUND AND AIMS: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. APPROACH AND RESULTS: We enrolled recipients receiving OLT and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, 2 cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In the mouse model, liver IRI mobilized MDSCs and promoted their infiltration in the damaged liver, and intrahepatic MDSCs were possessed with enhanced immunosuppressive function by upregulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that C-X-C motif chemokine ligand 17 (CXCL17) was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs through binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated the YAP/TEAD1 complex to promote CXCL17 transcription. CONCLUSIONS: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of therapeutic potential for managing IRI in liver surgery.

Dual-Function Nanoscale Coordination Polymer Nanoparticles for Targeted Diagnosis and Therapeutic Delivery in Atherosclerosis.

Atherosclerosis is the primary cause of cardiovascular events such as heart attacks and strokes. However, current medical practice lacks non-invasive, reliable approaches for both imaging atherosclerotic plaques and delivering therapeutic agents directly therein. Here, a biocompatible and biodegradable pH-responsive nanoscale coordination polymers (NCPs) based theranostic system is reported for managing atherosclerosis. NCPs are synthesized with a pH-responsive benzoic-imine (BI) linker and Gd3+. Simvastatin (ST), a statin not used for lowering blood cholesterol but known for its anti-inflammatory and antioxidant effects in mice, is chosen as the model drug. By incorporating ST into the hydrophobic domain of a lipid bilayer shell on NCPs surfaces, ST/NCP-PEG nanoparticles are created that are designed for dual purposes: they diagnose and treat atherosclerosis. When administered intravenously, they target atherosclerotic plaques, breaking down in the mild acidic microenvironment of the plaque to release ST, which reduces inflammation and oxidative stress, and Gd-complexes for MR imaging of the plaques. ST/NCP-PEG nanoparticles show efficacy in slowing the progression of atherosclerosis in live models and allow for simultaneous in vivo monitoring without observed toxicity in major organs. This positions ST/NCP-PEG nanoparticles as a promising strategy for the spontaneous diagnosis and treatment of atherosclerosis.

The Spectrum and Impact of Metabolic Dysfunction in MAFLD: A Longitudinal Cohort Analysis of 32,683 Overweight and Obese Individuals.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) was recently proposed as an alternative name change for better encapsulation of disease. However, there exists a spectrum of MAFLD where both metabolically healthy (MH) and metabolically unhealthy (MU) individuals are included. In view of limited evidence, we sought to examine the prevalence, clinical characteristics, and differences in outcomes of MH-MAFLD at the population level. METHODS: Data were used from the United States National Health and Nutrition Examination Survey 1999 to 2018. Multivariate logistic regression analysis was used to obtain odds ratios for the estimation of events. Survival analysis was conducted with Cox regression and the Fine-Gray subdistribution model. RESULTS: There were 32,683 overweight and obese individuals included in the analysis. In MAFLD patients, the prevalence of MH-MAFLD was 6.92% (95% confidence interval [CI], 6.58%-7.27%), and 93.08% (95% CI, 92.73%-93.42%) were considered as MU-MAFLD. Multivariate analysis found a significantly higher risk of MACE (odds ratio, 1.38; 95% CI, 1.28-1.49; P < .01), all-cause (hazard ratio, 1.24; 95% CI, 1.17-1.32; P < .01), cardiovascular disease (SHR, 1.20; 95% CI, 1.02-1.42; P = .03), and cancer mortality (SHR, 1.24; 95% CI, 1.07-1.44; P < .01) in MU-MAFLD relative to non-MAFLD. However, MH-MAFLD individuals were not associated with a statistically significant increased risk of these adverse outcomes compared with non-MAFLD. MU-MAFLD diabetics were also at a higher risk of adverse events compared with non-diabetics. CONCLUSIONS: This study reports on the heterogeneity and spectrum of metabolic dysfunction that exists in overweight and obese MAFLD. Although MAFLD may potentially be advantageous in improving awareness and patient outcomes, there remains substantial heterogeneity within patients included in MAFLD on the basis of the underlying metabolic burden.

Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for Pseudomonas aeruginosa Multiple Virulence Factor Regulator (MvfR).

Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, Pseudomonas aeruginosa, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis P. aeruginosa by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.

