Background and aims The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown. Methods The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation. Results Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways. Conclusions PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.

Atherosclerosis (AS) is a prevalent clinical vascular condition and serves as a pivotal pathological foundation for cardiovascular diseases. Understanding the pathogenesis of AS has significant clinical and societal implications, aiding in the development of targeted drugs. Neutrophils, the most abundant leukocytes in circulation, assume a central role during inflammatory responses and closely interact with AS, which is a chronic inflammatory vascular disease. Neutrophil extracellular traps (NETs) are substantial reticular formations discharged by neutrophils that serve as an immune defense mechanism. These structures play a crucial role in inducing dysfunction of the vascular barrier following endothelial cell injury. Components released by NETs pose a threat to the integrity of vascular endothelium, which is essential as it acts as the primary barrier to maintain vascular wall integrity. Endothelial damage constitutes the initial stage in the onset of AS. Recent investigations have explored the intricate involvement of NETs in AS progression. The underlying structures of NETs and their active ingredients, including histone, myeloperoxidase (MPO), cathepsin G, neutrophil elastase (NE), matrix metalloproteinases (MMPs), antimicrobial peptide LL-37, alpha-defensin 1-3, and high mobility group protein B1 have diverse and complex effects on AS through various mechanisms. This review aims to comprehensively examine the interplay between NETs and AS while providing insights into their mechanistic underpinnings of NETs in this condition. By shedding light on this intricate relationship, this exploration paves the way for future investigations into NETs while guiding clinical translation efforts and charting new paths for therapeutic interventions.
Extracellular Traps/physiology* ; Humans ; Atherosclerosis/immunology* ; Neutrophils/physiology* ; Leukocyte Elastase/metabolism* ; Peroxidase/physiology* ; Matrix Metalloproteinases/physiology* ; Cathepsin G/metabolism* ; Cathelicidins ; HMGB1 Protein/physiology* ; Histones ; Animals ; Endothelium, Vascular

Objective:To investigate effect of comprehensive management intervention based on WeChat multimedia classroom on cardiac function and prognosis in elderly patients with acute myocardial infarction(AMI).Methods:Clinical data of 118 elderly patients diagnosed with AMI in the Second Affiliated Hospital of Chinese PLA Air Force Military Medical University between August 2021 and December 2022 were retrospectively collected.According to nursing way after operation,they were divided into control group(n=60,comprehensive management interven-tion)and intervention group(n=58,comprehensive management intervention based on WeChat multimedia class-room),both groups were intervened for 5 months.Cardiac function,exercise tolerance,compliance to rehabilita-tion management,self-efficacy and healthy behavior were compared between two groups.Kaplan-Meier survival curve was employed to compare incidence of adverse cardiovascular events during follow-up between two groups.Results:After 5-month intervention,compared with patients in control group,those in intervention group had sig-nificant higher left ventricular ejection fraction(LVEF)[(58.14±1.88)％vs.(54.48±1.34)％],6min walking distance(6MWD)[(490.41±59.59)m vs.(394.97±28.20)m],scores of compliance to rehabilitation manage-ment[(6.97±2.03)points vs.(5.03±1.40)points],General Self-Efficacy Scale(GSES)[(30.34±4.67)points vs.(23.55±4.86)points]and Health Promoting Lifestyle Profile-Ⅱ[(137.62±30.17)points vs.(115.95±22.66)points],and significant lower left ventricular end-diastolic volume(LVEDV)[(117.90±4.22)ml vs.(131.28±3.61)ml],left ventriadar end-systolic volume(LVESV)[(54.46±2.10)ml vs.(63.15±2.06)ml],serum brain natriuretic peptide(BNP)[(362.32±25.36)pg/ml vs.(567.58±21.90)pg/ml]and incidence of ad-verse cardiovascular events(6.90％vs.21.67％)(P＜0.05 or＜0.01).Conclusion:Comprehensive management intervention based on the WeChat multimedia classroom could significantly improve cardiac function,exercise toler-ance,compliance to rehabilitation,self-efficacy and healthy behavior,and reduce incidence of adverse cardiovas-cular events after operation in elderly AMI patients.

