ObjectiveTo compare the clinical features of patients with hepatitis B virus （HBV）-related early-onset liver cancer and those with late-onset liver cancer， to assess the severity of the disease， and to provide a theoretical basis for the early diagnosis and treatment of liver cancer. MethodsA retrospective analysis was performed for 695 patients who were diagnosed with HBV-related liver cancer for the first time in Guangzhou Eighth People’s Hospital， Guangzhou Medical University， from January 2019 to August 2023， among whom 93 had early-onset liver cancer （defined as an age of50 years for female patients and40 years for male patients） and 602 had late-onset liver cancer （defined as an age of ≥50 years for female patients and ≥40 years for male patients）. Related clinical data were collected， including demographic data， clinical symptoms at initial diagnosis， comorbidities， smoking history， drinking history， family history， routine blood test results， biochemical parameters of liver function， serum alpha-fetoprotein（AFP）， virological indicators， coagulation function， and imaging findings. The pan-inflammatory indices neutrophil-to-lymphocyte ratio （NLR）， platelet-to-lymphocyte ratio （PLR）， and lymphocyte-to-monocyte ratio （LMR） were calculated， as well as FIB-4 index， aspartate aminotransferase-to-platelet ratio index （APRI）， S index， Model for End-Stage Liver Disease （MELD） score， Child-Turcotte-Pugh （CTP） score， albumin-bilirubin （AIBL） grade， and Barcelona Clinic Liver Cancer （BCLC） stage. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or Fisher’s exact test were used for comparison of categorical data between two groups. ResultsThere were significant differences between the two groups in the proportion of male patients and the incidence rates of diabetes， hypertension， and fatty liver disease （χ²=6.357， 15.230， 11.467， and 14.204， all P0.05）， and compared with the late-onset liver cancer group， the early-onset liver cancer group had a significantly higher proportion of patients progressing to liver cancer without underlying cirrhosis （χ²=24.657， P0.001） and a significantly higher proportion of patients with advanced BCLC stage （χ²=6.172， P=0.046）. For the overall population， the most common clinical symptoms included abdominal distension， abdominal pain， poor appetite， weakness， a reduction in body weight， edema of both lower limbs， jaundice， yellow urine， and nausea， and 55 patients （7.9%） had no obvious symptoms at the time of diagnosis and were found to have liver cancer by routine reexamination， physical examination suggesting an increase in AFP， or radiological examination indicating hepatic space-occupying lesion； compared with the late-onset liver cancer group， the patients in the early-onset liver cancer group were more likely to have the symptoms of abdominal distension， abdominal pain， and jaundice （all P0.05）. Compared with the late-onset liver cancer group， the early-onset liver cancer group had a significantly larger tumor diameter （Z=2.845， P=0.034）， with higher prevalence rates of multiple tumors and intrahepatic， perihepatic， or distant metastasis （χ²=5.889 and 4.079， both P0.05）， and there were significant differences between the two groups in tumor location and size （χ²=3.948 and 11.317， both P0.05）. Compared with the late-onset liver cancer group， the early-onset liver cancer group had significantly lower FIB-4 index， proportion of patients with HBsAg ≤1 500 IU/mL， and levels of LMR and Cr （all P0.05）， as well as significantly higher positive rate of HBeAg and levels of log₁₀ HBV DNA， AFP， WBC， Hb， PLT， NLR， PLR， TBil， ALT， Alb， and TC （all P0.05）. ConclusionCompared with late-onset liver cancer， patients with early-onset liver cancer tend to develop liver cancer without liver cirrhosis and have multiple tumors， obvious clinical symptoms， and advanced BCLC stage， which indicates a poor prognosis.