Innovative hydrolysis of corn stover biowaste by modified magnetite laccase immobilized nanoparticles.

Intensive studies have been performed on the improvement of bioethanol production by transformation of lignocellulose biomass. In this study, the digestibility of corn stover was dramatically improved by using laccase immobilized on Cu2+ modified recyclable magnetite nanoparticles, Fe3O4-NH2. After digestion, the laccase was efficiently separated from slurry. The degradation rate of lignin reached 40.76%, and the subsequent cellulose conversion rate 38.37% for 72 h at 35 °C with cellulase at 50 U g-1 of corn stover. Compared to those of free and inactivated mode, the immobilized laccase pre-treatment increased subsequent cellulose conversion rates by 23.98% and 23.34%, respectively. Moreover, the reusability of immobilized laccase activity remained 50% after 6 cycles. The storage and thermal stability of the fixed laccase enhanced by 70% and 24.1% compared to those of free laccase at 65 °C, pH 4.5, respectively. At pH 10.5, it exhibited 16.3% more activities than its free mode at 35 °C. Our study provides a new avenue for improving the production of bioethanol with immobilized laccase for delignification using corn stover as the starting material.

cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model.

TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.

Ethanol production by simultaneous saccharification and cofermentation of pretreated corn stalk.

The recalcitrance of lignocellulosic biomass is a major factor limiting its conversion into biofuels. Therefore, in this study, we pretreated corn stalk with 2% Na2 CO3 and 2% H2 O2 for time 70 min at 130°C using a corn stalk to liquid ratio of 1:10. The fermentation broth from multicopy Saccharomyces cerevisiae strains engineered for lignocellulase synthesis was used to enzymatically hydrolyze the pretreated corn stalk. The highest monosaccharide yield (102 mmol/L) was obtained using 15 IU endocellulase, 10 IU exocellulase, and 15 IU ß-glucosidase per gram of cellulose and 20 IU xylanase per gram of hemicellulose. Subsequently, the high-efficiency ethanol-producing S. cerevisiae strain WXY12, which can produce ethanol from glucose and xylose simultaneously, was added to the fermentation system. The entire process involved ethanol production through simultaneous saccharification and fermentation (SSF). Optimization of the fermentation conditions (yeast powder as a nitrogen source, temperature of 30°C, MgSO4 as a metal ion inducer, rotation speed of 180 rpm, solid-liquid ratio of 1:8, and inoculation amount of 2%) resulted in an ethanol output of 46.87 g/L and a theoretical conversion rate of 27.4%. The results of this study improved corn stalk utilization, reduced hydrolysis costs, and generated high ethanol yields.

Co-Immobilization of Tri-Enzymes for the Conversion of Hydroxymethylfurfural to 2,5-Diformylfuran.

Acting as a "green" manufacturing route, the enzyme toolbox made up of galactose oxidase, catalase, and horseradish peroxidase can achieve a satisfactory yield of 2,5-diformylfuran derived from 30 mM hydroxymethylfurfural. However, as the concentration of hydroxymethylfurfural increases, the substrate causes oxidative damage to the activity of the tri-enzyme system, and the accumulated hydrogen peroxide produced by galactose oxidase causes tri-enzyme inactivation. The cost of tri-enzymes is also very high. These problems prevent the utilization of this enzyme toolbox in practice. To address this, galactose oxidase, catalase, and horseradish peroxidase were co-immobilized into Cu3(PO4)2 nanoflowers in this study. The resulting co-immobilized tri-enzymes possessed better tolerance towards the oxidative damage caused by hydroxymethylfurfural at high concentrations, as compared to free tri-enzymes. Moreover, the 2,5-diformylfuran yield of co-immobilized tri-enzymes (95.7 ± 2.7%) was 1.06 times higher than that of separately immobilized enzymes (90.4 ± 1.9%). This result could be attributed to the boosted protective effect provided by catalase to the activity of galactose oxidase, owing to the physical proximity between them on the same support. After 30 recycles, co-immobilized tri-enzymes still achieves 86% of the initial yield. Moreover, co-immobilized tri-enzymes show enhanced thermal stability compared with free tri-enzymes. This work paves the way for the production of 2,5-diformylfuran from hydroxymethylfurfural via co-immobilized tri-enzymes.

