Background Silicosis, caused by inhalation of silica (SiO₂) dust, remains the most prevalent occupational pneumoconiosis in China. While galectin-3 (Gal-3) is known to play pro-inflammatory and pro-fibrotic roles in various diseases, its specific mechanism in the pathogenesis of silicosis has not been fully clarified. Objective To investigate the role and underlying mechanisms of Gal-3 in silicosis using clinical samples of silicosis and a silicosis mouse model. Methods Lung nodule biopsy samples were collected from patients with stage III pneumoconiosis. Concurrently a silicosis mouse model was constructed via non-exposed tracheal intubation with instillation of a SiO₂ suspension. The expression levels of Gal-3 mRNA and protein in the lung tissues of the silicosis model mice were then detected using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) staining. Single-cell transcriptomic sequencing (scRNA-seq) was performed on both human and murine lung samples to analyze the expression of the Gal-3-encoding gene Lgals3 across different cell types. In vitro, RAW264.7 macrophages were treated with varying concentrations of SiO₂ suspension for 24 h and 48 h; the expression levels of Gal-3 mRNA and protein were measured by RT-qPCR and Western blot. The Gal-3 inhibitor TD139 was used to intervene in the SiO₂-induced in vitro macrophage model, and Western blot was used to detect the intracellular expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). Finally, mouse embryonic lung fibroblasts NIH/3T3 and Mlg2908 were treated with varying concentrations of recombinant mouse Gal-3 protein (rmGal-3) for 48 h, and Western blot was used to detect the expression of fibrosis markers [(Collagen I, Collagen III, Fibronectin, and α smooth muscle actin (α-SMA)] and proteins associated with the TGF-β1/Smads signaling pathway. Results RT-qPCR and IHC staining showed that both the gene and protein expression levels of Gal-3 were significantly elevated at all consecutive time points in the silicosis mouse model (P < 0.05). scRNA-seq revealed that Lgals3 was aberrantly highly expressed in lung tissues from pneumoconiosis patients and silicosis mouse models, with the highest expression observed in macrophages. After treatment of macrophages with different concentrations of SiO₂ for 24 h and 48 h, the mRNA and protein expression levels of Gal-3 were significantly upregulated compared with the control group (P < 0.05). Following TD139 intervention, the protein expression levels of IL-1β, TNF-α, and TGF-β1 in dust-exposed macrophages were markedly downregulated (P < 0.0001). After 48 h of stimulation with rmGal-3, the protein expression levels of Collagen I, Fibronectin, and α-SMA in mouse embryonic lung fibroblasts (NIH/3T3 and Mlg2908) were significantly increased in all treatment groups compared with the control group (P < 0.01). Moreover, Gal-3 treatment markedly upregulated TGF-β1 protein expression in Mlg2908 cells and enhanced the phosphorylation levels of Smad2 and Smad3 (P < 0.0001). Conclusion Gal-3 is abnormally expressed in silicotic lung tissues, which primarily originates from macrophages, and inhibition of Gal-3 suppresses SiO₂-induced inflammatory and pro-fibrotic responses. In addition, Gal-3 promotes fibroblast differentiation and extracellular matrix production by activating the TGF-β1/Smads signaling pathway.