OBJECTIVES: To investigate the subcellular localization and biological functions of transmembrane protein 240 (TMEM240). METHODS: NCBI BLAST and TMHMM bioinformatics software were used for protein sequence analysis and prediction of transmembrane domain of TMEM240. Brain tissues from male C57BL/6 mice (18-20 days old) were examined for distribution of TMEM240 using in situ hybridization, and qPCR and Western blotting were used to detect TMEM240 expression in different mouse tissues and in cortical neurons at different time points (n=3). In the in vitro experiment, HepG2 and Neuro-2a cells were transfected with plasmids for overexpression of TMEM240, and subcellular localization of TMEM240 was analyzed using cell imaging. In primary cultures of cortical neurons isolated from C57BL/6 mice, TMEM240 expression and its biological functions were investigated using qPCR, Western blotting, and immunofluorescence staining. RESULTS: Human and mouse TMEM240 proteins share a 97.69% similarity in the protein sequences, and both are transmembrane proteins with two transmembrane domains. TMEM240 mRNA and protein were highly expressed in mouse brain tissues and cortical neurons. In isolated mouse cortical neurons, TMEM240 expression reached the peak level after primary culture for 9 days and distributed in scattered spots within the cells. In HepG2 cells, TMEM240 was characterized as intracellular membrane structures and showed 80% colocalization with peroxisomes. In Neuro-2a cells, TMEM240 overexpression caused significant enhancement of the expressions of Rho GDP dissociation inhibitor β (ARHGDIB) at both the mRNA and protein levels. CONCLUSIONS TMEM240 is a novel intracellular subcellular structure specifically expressed in neurons with significant potential for targeted cellular function regulation.
Animals ; Humans ; Mice ; Peroxisomes/metabolism* ; Membrane Proteins/genetics* ; Mice, Inbred C57BL ; Neurons/metabolism* ; Male ; rho-Specific Guanine Nucleotide Dissociation Inhibitors ; Hep G2 Cells ; Brain/metabolism*

Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

OBJECTIVE: Recent studies have overturned the traditional concept of the lung as a "sterile organ" revealing that pulmonary microbiota dysbiosis and abnormal surfactant proteins (SPs) expression are involved in the progression of silicosis. This study aimed to investigate the relationship between abnormal SPs expression and dysbiosis of lung microbiota in silica-induced lung fibrosis, providing insights into mechanisms of silicosis. METHODS: Lung pathology, SPs expression, and microbiota composition were evaluated in silica-exposed mice. A mouse model of antibiotic-induced microbiota depletion was established, and alveolar structure and SPs expression were assessed. The roles of the lung microbiota and SPs in silicosis progression were further evaluated in mice with antibiotic-induced microbiota depletion, both with and without silica exposure. RESULTS: Silica exposure induced lung inflammation and fibrosis, along with increased expression of SP-A expression. Antibiotics (Abx)-induced microbiota depletion elevated SP-A and SP-D expression. Furthermore, silica exposure altered lung microbiota composition, enriching potentially pathogenic taxa. However, antibiotic-induced microbiota depletion prior to silica exposure reduced silica-mediated lung fibrosis and inflammation. CONCLUSION Lung microbiota is associated with silica-induced lung injury. Overproduction of SP-A and SP-D, induced by Abx-induced microbiota depletion, may enhance the resistance of mouse lung tissue to silica-induced injury.
Animals ; Silicosis/prevention & control* ; Lung/metabolism* ; Mice ; Anti-Bacterial Agents/pharmacology* ; Microbiota/drug effects* ; Silicon Dioxide/toxicity* ; Mice, Inbred C57BL ; Male ; Pulmonary Surfactant-Associated Proteins/genetics*

Objective The aim of this study was to explore the role and mechanism of ferroptosis in SiO2-induced cardiac injury using a mouse model. Methods Male C57BL/6 mice were intratracheally instilled with SiO2 to create a silicosis model.Ferrostatin-1(Fer-1)and deferoxamine(DFO)were used to suppress ferroptosis.Serum biomarkers,oxidative stress markers,histopathology,iron content,and the expression of ferroptosis-related proteins were assessed. Results SiO2 altered serum cardiac injury biomarkers,oxidative stress,iron accumulation,and ferroptosis markers in myocardial tissue.Fer-1 and DFO reduced lipid peroxidation and iron overload,and alleviated SiO2-induced mitochondrial damage and myocardial injury.SiO2 inhibited Nuclear factor erythroid 2-related factor 2(Nrf2)and its downstream antioxidant genes,while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion Iron overload-induced ferroptosis contributes to SiO2-induced cardiac injury.Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO2 cardiotoxicity,potentially via modulation of the Nrf2 pathway.