Association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with preterm delivery and placental abruption: a systematic review and meta-analysis.

INTRODUCTION: The aim of this study was to summarize evidence on the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and odds of preterm delivery and placental abruption. MATERIAL AND METHODS: PubMed, EMBASE, CBM (Chinese Biomedical Database) and CNKI (Chinese National Knowledge Infrastructure) were searched to identify eligible studies published in English or Chinese before 12 August 2014. The pooled odds ratios (ORs) with 95% confidence intervals were estimated for the association of MTHFR C677T polymorphism with preterm delivery and placental abruption using random effects models. RESULTS: A total of 22 studies that met inclusion and exclusion criteria were included in this meta-analysis. Regardless of the genetic model tested we found no statistically significant association of MTHFR C677T polymorphism with preterm delivery or placental abruption. Funnel plots inspections, Begg's test and Egger's test did not show evidence of publication bias. CONCLUSIONS: This meta-analysis demonstrated that overall there was no association of MTHFR C677T polymorphism with preterm delivery or placental abruption.

Green Synthesis of Gold Nanoparticles from Polygahatous Polysaccharides and Their Anticancer Effect on Hepatic Carcinoma through Immunoregulation.

Hepatic carcinoma is one of the leading causes of morbidity and mortality among all cancers, but no effective treatment measures have been developed. Herein, polystyrene polysaccharide (PSP) extracted from Polygonatum was used to synthesize gold nanoparticles (PSP-AuNPs) by heating and reduction methods, and the characteristics of the PSP-AuNPs were detected after successful synthesis. In vitro, the immunoregulatory effects of PSP-AuNPs were studied by testing the concentrations of NO, TNF-α, and IL-12p70 in the culture media of PSP-AuNPs-treated RAW264.7 macrophages, and the effect of biocompatibility on the viability of RAW264.7 macrophages and L02 cells was studied via a CCK-8 assay. In vivo, tumor-bearing mice were established and treated with PSP-AuNPs, and the anticancer effects were studied by detecting trends in tumor volume, tumor inhibition rate, and tumor cell proliferation index. Immunoregulation was assessed by evaluating the serum levels of TNF-α and IL-10, the CD4+/CD8+ lymphocyte ratio in peripheral blood and the spleen and thymus indices; toxicity was investigated by measuring body weight, liver and renal function indices. The results showed that PSP-AuNPs could regulate immune function both in vitro and in vivo with almost no toxicity. PSP-AuNPs exhibited excellent anticancer effects on hepatic carcinoma in vivo. The anticancer effect could be strengthened, and the toxicity could be reduced by the combined use of PSP-AuNPs and ADM. In conclusion, PSP-AuNPs could be effective as a therapy and adjuvant therapy for treating hepatic carcinoma, providing potential treatment strategies for this disease.

Anti-hepatoma immunotherapy of Pholiota adiposa polysaccharide-coated selenium nanoparticles by reversing M2-like tumor-associated macrophage polarization.

Targeting macrophages to regulate the tumor microenvironment is a promising strategy for treating cancer. This study developed a stable nano drug (PAP-SeNPs) using Se nanoparticles (SeNPs) and the Pholiota adiposa polysaccharide component (PAP-1a) and reported their physical stability, M2-like macrophages targeting efficacy and anti-hepatoma immunotherapy potential, as well as their molecular mechanisms. Furthermore, the zero-valent and well-dispersed spherical PAP-SeNPs were also successfully synthesized with an average size of 55.84 nm and a negative ζ-potential of -51.45 mV. Moreover, it was observed that the prepared PAP-SeNPs were stable for 28 days at 4 °C. Intravital imaging highlighted that PAP-SeNPs had the dual effect of targeting desirable immune organs and tumors. In vitro analyses showed that the PAP-SeNPs polarized M2-like macrophages towards the M1 phenotype to induce hepatoma cell death, triggered by the time-dependent lysosomal endocytosis in macrophages. Mechanistically, PAP-SeNPs significantly activated the Tlr4/Myd88/NF-κB axis to transform tumor-promoting macrophages into tumor-inhibiting macrophages and successfully initiated antitumor immunotherapy. Furthermore, PAP-SeNPs also enhanced CD3+CD4+ T cells and CD3+CD8+ T cells, thereby further stimulating anti-hepatoma immune responses. These results suggest that the developed PAP-SeNPs is a promising immunostimulant that can assist hepatoma therapy.