Background Silicosis, caused by inhalation of silica (SiO₂) dust, remains the most prevalent occupational pneumoconiosis in China. While galectin-3 (Gal-3) is known to play pro-inflammatory and pro-fibrotic roles in various diseases, its specific mechanism in the pathogenesis of silicosis has not been fully clarified. Objective To investigate the role and underlying mechanisms of Gal-3 in silicosis using clinical samples of silicosis and a silicosis mouse model. Methods Lung nodule biopsy samples were collected from patients with stage III pneumoconiosis. Concurrently a silicosis mouse model was constructed via non-exposed tracheal intubation with instillation of a SiO₂ suspension. The expression levels of Gal-3 mRNA and protein in the lung tissues of the silicosis model mice were then detected using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) staining. Single-cell transcriptomic sequencing (scRNA-seq) was performed on both human and murine lung samples to analyze the expression of the Gal-3-encoding gene Lgals3 across different cell types. In vitro, RAW264.7 macrophages were treated with varying concentrations of SiO₂ suspension for 24 h and 48 h; the expression levels of Gal-3 mRNA and protein were measured by RT-qPCR and Western blot. The Gal-3 inhibitor TD139 was used to intervene in the SiO₂-induced in vitro macrophage model, and Western blot was used to detect the intracellular expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). Finally, mouse embryonic lung fibroblasts NIH/3T3 and Mlg2908 were treated with varying concentrations of recombinant mouse Gal-3 protein (rmGal-3) for 48 h, and Western blot was used to detect the expression of fibrosis markers [(Collagen I, Collagen III, Fibronectin, and α smooth muscle actin (α-SMA)] and proteins associated with the TGF-β1/Smads signaling pathway. Results RT-qPCR and IHC staining showed that both the gene and protein expression levels of Gal-3 were significantly elevated at all consecutive time points in the silicosis mouse model (P < 0.05). scRNA-seq revealed that Lgals3 was aberrantly highly expressed in lung tissues from pneumoconiosis patients and silicosis mouse models, with the highest expression observed in macrophages. After treatment of macrophages with different concentrations of SiO₂ for 24 h and 48 h, the mRNA and protein expression levels of Gal-3 were significantly upregulated compared with the control group (P < 0.05). Following TD139 intervention, the protein expression levels of IL-1β, TNF-α, and TGF-β1 in dust-exposed macrophages were markedly downregulated (P < 0.0001). After 48 h of stimulation with rmGal-3, the protein expression levels of Collagen I, Fibronectin, and α-SMA in mouse embryonic lung fibroblasts (NIH/3T3 and Mlg2908) were significantly increased in all treatment groups compared with the control group (P < 0.01). Moreover, Gal-3 treatment markedly upregulated TGF-β1 protein expression in Mlg2908 cells and enhanced the phosphorylation levels of Smad2 and Smad3 (P < 0.0001). Conclusion Gal-3 is abnormally expressed in silicotic lung tissues, which primarily originates from macrophages, and inhibition of Gal-3 suppresses SiO₂-induced inflammatory and pro-fibrotic responses. In addition, Gal-3 promotes fibroblast differentiation and extracellular matrix production by activating the TGF-β1/Smads signaling pathway.

Objective To elucidate the changes in the gut microbiota and molecular mechanism of huaier in enhancing the efficacy of oxaliplatin (OXA) chemotherapy in gastric cancer (GC). Methods The effects of huaier on the gut microbiota structure and intestinal barrier function in MKN45-bearing mice were analyzed by using 16S rRNA sequencing, RT-qPCR, and IHC. UPLC-MS and network pharmacology, as well as in vivo experimental approaches, were employed to investigate the key bioactive constituents of huaier systematically and elucidate the underlying mechanisms by which huaier exerts therapeutic effects against GC. The expression of the PI3K/AKT/SREBP pathway was detected in cancer cells and tissues via Western blot analysis. The safety profile of huaier combined with OXA was verified through serum biochemistry and HE-stained tissue section analyses. Results Huaier inhibited the PI3K/AKT/SREBP pathway by increasing the abundance of Akkermansia muciniphila, reduced lipid droplet deposition, and ultimately enhanced the sensitivity to OXA in the treatment of GC. Conclusion This study demonstrates the value of huaier in gastric cancer treatment by enhancing chemosensitivity and provides novel insights into its systemic therapeutic effects through molecular mechanisms and gut microbiota modulation.

OBJECTIVE: To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. METHODS: Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). RESULTS: In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. CONCLUSION This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families.
Humans ; Female ; Male ; Pedigree ; Exostoses, Multiple Hereditary/diagnosis* ; N-Acetylglucosaminyltransferases/genetics* ; Adult ; Exostosin 1 ; Asian People/genetics* ; Genetic Testing ; Exostosin 2 ; Mutation ; China ; Prenatal Diagnosis ; Pregnancy ; Genetic Counseling ; Preimplantation Diagnosis ; Exome Sequencing ; East Asian People

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is the primary cause of mortality in sepsis, with its core pathophysiological mechanism being severe ischemia and hypoxia in critical units—composed of microcirculation and the mitochondria of functional cells—resulting from disruptions in blood flow and oxygen flow following a dysregulated host response. Due to the systemically convergent yet clinically heterogeneous nature of the host response, current understanding and management strategies for hemodynamics remain inconsistent, often leading to inadequate resuscitation or overtreatment. To improve the quality of care, based on a systematic review of the "blood flow-oxygen flow" theory, an expert panel emphasizes reevaluating septic shock from an integrated perspective of blood flow and oxygen flow, and has formulated the Expert Consensus on Blood Flow and Oxygen Delivery Phenotyping and Clinical Management of Septic Shock (2025). The consensus proposes that clinical typing of blood flow-oxygen flow should comprehensively consider cardiac function, vascular tone, oxygen flow utilization status in critical units, and disease trajectory, while optimizing subtype identification by integrating host response phenotypes and artificial intelligence technologies. It advocates establishing a continuous assessment system through multi-site oxygen flow monitoring for organ perfusion, peripheral perfusion monitoring, and critical care ultrasound. Under the framework of the "critical care triangle", the consensus promotes the implementation of individualized, bundled management strategies, providing guidance for multiple management points to restore blood flow-oxygen flow matching, reduce the risk of organ failure, and decrease patient mortality.