Objective To study the effect of auditory and speech development after cochlear implant(CI)in children with bilateral cochlear nerve deficiency(CND)and its influencing factors.Methods A total of 20 children with bilateral CND were included in the study,of which 5 were implanted bilaterally and 15 unilaterally.CT of the temporal bone showed stenosis of the cochlear aperture in 14 cases and atresia of the cochlear aperture in 6 cases.There were 8 cases accompanied by other inner ear malformations,and 12 cases with no accompanying inner ear mal-formations.MRI of the internal auditory canal showed 1 nerve in 5 cases,2 nerves in 6 cases,3 nerves in 8 cases,and 4 nerves in 1 case.There were 6 cases in which the EABR was not elicited and 14 cases in which it was elicited.The postoperative auditory and speech abilities of the subjects were evaluated using categories of auditory perform-ance(CAP)and speech intelligibility rating(SIR).Results ① The CAP(P＜0.001)and SIR(P＜0.001)scores of the children with stenosis of the cochlea nerve canal were higher than those of the patients with atresia of the cochlea nerve canal.② The more nerve roots in the internal auditory canal,the higher the score of CAP(P=0.003)and SIR(P=0.008).③ CAP score of the children with EABR elicited was higher than that of the children without EABR elicited(P=0.030).The difference in SIR scores was not statistically significant(P=0.14).④The differences in CAP and SIR between those with bilateral CI and unilateral CI,as well as between those with and without other inner ear malformations,were not statistically significant(P＞0.05).Conclusion Children with bi-lateral CND had significant postoperative improvement in auditory function but poor speech development after CI.Postoperative auditory speech ability was related to the condition of the cochlear foramen,the number of nerve roots in the internal auditory canal,and whether or not the EABR was elicited intraoperatively.

Objective To analyze the composition characteristics and biological functions of tumor cell subpopulations in glioblastoma(GBM)through multi-transcriptomics sequencing technology,and explore the hypoxia characteristics and spatial localization features of the mesenchymal-like(MES-like)tumor cell subpopulation in GBM and the influence on malignant biological behaviors.Methods Multi-transcriptomics sequencing data,including single-cell RNA sequencing(scRNA-seq)data(18 patients),bulk RNA sequencing(bulk RNA-seq)and spatial transcriptomics(ST)data of GBM,were employed to define cell subpopulations in GBM,and Gene Ontology(GO)and Gene Set Enrichment Analysis(GSEA)were utilized to analyze their functions.The proportions and locations of cell subpopulations in bulk RNA-seq data were evaluated with BayesPrism deconvolution.Immunofluorescence assay was conducted for verification on 12 paraffin samples of GBM from patients who visited the neurosurgical department of our hospital from 2015 to 2023 and met the pathological diagnostic criteria for GBM(10 males and 2 females,at an average age of 53.50 years and a median age of 54.50 years).pySCENIC was applied to predict specific transcription factors of tumor cell subpopulations.Results Tumor cells in GBM were highly heterogeneous,and could be mainly divided into 4 subpopulations:astrocyte-like(AC-like),neural progenitor-like(NPC-like),oligodendrocyte progenitor-like(OPC-like)and MES-like.Differential gene analysis found that the MES-like tumor cells highly expressed vascular endothelial growth factor A(VEGFA),adrenomedullin(ADM),N-myc downstream regulated 1(NDRG1),insulin like growth factor binding protein 5(IGFBP5),and A-kinase anchoring protein 12(AKAP12)(P<0.001).pySCENIC transcription factor prediction found that the high-active transcription factors of the MES-like tumor cells were AT-rich interaction domain 3A(ARID3A),FOS like 2,AP-1 transcription factor subunit(FOSL2),endothelial PAS domain protein 1(EPAS1),CCAAT enhancer binding protein delta(CEBPD),and CCAAT enhancer binding protein beta(CEBPB)(P<0.05).GO and GSEA enrichment analyses found that the MES-like tumor cells were enriched in hypoxia-related pathways,especially the pathway of cell responses to hypoxia levels(NES=2.437,P<0.001).BayesPrism deconvolution showed that the MES-like tumor cells mainly existed in PAN(Pseudopalisading cells around necrosis)and perinecrotic zone.Immunofluorescence assay confirmed CD44+(CD44 antigen)MES-like tumor cells were mainly located in hypoxia areas with highly expression of hypoxia inducible factor 1 subunit alpha(HIF1α)(P<0.01).Multivariate Cox regression analysis indicated that the MES-like tumor cells were significantly correlated with the adverse prognosis of GBM patients(HR=1.71,95%CI:1.38～2.11,P<0.001).Conclusion Tumor cells in GBM are of highly heterogeneity.They could be mainly divided into 4 subpopulations:AC-like,NPC-like,OPC-like and MES-like.MES-like tumor cells,mainly locating in PAN and perinecrotic zone,are characterized by hypoxia,which can promote the malignant progression of GBM.