Objective:Based on gene expression omnibus(GEO),differential expressed genes,gene set enrichment analysis(GSEA)and immune cell infiltration analysis were performed on microarray data of chronic spontaneous urticaria(CSU)expression profile,to gain more insight into the pathogenesis of CSU.Methods:The GSE72541 raw data were obtained from the GEO.Differential expressed genes were screened using R software.String database were used to construct the the protein-protein interaction(PPI)net-work.Gene ontology(GO)and Kyoto encyclopedia of gene and genomes(KEGG)enrichment analysis were performed using GSEA software.The ssGSEA method was used to analyze the infiltration of immune cells in the expression profile.Results:Genes closely related to platelet activation and its function were up-regulated in CSU serum,while genes related to Th1 cell chemotaxis were down-regulated in CSU serum.Biological processes and signal pathways related to coagulation cascade reaction,regulation of vascular per-meability,immune and inflammatory reactions,and mood-modulating were up-regulated in CSU group.Immunized cell infiltration analysis showed that activated B cells,immature B cells,follicular helper T cells,and Th2 cells were down-regulated in the CSU serum.Conclusion:Platelet activation,coagulation cascade reaction and the imbalance of Th1/Th2 immunity play important roles in the pathogenesis of CSU.

Objective:In order to construct a multisectoral cooperation evaluation index system for chronic disease prevention and control in the Healthy China strategy,so as to provide a reference for the evaluation and improvement of multisectoral cooperation work.Methods:The initial indicator system was constructed based on D'Amour's cooperative structure model.Fifteen public health experts were selected to refine the evaluation indicators through two rounds of expert consultation using the Delphi method.Then weights of indicators were assigned according to AHP.Results:Experts'positive coefficient,level of authority and coordination of opinions were confirmed.The finalized evaluation index system for multisectoral cooperation in chronic disease prevention and control contains 5 first-level indicators,12 second-level indicators and 34 third-level indicators.According to the weight,the indicators in first level were Shared Goals and Vision(0.222 8),Internalization(0.158 7),Formalization(0.252 3),Governance(0.154 5)and Cooperation effects(0.211 8).Conclusions:The evaluation index system applicable to multisectoral cooperation in the prevention and control of chronic diseases in counties(cities/districts)is preliminarily established,which is highly scientific and operable,and lays the foundation for the next step of application and promotion.

Objective To explore the correlation between daunorubicin(DNR)resistance and expression of pro-grammed death receptor ligand 1(PD-L1)in children with acute myeloid leukemia(AML).Methods Totally 110 bone marrow samples were selected from AML patients admitted to Zhengzhou University Affiliated Children's Hos-pital from January 2016 to December 2022 as the study group,50 bone marrow samples from normal bone marrow donors were used as the control group.Human AML cell lines HL60,THP-1,U-937,and Molm-13 were cultured,and the expression of PD-L1 protein was detected by Western blot.LV-PD-L1-shRNA and LV-PD-L1-WT-OE lenti-viral vectors were constructed.The effect and mechanism of PD-L1 on DNR resistance in Molm-13 cells were ana-lyzed.Results The expression level of PD-L1 protein was higher than that in control group and the expression level of PD-L1 protein in AMI cell lines was higher than that in healthy bone marrow mononuclear cells(BMMC)(P＜0.05).PD-L1 expression was related to white blood cell count,bone marrow primitive cell ratio,prognostic risk stratification and disease remission after two standard chemotherapy regimens in AML patients(P＜0.05).The overall survival rate of the PD-L1 high expression group was lower than that of the PD-L1 low expression group(P＜0.05).Compared with the LV-PD-L1-WT-OE group,the LV-PD-L1-shRNA group showed a decrease in PD-L1 mRNA expression,cell proliferation activity but an increased apoptosis rate(P＜0.05).LV-PD-L1-shRNA enhanced sensitivity of Molm-13 cells to DNR.TCGA database analysis showed that glucose 6-phosphate dehydro-genase(G6PD)was a potential target gene for PD-L1.Conclusions The high expression of PD-L1 in pediatric AML is related to chemotherapy resistance in children with AML,and DNR resistance might be caused through reg-ulation of G6PD.