ObjectiveTo investigate whether macrophage lipolysis-stimulated lipoprotein receptor （LSR） deficiency affects the progression of metabolic dysfunction-associated steatohepatitis （MASH） by activating the Yes-associated protein （YAP） signaling pathway. MethodsMale wild-type （WT） mice and macrophage-specific Lsr knockout （Lsr^MφKO， KO） mice， with an age of 8 weeks and similar body weights， were selected and fed with a normal diet， a high-fat diet （HFD）， or a high-fat high-cholesterol （HFHC） diet for 30 weeks. HE staining and oil red O staining were used to evaluate liver pathological changes； immunofluorescent staining was used to measure the expression levels of F4/80 and α-smooth muscle actin； RT-qPCR and Western blot were used to measure the levels of markers associated with lipid metabolism， inflammation， and fibrosis. Bone marrow transplantation rescue experiments （WT→KO vs KO→KO groups） were conducted to explore the functional role of LSR in macrophages. At the cellular level， hepatic macrophages were isolated from WT and KO mice to measure the expression levels of YAP signaling pathway-related proteins and their downstream target genes， and in addition， these cells were treated in vitro with verteporfin （VP）， a specific inhibitor of YAP， to verify the regulatory effect of this pathway on the expression of inflammatory factors. The independent samples t-test was used for comparison of normally distributed measurement data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed measurement data. ResultsUnder the condition of normal diet， there were no significant differences in hepatic indicators between WT and KO mice. KO mice fed an HFD or HFHC diet showed a significant increase in hepatic lipid droplet accumulation， accompanied by lipid metabolism disorder and significant increases in the levels of indicators associated with inflammation and fibrosis （P<0.05）. Bone marrow transplantation experiments confirmed that compared with the KO→KO group， the WT→KO group had significant alleviation of liver injury （P<0.05）. Mechanistic studies showed that there were significant reductions in the levels of phosphorylated large tumor suppressor kinase 1 （LATS1） and phosphorylated YAP and significant increases in the expression levels of total YAP protein and its downstream target genes in hepatic macrophages of KO mice （P<0.05）. In vitro VP intervention significantly inhibited the expression levels of inflammatory factors in hepatic macrophages isolated from KO mice （P<0.05）. ConclusionMacrophage LSR deficiency activates the YAP signaling pathway by inhibiting LATS1/2 kinase activity and promotes the expression of inflammatory factors， thereby accelerating the progression of liver injury in a mouse model of MASH.

The traditional detection methods for monitoring the biomass,protein,chlorophyll content and other key indicators in the growth of chlorella have some problems,including complicated operation,slow detection speed and difficult large-scale application.In this study,a fast and efficient monitoring method for the key indicators in the growth of chlorella was established using near infrared spectroscopy and chemometrics.Near-infrared spectroscopy was used to collect near-infrared spectra of chlorella algal fluid at different growth stages,and standard methods were used to detect the biomass,protein and chlorophyll contents of corresponding samples.A quantitative analysis model was established based on partial least squares regression(PLSR).To improve the prediction ability of the model,multiplicative scatter correction(MSC)was used to reduce the interference of scattering on the raw spectrum(RS),standard normal variate(SNV)was used to normalize the original spectral data to eliminate differences between samples,continuous wavelet transform(CWT)was used to obtain the key features of spectral data,the first derivative(1st)was used to enhance the differentiation of the original spectral features,and monte carlo-uninformative variable elimination(MC-UVE)and randomization test(RT)were used to screen the valid variables in the wavelength.By evaluating the prediction ability of different models,the quantitative analysis models of chlorella biomass,protein and chlorophyll content were finally determined.The results showed that the model based on 1st combined with RT spectra had better predictive ability for chlorella nutrient content detection,and the root mean square errors of prediction(RMSEP)and coefficients of determination(R2)were 0.041 and 0.933 for biomass,0.012 and 0.973 for protein,and 0.517 and 0.962 for chlorophyll,respectively.This model showed practical application value,and could realize the rapid and accurate detection of chlorella biomass,protein and chlorophyll content at the same time.

