To investigate the clinical characteristics and prognosis of extracranial malignant rhabdoid tumor (eMRT) in children, and to provide a reference for the clinical treatment of this disease.

ObjectiveTo investigate the effects of Erchentang （ECD） on the body weight of the mouse model of simple obesity induced by a high-fat diet （HFD） and decipher the underlying mechanisms. MethodsFirstly， single-cell transcriptomics （Sc-RNAseq） was employed to analyze the transcriptional changes in the ileum tissue of mice in the normal group and model group. Then， a mouse model of simple obesity was established with a high-fat diet. The successfully modeled mice were randomly allocated into the following four groups （n=8）： model， low-dose （7.5 g·kg^-1） ECD， medium-dose （15 g·kg^-1） ECD， and high-dose （30 g·kg^-1） ECD. Additionally， 8 mice of the same age were selected as the normal group. The body weight was measured at fixed time points during the 4-week gavage period. The overall efficacy of ECD in alleviating obesity was evaluated through glucose tolerance testing， behavioral analysis， hematoxylin-eosin （HE） staining， and biochemical testing. Protein docking was employed to predict the degree of binding between corresponding proteins. Molecular docking was employed to predict the binding degree between key components of ECD and target proteins. Real-time PCR was employed to determine the mRNA levels of tumor necrosis factor-α （TNF-α）， inducible nitric oxide synthase （iNOS）， interleukin-1β （IL-1β）， CD68， CD206， zonula occludens-1 （ZO-1）， and Claudin-5 in the ileum. Immunofluorescence staining was used to observe the expression and distribution of Claudin-5 and ZO-1. ResultsThe Sc-RNAseq results indicated that the differentially expressed genes of immune cells in the model group in comparison with the normal group were primarily enriched in biological functions related to lipid metabolism and inflammatory metabolism. Additionally， these genes were associated with the janus kinases（JAK）/signal transducers and activators of transcription （STAT） signaling pathway， an inflammation-related pathway. Compared with the normal group， the model group showed increases in body weight （P<0.01） and blood glucose level （P<0.01）， a decrease in limb strength （P<0.01）， an increase in liver weight （P<0.05）， and elevated serum alanine amino-transferase （ALT） and aspartate transferase （AST） levels （P<0.05， P<0.01）. Additionally， the model group exhibited increased hepatic fat vacuoles， notably enlarged adipocytes in the epididymal and inguinal white adipose tissue， and increased inflammation. Compared with the model group， ECD groups showed reduced body weights （P<0.01） and blood glucose levels （P<0.01）， increased limb strength （P<0.05， P<0.01）， decreased liver weights （P<0.05， P<0.01）， and declined serum ALT and AST levels （P<0.05， P<0.01）. Additionally， ECD reduced hepatic fat vacuoles and the adipocyte volume in the epididymal and inguinal white adipose tissue， and alleviated inflammation. Potential interactions existed between CD68 and ZO-1/Claudin-5， as well as between CD206 and ZO-1/Claudin-5. The key components of ECD， nobiletin， diosmetin， and naringenin， all demonstrated strong binding affinity with the target proteins ZO-1 and Claudin-5. Compared with the normal group， the model group exhibited up-regulated mRNA levels of the pro-inflammatory cytokines TNF-α， iNOS， IL-1β， and CD68 （P<0.05， P<0.01） and down-regulated mRNA levels of the anti-inflammatory cytokine CD206 （P<0.01） and the tight junction proteins Claudin-5 and ZO-1 （P<0.05， P<0.01）. In comparison with the model group， the ECD groups showed down-regulated mRNA levels of TNF-α， iNOS， IL-1β， and CD68 （P<0.05， P<0.01） and up-regulated mRNA levels of CD206， Claudin-5， and ZO-1 （P<0.05， P<0.01）. Compared with the normal group， the model group exhibited down-regulated expression of tight junction proteins Claudin-5 and ZO-1 （P<0.01）. Compared with the model group， ECD groups showed up-regulated expression of Claudin-5 and ZO-1 （P<0.05， P<0.01）. ConclusionECD can significantly ameliorate HFD-induced obesity and excessive body weight gain in mice by improving the inflammatory microenvironment in the ileum and further restoring the integrity of the impaired ileal barrier.