Objective:To retrospectively analyze the clinical features and surgical efficacy of congenital cholesteatoma （CC） and acquired cholesteatoma （AC） in children. Methods:Clinical data of 169 children with middle ear cholesteatoma were reviewed in the Department of Otorhinolaryngology Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University from January 2010 to July 2020. The clinical characteristics, stages, surgical methods, and postoperative recurrence rates were analyzed and summarized. Results:The age distribution of enrolled children ranged from 2 to 14 years. The mean age of the CC group was （5.60±2.48） years compared with （6.45±2.48） years in the AC group, and the difference was statistically significant （P<0.05）. Preoperative hearing in the CC group was （40.06±13.52） dB HL, which was better than in the AC group at （48.40±13.84） dB HL （P<0.05）. The proportion of stage Ⅰ in the CC group was lower than that in the AC group according to EAONO/JOS staging （P<0.05）. The recurrence rate after primary surgery was 19.23% （10/52） in the CC group compared with 36.29% （45/124） in the AC group （P<0.05）. The mastoid retention rates after all operations were 28.85% （15/52） in the CC group and 5.65% （7/124） in the AC group （P<0.05）. Conclusion:Compared with congenital cholesteatoma, acquired cholesteatoma in children is more aggressive and has more complications, higher postoperative recurrence rate, and less possibility of mastoid retention. Early clinical detection and treatment are required, and canal wall-down tympanoplasty should be considered in surgery.
Humans ; Cholesteatoma, Middle Ear/congenital* ; Child ; Retrospective Studies ; Child, Preschool ; Adolescent ; Male ; Female ; Recurrence ; Cholesteatoma/congenital* ; Tympanoplasty ; Treatment Outcome

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Objective:To establish a detection method for fatty acid composition and methoxylaniline value in pharmaceutical excipient castor oil.Methods:The detection of fatty acid composition involves pre-test of the sam-ple using the methanol sodium methylation method,followed by direct injection analysis using gas chromatography,and finally calculating the content of each fatty acid composition using the area normalization method with correction factors.The detection of methoxylaniline value is achieved by dissolving and diluting the sample with isooctane:isopropanol(8∶2,volume ratio),reacting with 4-methoxylaniline,measuring the absorbance at a wavelength of 350 nm,and calculating the methoxylaniline value.Results:Under the composition of fatty acids,the 8 kinds of fatty acids have good separation degree.The methyl ricinoleate and methyl stearate have good linear relationship in the range of 0.1-5.0 mg·mL-1.The repeatabilityand intermediate precision(RSD)ofthe determination results of each fatty acid in the sample are all less than 5%.It is also found that only α-type of linolenic acid is present in castor oil,without γ-type.In the determination of methoxyaniline value,the blank solvent does not interfere with the determination of the sample,and the repeatability RSD is 3.6%.Conclusion:The detection method for fatty acid composition and meth-oxylaniline value established in this article is accurate and reliable,and can be used for the detection of fatty acid composition and methoxylaniline value in pharmaceutical excipient castor oil.

Objective To investigate the protective effect of Liraglutide in rats with diabetic kidney disease(DKD)by regulating the nuclear factor E2-related factor 2(Nrf2)/glutathione peroxidase 4(GPX4)ferroptosis signaling pathway.Methods Twelve male Sprague-Dawley(SD)rats were randomly divided into normal control(NC)group,DKD group,and Liraglutide treatment(Lir)group,with 4 rats in each group.The 24 hUAlb,TC,TG,LDL-C,serum creatinine(Scr),BUN,ferrous ion(Fe2+),the activity of glutathione peroxidase(GSH-Px),and malondialdehyde(MDA)were detected in each group.Hematoxylin and eosin(HE),periodic acid-Schiff(PAS),and periodic acid-silver methenamine-Masson(PASM-Masson)staining were used to observe the pathological changes of the kidneys.Immunofluorescence was performed to detect the localization and expression of reactive oxygen species(ROS)in the renal tissue.The protein expressions of Nrf2 and GPX4 were detected by Western blot.Results Compared with the NC group,the levels of 24 hUAlb,Scr,BUN,TC,TG,LDL-C,MDA,ROS,and Fe2+were increased(P＜0.05 or P＜0.01),while the expressions of GSH-Px,Nrf2,and GPX4 proteins were decreased in the DKD group(P＜0.01).Compared with the DKD group,the levels of 24 hUAlb,BUN,TC,TG,LDL-C,MDA,ROS,and Fe2+were decreased(P＜0.05 or P＜0.01),and the expressions of GSH-Px,Nrf2,and GPX4 proteins were increased in the Lir group(P＜0.01).Conclusions Liraglutide may exert a protective effect in DKD by upregulating the Nrf2/GPX4 signaling pathway and inhibiting ferroptosis.