Objective To retrospectively analyze the changes in cerebral blood flow(CBF)of hippocampus before and after radiotherapy(RT)and to explore its relationship with dose for providing a feasible approach for dynamically monitoring hippocampal response after whole brain radiation therapy in patients with brain metastases(BMs).Methods A retrospective analysis was conducted on magnetic resonance(MR)images from 43 BMs patients before and after RT,including T1-weighted imaging(T1WI)and three-dimensional arterial spin labeling(3D-ASL)imaging.Manual segmentation of the hippocampal structures was performed on T1WI to determine hippocampal volume,while CBF within the hippocampus was derived from 3D-ASL images.Patients were categorized into different groups according to the time interval between two MR scans and the dose received by the hippocampus,namely short time interval[<30 d,with an average of(19.74±7.15)d]≤1 Gy,1-30 Gy and≥30 Gy groups;long time interval[>3 months,with an average of(495.50±226.06)d]≤1 Gy,1-30 Gy and≥30 Gy groups.The patterns of changes in hippocampal CBF and volume,as well as the dose-effect relationship following RT were analyzed.Results(1)A total of 86 hippocampi were enrolled,showing reductions of 8.32%in minimum CBF(CBF-min),7.31%in maximum CBF(CBF-max),8.09%in mean CBF(CBF-mean),and 4.11%in hippocampal volume after RT(P<0.05).The decrease rates of CBF-min,CBF-max and CBF-mean were 6.33%,7.01%and 8.23%higher than the reduction rate of hippocampal volume,respectively.(2)With a brief interval between two MR simulation localization scans,hippocampal CBF in the groups receiving≤1 Gy and 1-30 Gy exhibited an increase,with the increase rate positively correlated to the radiation dose absorbed by the hippocampus.Conversely,in the group receiving≥30 Gy,hippocampal CBF decreased.The variations in the rate of hippocampal CBF change across the dose groups were statistically significant,except when comparing≤1 Gy and 1-30 Gy groups(P<0.05).Additionally,the hippocampal volume in all 3 dose groups experienced a slight increase,with the growth rate also positively correlated to the radiation dose received by the hippocampus;however,these differences were not statistically significant(P>0.05).(3)With a long interval between MR simulation localization scans,both hippocampal CBF and volume in all 3 dose groups demonstrated decreasing trends,with the decrease rate positively correlated to the radiation dose received by the hippocampus.Statistically significant differences in the rate of CBF change were noted among the dose groups,except for the comparison between≤1 Gy and 1-30 Gy groups(P<0.05).The reduction rate of hippocampal volume across 3 dose groups was statistically significant(P<0.05).Conclusion The reduction in hippocampal CBF following RT in BMs patients is more sensitive than the reduction in hippocampal volume,exhibiting a pronounced dependence on both time and radiation dose.Consequently,CBF changes should be employed as a standard bioindicator for monitoring the response to hippocampal RT and predicting radiological injuries after whole brain radiotherapy in BMs patients.

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.

Objective To summarize the changing prevalence of carbapenem resistance in Enterobacterales based on the data of CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021 for improving antimicrobial treatment in clinical practice.Methods Antimicrobial susceptibility testing was performed using a commercial automated susceptibility testing system according to the unified CHINET protocol.The results were interpreted according to the breakpoints of the Clinical & Laboratory Standards Institute(CLSI)M100 31st ed in 2021.Results Over the seven-year period(2015-2021),the overall prevalence of carbapenem-resistant Enterobacterales(CRE)was 9.43％(62 342/661 235).The prevalence of CRE strains in Klebsiella pneumoniae,Citrobacter freundii,and Enterobacter cloacae was 22.38％,9.73％,and 8.47％,respectively.The prevalence of CRE strains in Escherichia coli was 1.99％.A few CRE strains were also identified in Salmonella and Shigella.The CRE strains were mainly isolated from respiratory specimens(44.23±2.80)％,followed by blood(20.88±3.40)％and urine(18.40±3.45)％.Intensive care units(ICUs)were the major source of the CRE strains(27.43±5.20)％.CRE strains were resistant to all the β-lactam antibiotics tested and most non-β-lactam antimicrobial agents.The CRE strains were relatively susceptible to tigecycline and polymyxins with low resistance rates.Conclusions The prevalence of CRE strains was increasing from 2015 to 2021.CRE strains were highly resistant to most of the antibacterial drugs used in clinical practice.Clinicians should prescribe antimicrobial agents rationally.Hospitals should strengthen antibiotic stewardship in key clinical settings such as ICUs,and take effective infection control measures to curb CRE outbreak and epidemic in hospitals.