Production and characterization of bacterial cellulose by Rhizobium sp. isolated from bean root.

Bacterial cellulose (BC) is a natural polymer renowned for its unique physicochemical and mechanical attributes, including notable water-holding capacity, crystallinity, and a pristine fiber network structure. While BC has broad applications spanning agriculture, industry, and medicine, its industrial utilization is hindered by production costs and yield limitations. In this study, Rhizobium sp. was isolated from bean roots and systematically assessed for BC synthesis under optimal conditions, with a comparative analysis against BC produced by Komagataeibacter hansenii. The study revealed that Rhizobium sp. exhibited optimal BC synthesis when supplied with a 1.5% glucose carbon source and a 0.15% yeast extract nitrogen source. Under static conditions at 30 °C and pH 6.5, the most favorable conditions for growth and BC production (2.5 g/L) were identified. Modifications were introduced using nisin to enhance BC properties, and the resulting BC-nisin composites were comprehensively characterized through various techniques, including FE-SEM, FTIR, porosity, swelling, filtration, and antibacterial activity assessments. The results demonstrated that BC produced by Rhizobium sp. displayed properties comparable to K. hansenii-produced BC. Furthermore, the BC-nisin composites exhibited remarkable inhibitory activity against Escherichia coli and Pseudomonas aeruginosa. This study contributes valuable insights into BC's production, modification, and characterization utilizing Rhizobium sp., highlighting the exceptional properties that render it efficacious across diverse applications.

Enhanced mechanical and long-lasting antibacterial properties of starch/PBAT blown films via designing of reactive micro-crosslinked starch.

A functional starch (TPS-E) was designed and constructed by incorporating epoxy soybean oil (ESO) and an antibacterial agent polyhexamethylene guanidine hydrochloride (PHMG), then the film was prepared by reaction extrusion and blow molding using TPS-E and poly(butylene adipate-co-terephthalate) (PBAT). The micro-crosslinking structure, forming through ring-opening reaction between the epoxy active site of TPS-E and the end group of PBAT, improved the compatibility of starch/PBAT blend and reduce the dispersed starch phase size, leading to significantly increase the tensile strength. Compared to starch/PBAT films, the tensile strength of TPS-E/PBAT in the longitudinal direction increase by 112% with the same starch content of 30%. Furthermore, these TPS-E/PBAT films demonstrated long-lasting antibacterial performance with a 98% inhibition ratio even after 10 cycles, without any observed leaching of the antibacterial agent, highlighting the high coupling efficiency of PHMG. TPS-E with the degradable ESO also promotes the degradation of PBAT. Thus, an important method of synergistic improving the mechanical, degradable and antibacterial properties of blown films through the design of reactive micro-crosslinked starch structures was established.

Inflammation-Responsive Cell Membrane-Camouflaged Nanoparticles against Liver Fibrosis via Regulating Endoplasmic Reticulum Stress and Oxidative Stress.

Liver fibrosis represents a reversible stage of various chronic liver diseases that progresses to cirrhosis. This condition is characterized by an imbalance between tissue damage and repair, and the production of fibers in the liver exceeds their degradation. Oxidative stress (OS) resulting from tissue injury and endoplasmic reticulum stress (ERS) triggered by the overproduction of proteins are pivotal factors in liver fibrosis. Melatonin demonstrates the capability to neutralize free radicals, shielding cells from oxidative harm. It is also a specific inhibitor of the ERS receptor transcription activating factor 6 (ATF6), indicating its great potential in ameliorating liver fibrosis. However, its limited water solubility and oral bioavailability of under 15% present hurdles in achieving therapeutic blood concentrations for treating liver fibrosis. The PLGA@Melatonin is constructed by loading melatonin with poly (lactic-co-glycolic acid) (PLGA). Platelet membranes (PM) and activated hepatic stellate cell membranes (HSCM) with high expression of the platelet-derived growth factor receptor (PDGFR) are extracted to successfully construct PM@PLGA@Melatonin and HSCM@PLGA@Melatonin, which are subsequently utilized to treat mice with liver fibrosis. The results illustrated the remarkable therapeutic effects of the two nanoparticles on liver fibrosis, along with their excellent targeting and biosafety properties.