Objective To investigate the effect of continuous intraoperative insulin infusion on my-ocardial blood perfusion after cardiac surgery under cardiopulmonary bypass(CPB).Methods Forty-eight patients,21 males and 27 females,aged 55-80 years,BMI 18-28 kg/m2,ASA physical status Ⅱ-Ⅳ,who underwent elective cardiac surgery with CPB were selected and randomly divided into two groups:the insulin group(group I,n = 25)and the control group(group C,n = 23).The same anesthesia protocol was implemented in both groups.After induction of anesthesia,group Ⅰ received intravenously infusion of in-sulin 30 mU·kg-1·h-1,glucose 0.12 g·kg-1·h-1,and potassium chloride 0.06 mmol·kg-1·h-1,and group C received saline 10 ml/h,all of which were infused until the end of surgery.The targeted blood glucose range for both groups was set at 6.1-11.1 mmol/L.Transesophageal echocardiography(TEE)was performed 10 minutes after induction of general anesthesia(T2)and before the end of surgery(T6)to ex-amine the coronary sinus(CS)flow spectrum and diameter,pulmonary venous flow spectrum,and calculate CS net antegrade flow velocity time integral(VTI).Femoral mean arterial pressure(MAP),central venous pressure(CVP),stroke volume(SV),cardiac index(CI)and peripheral vascular resistance index(SVRI)were recorded at T2,2 minutes before CPB(T3),the end of CPB(T5),and T6.The concentra-tions of blood glucose and lactate 5 minutes before anesthesia induction(T1),T3,30 minutes after CPB(T4),T5,T6,6 hours after surgery(T7),12 hours after surgery(T8),and 24 hours after surgery(T9)were recorded.The levels of high-sensitivity C-reactive protein(hs-CRP),high-sensitivity troponin I(hs-TnI),and creatine kinase isoenzyme(CK-MB)were recorded 1 day preoperatively,1 and 2 days post-operatively.Results Compared with group C,in group I,CS net antegrade flow VTI and blood flow per minute were significantly increased(P<0.05),and pulmonary venous peak atrial reversal wave velocity(ARp)was significantly reduced at T6(P<0.05),SV and CI were significantly increased and SVRI was significantly decreased at T5 and T6(P<0.05),lactate concentration was significantly decreased at T7 and T8(P<0.05),hs-CRP and CKMB were significantly decreased 1 and 2 days postoperatively(P<0.05),hs-TnI was significantly reduced 2 days postoperatively(P<0.05).Conclusion Continuous insulin admin-istration during cardiac surgery with CPB while maintaining blood glucose at 6.1-11.1 mmol/L can enhance myocardial blood perfusion,mitigate postoperative inflammatory response,and reduce myocardial injury.

Objective To investigate the correlation between blood glucose variability index(GLUCV)and postoperative delirium(POD)in elderly patients undergoing knee arthroplasty.Methods A total of 112 elderly patients undergoing elective knee arthroplasty were analyzed retrospectively,16 males and 96 females,aged 65-80 years,BMI 22.0-28.0 kg/m2,ASA physical status Ⅰ or Ⅱ.They were di-vided into two groups according to whether they had POD within 5 days after operation:POD group and non-POD group.The score of the last preoperative mini-mental state examination(MMSE),operation time,the duration of the intraoperative regional cerebral oxygen saturation(rScO2)value decreased by more than 13％of the rScO2 basic value(△rScO2＞13％),the preoperative hemoglobin(Hb)and C-reactive protein(CRP)concentration,the fingertip blood glucose concentration before entry,before anesthesia induction,5 minutes after anesthesia induction,1 minute after skin incision,and before leaving the chamber were col-lected,and the GLUCV was calculated.The risk factors of POD in elderly patients undergoing knee arthro-plasty were analyzed by univariate and multivariate logistic regression,and the odds ratio(OR)and 95％confidence interval(CI)were calculated.The receiver operating characteristic(ROC)curve was drawn to calculate the area under the curve(AUC)and analyze the predictive value of GLUCV.Results Thirty patients(26.8％)showed POD symptoms within 5 days after surgery.Compared with the non-POD group,the operation time and duration of intraoperative △rScO2＞13％in the POD group were significantly prolonged(P＜0.05),the CRP concentration and GLUCV were significantly increased(P＜0.05).Multi-variate logistic regression analysis showed that prolonged time of △rScO2＞13％(OR=3.542,95％CI 1.380-9.093,P=0.011),elevated CRP concentration(OR=1.984,95％CI 1.078-3.650.P=0.015),and elevated GLUCV(OR=5.257,95％CI 1.690-16.353,P=0.008)were risk factors of POD in elderly patients undergoing knee arthroplasty.ROC curve analysis showed that the area under the AUC of GLUCV in predicting POD in elderly patients undergoing knee arthroplasty was 0.747(95％CI 0.650-0.844,P＜0.001),while the optimal cutoff value was 23.4％,the sensitivity was 71.4％,and the specificity was 63.3％.Conclusion GLUCV is closely related to POD,and GLUCV level has a good pre-dictive effect on POD in elderly patients undergoing knee arthroplasty.