Caffeic acid (CA) is a naturally occurring phenolic compound known for its strong antioxidant and cytoprotective properties.Particulate matter (PM) with an aerodynamic diameter of 2.5 μm (PM2.5) or less is a major atmospheric pollutant that induces excessive oxidative stress and apoptosis in human skin cells, contributing to various adverse effects on the skin. In this study, we investigated the protective role of CA against PM2.5-induced cellular injury in human HaCaT keratinocytes. CA reduced PM2.5-induced reactive oxygen species (ROS) accumulation and mitigated oxidative damage, including lipid peroxidation, protein carbonyl formation, mitochondrial membrane depolarization, and intracellular calcium overload. In addition, CA attenuated PM2.5-induced apoptosis by upregulating B-cell lymphoma 2 (Bcl-2) and suppressing Bcl-2-associated X protein (Bax), caspase-3, caspase-9, and phosphorylated c-Jun N-terminal kinase (phospho-JNK). Collectively, these findings demonstrate that CA protects HaCaT keratinocytes from PM2.5-induced oxidative stress and apoptosis by regulating the Bcl-2/Bax axis and inhibiting JNK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for preventing pollutant-induced skin damage.

Multidrug-resistant (MDR) bacterial infections have emerged as a serious challenge of global public health crisis. The overuse and misuse of conventional antibiotics have dramatically accelerated the emergence, evolution and worldwide spread of drug-resistant bacterial strains, necessitating urgent exploration of novel antibacterial strategies. Bacteriophages serve as natural bacterial predators offering distinct advantages including high host specificity, autonomous self-replication capabilities and cost-effective large-scale production. However, wild-type phages present significant clinical limitations due to their narrow host ranges, susceptibility to rapid immune clearance and poor penetration of bacterial biofilms, which severely restrict their therapeutic applications. The convergence of synthetic biology, nanotechnology and advanced gene editing technologies has accelerated the development of engineered bacteriophage platforms, providing programmable, scalable and clinically translatable pathways to overcome these inherent biological constraints. Here, we systematically delineate four fundamental strategies for engineered bacteriophage development. Chemical modification utilizes reactive functional groups such as amino, carboxyl and thiol moieties on capsid proteins through esterification, amidation or click chemistry reactions to achieve precise drug conjugation and surface functionalization. In vivo editing encompasses ultraviolet or chemical mutagenesis for random mutation induction, homologous recombination for targeted genetic alterations, recombineering methodologies including electroporation-mediated bacteriophage recombination engineering, and CRISPR-Cas systems for precise genome editing to enable exact genetic reconstruction and host range reprogramming. In vitro synthesis leverages genome engineering platforms where intact phage genomes are transferred into yeast or host bacteria to facilitate highly efficient homologous recombination, enabling large DNA fragment assembly and cross-gene host range expansion without bacterial toxicity constraints. Directed evolution combines artificial selection through mutation library screening with rational design approaches involving chimeric receptor binding protein construction or site-specific mutagenesis, effectively balancing the discovery of unknown adaptive pathways with targeted host specificity modification. Moreover, we comprehensively discuss therapeutic applications across diverse clinical scenarios. Engineered bacteriophage effectively disrupt bacterial biofilms through sophisticated functionalized delivery platforms including nanozyme-conjugated phages, phage-liposome nanoconjugates and bio-responsive hydrogels, demonstrating significantly enhanced bactericidal efficiency compared to unmodified free phages. These bioengineered vectors attenuate bacterial virulence and resensitize pathogens to antibiotics by delivering CRISPR-Cas systems or base editors to disrupt critical virulence factors such as pili, capsule synthesis machineries and quorum sensing systems, or by inactivating antibiotic resistance determinants including beta-lactamase genes. As an intelligent nanomedicine delivery platform, engineered bacteriophage enable precise pathogen elimination an through photocatalytic reactive oxygen species generation, immunomodulatory interventions, or controlled release of antibacterial drugs. Furthermore, oral administration of engineered bacteriophage facilitates microbiota modulation, which selectively eliminate intestinal pathogens while preserve beneficial commensal microbiota, thereby restoring microbial community balance and preventing complications associated with dysbiosis. Finally, we critically analyze persistent challenges including host strain matching complexity, evolution of bacterial resistance mechanisms, pharmacokinetic optimization requirements, optimal administration route selection, large-scale production quality control standards and clinical dosing determination protocols. Through multidisciplinary integration of synthetic biology, infectious disease medicine and immunology, future translational medicine studies of bacteriophage should establish comprehensive technical platforms encompassing rapid phage screening, intelligent rational design, rigorous in vivo evaluation and standardized clinical validation processes, ultimately advancing engineered bacteriophage from laboratory innovations to clinically approved therapeutics for effectively combating MDR bacterial infections.