High-Value and Environmentally Friendly Recycling Method for Coal-Based Solid Waste Based on Polyurethane Composite Materials.

This study aims to provide a high-value and environmentally friendly method for the application of coal-based solid waste. Modified fly ash/polyurethane (MFA/PU) and modified coal gangue powder/polyurethane (MCG/PU) composites were prepared by adding different contents of MFA and MCG (10%, 20%, 30%, 40%). At the filler content of 30%, the compressive strengths of MFA/PU and MCG/PU are 84.1 MPa and 46.3 MPa, respectively, likely due to an improvement in interface compatibility, as indicated by scanning electron microscopy (SEM). The MFA/PU and MCG/PU composites present their highest limiting oxygen index (LOI) values of 29% and 23.5%, respectively, when their filler content is 30%. MFA has advantages in improving the LOIs of composites. Cone calorimetry (CCT) and SEM demonstrate that the two composites exhibit similar condensed-phase flame-retardant behaviors during combustion, which releases CO2 in advance and accelerates the formation of a dense barrier layer. Compared with the MFA/PU composites, the MCG/PU composites could produce a more stable and dense barrier structure. Water quality tests show that heavy metals do not leak from FA and CG embedded in PU. This work provided a new strategy for the safe and high-value recycling of coal-based solid waste.

Isolation and Characterization of a Low-Temperature, Cellulose-Degrading Microbial Consortium from Northeastern China.

The lack of efficient ways to dispose of lignocellulosic agricultural residues is a serious environmental issue. Low temperatures greatly impact the ability of organisms to degrade these wastes and convert them into nutrients. Here, we report the isolation and genomic characterization of a microbial consortium capable of degrading corn straw at low temperatures. The microorganisms isolated showed fast cellulose-degrading capabilities, as confirmed by scanning electron microscopy and the weight loss in corn straw. Bacteria in the consortium behaved as three diverse and functionally distinct populations, while fungi behaved as a single population in both diversity and functions overtime. The bacterial genus Pseudomonas and the fungal genus Thermoascus had prominent roles in the microbial consortium, showing significant lignocellulose waste-degrading functions. Bacteria and fungi present in the consortium contained high relative abundance of genes for membrane components, with amino acid breakdown and carbohydrate degradation being the most important metabolic pathways for bacteria, while fungi contained more genes involved in energy use, carbohydrate degradation, lipid and fatty acid decomposition, and biosynthesis.

Characterization of active alkaloids and metabolites in rats after oral administration of Zuojin Pill using UHPLC-Q-TOF-MS combined with bioinformatics and molecular docking analyses.

Zuojin Pill (ZJP), a traditional Chinese medicine prescription composed of Rhizoma Coptidis and Euodiae Fructus in the ratio of 6:1 (w/w), has been widely used for the treatment of gastric disorders. However, an in-depth understanding of in vivo metabolism and distribution profiles of protoberberine alkaloids (PBAs) and indole alkaloids (IDAs) in ZJP is lacking. In this study, a method using ultra-high performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed to systematically screen the alkaloids and their metabolites in rat plasma and various tissues after oral administration of ZJP. Furthermore, bioinformatics and molecular docking analyses were conducted to elucidate the contribution of the alkaloids and metabolites enriched in the stomach to the therapeutic effect of ZJP on gastritis. A total of 33 compounds, including 7 prototype alkaloids and 26 metabolites, were chemically defined or tentatively identified in this work. The metabolic pathways of PBAs (hydroxylation, oxidation, reduction, demethylation, demethylenation, glucuronide conjugation, sulfate conjugation) and IDAs (hydroxylation, glucuronide conjugation) were revealed. Notably, 7 prototype alkaloids and 18 metabolites were detected in the stomach, indicating their propensity for gastric distribution. These alkaloids and metabolites showed strong affinities with the 7 hub targets associated with gastritis, such as CCR7, CXCR4, IL6, IFNG, CCL2, TNF, and PTPRC, and could be considered the potential active substances of ZJP for treating gastritis. In conclusion, this study clarified the gastric distribution propensity of PBAs and IDAs and their metabolites, as well as their favorable binding interactions with gastritis-related targets, which could provide essential data for the further study of the pharmacodynamic material basis and gastroprotective mechanism of ZJP.

Gut-liver axis: Potential mechanisms of action of food-derived extracellular vesicles.

Food-derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non-gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non-gastrointestinal diseases via the gut-liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut-liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non-alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut-liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases.

Exploring teacher wellbeing in educational reforms: a Chinese perspective.

Teaching is a demanding profession and maintaining teacher wellbeing is significant in ensuring educational quality. However, teacher wellbeing is easily affected by educational reforms, and systematic research on this topic is still relatively rare. In China, with the enactment of the Double Reduction Policy in 2021, the job characteristics of primary and secondary school teachers have undergone various changes. Thus, the current study examined the new job characteristics that China's Double Reduction Policy imposed on the wellbeing of school teachers and their relationships with teachers' inner world (i.e., emotional regulation and mindset). A cross-sectional study was carried out from June to October 2022 across China, employing self-reporting questionnaires for data collection and analysis. With a random sample of 902 teachers, we investigated the associations between teacher wellbeing, job characteristics, emotional regulation strategies, and mindset. The results indicated that teachers showed a lower level of wellbeing after the educational reform. Higher job resources contributed positively to predicting teacher wellbeing, while higher job demands contributed negatively. Genuinely expressing had positive impacts on teacher wellbeing while surface acting had negative impacts and deep acting none. Mindset was found to affect emotional regulation strategies and teacher wellbeing simultaneously. These findings shed light on how teachers can appropriately regulate emotions and maintain wellbeing in the wake of educational reforms.

A pairwise immune gene model for predicting overall survival and stratifying subtypes of colon adenocarcinoma.

OBJECTIVES: There is increasing evidence for a close correlation between risk stratification, prognosis and the immune environment in colon adenocarcinoma (COAD). However, the efficacy of immunotherapy is different among different patients with COAD. Therefore, the current work tends to use immune-related gene to develop a gene-pair model to evaluate the COAD prognosis, and to develop a new method for risk stratification of COAD, which is conducive to better predict the immunotherapy effect of patients. METHODS: Specifically, from the TCGA and GEO (GSE14333 and GSE39582) databases, we first collected gene expression profiles, associated survival follow-up information of COAD patients. Through systematic bioinformatics analysis, we established a prognosis-related model of colon cancer with three pairs of "immune gene pairs", with uni- and multivariate and lasso cox regression analyses verifying the model stability. Most immune cells showed markedly different levels of infiltration between the two risk subgroups calculated by the model. More, single-cell RNA-seq analyses were also performed to validate the selected genes in the immune gene-pair model. RESULTS: A prognosis-related model of colon cancer with three pairs of "immune gene pairs" were built and validated by several datasets. The analysis of immune landscape of COAD revealed that low-risk subgroup obtained by the prognosis-related model for COAD can be further divided into three subclusters with different prognosis. Then, we applied the Tumor online Prognostic analyses Platform (ToPP) to construct a prognostic model using these five genes. Results show that APOD, ISG20 and STC2 are risk factors, while CXCL9 and IL7R are protection factors. We also found that only the five-gene model could also predict the prognosis of COAD patients, indicating the robustness of the gene-pair model. Among the five genes, including CXCL9, APOD, STC2, ISG20, and IL7R, in the gene-pair model, single-cell RNA sequencing reveals the high expression of CXCL9 and IL7R in inflammatory macrophages. Using cell-cell interaction and trajectory analysis, data indicate that CXCL9+/IL7R+ pro-inflammatory macrophages were capable of secreting and activating more anti-tumor pathways than CXCL9-/IL7R- pro-inflammatory macrophages. CONCLUSIONS: In short, we have successfully developed an "immune gene pair" related model that can judge the prognostic status of patients with COAD and may contribute to risk stratification and evaluate potential beneficiaries of immunotherapy, providing new ideas for the anti-COAD management and therapy.