Connecting peptide (C-peptide), a byproduct of insulin biosynthesis, has diverse cellular and biological functions. Particulate mat-ter 2.5 (PM2.5 ) adversely affects human skin, leading to skin thickening, wrinkle formation, skin aging, and inflammation. This study aimed to investigate the protective effects of C-peptide against PM2.5 -induced damage to skin cells, focusing on oxidative stressas a key mechanism. C-peptide mitigated NADPH oxidation and intracellular reactive oxygen species (ROS) production inducedby PM2.5 . It also suppressed PM2.5 -induced NADPH oxidase (NOX) activity and alleviated PM2.5 -induced NOX1 and NOX4 expression. C-peptide protected against PM2.5 -induced DNA damage, lipid peroxidation, and protein carbonylation. Additionally, C-peptide mitigated PM2.5 -induced apoptosis by inhibiting intracellular ROS production. In summary, our findings suggest that C-peptide mitigates PM2.5 -induced apoptosis in human HaCaT keratinocytes by inhibiting intracellular ROS production and NOX activity.

γ-Radiation resistance is a major obstacle to the success of radiotherapy in colorectal cancer. Antioxidant-related factors contribute to resistance to radiation therapy and, therefore, are targets for improving the therapeutic response. In this study, we evaluated the molecular mechanisms underlying γ-radiation resistance using the colorectal cancer cell line SNUC5 and γ-radiation-resistant variant SNUC5/RR, including analyses of the role of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates antioxidant enzymes, and related epigenetic regulators. Reactive oxygen species (ROS) levels, antioxidant enzyme expression, NRF2 expression, and nuclear translocation were higher in SNUC5/RR cells irradiated with or without 8 Gy than in SNUC5 cells. The DNA demethylase ten-eleven translocation 1 (TET1) expression and TET1 binding to the NRF2 promoter in SNUC5/RR cells were stronger than those in SNUC5 cells, indicating lower methylation of CpG islands in the NRF2 promoter.TET1 knockdown in SNUC5/RR cells suppressed NRF2 expression significantly. Additionally, histone mixed-lineage leukemia (MLL), a histone methyltransferase, was upregulated, leading to increased trimethylation of histone H3 lysine 4, whereas enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, was downregulated, leading to decreased trimethylation of histone H3 lysine 27. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) levels were lower and higher in SNUC5/RR cells than in SNUC5 cells, respectively. MLL and HAT knockdown in SNUC5/RR cells irradiated with or without 8 Gy decreased levels of NRF2 and heme-oxygenase 1, resulting in enhanced γ-radiation sensitivity. These findings support NRF2 as a target for improving the response to radiotherapy in patients with colorectal cancer.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.