ObjectiveTo explore the therapeutic effect of Xuebijing injection （XBJ） on severe acute pancreatitis induced acute lung injury （SAP-ALI） by regulating formyl peptide receptors （FPRs）/nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） inflammatory pathway. MethodsSixty rats were randomly divided into a sham group， a SAP-ALI model group， low-， medium-， and high-dose XBJ groups （4， 8， and 12 mL·kg^-1）， and a positive drug （BOC2， 0.2 mg·kg^-1） group. For the sham group， the pancreas of rats was only gently flipped after laparotomy， and then the abdomen was closed， while for the remaining five groups， SAP-ALI rat models were established by retrograde injection of 5% sodium taurocholate （Na-Tc） via the biliopancreatic duct. XBJ and BOC2 were administered via intraperitoneal injection once daily for 3 d prior to modeling and 0.5 h after modeling. Blood was collected from the abdominal aorta 6 h after the completion of modeling， and the expression of interleukin （IL）-1β， IL-6， and tumor necrosis factor-α （TNF-α） in plasma was measured by enzyme-linked immunosorbent assay （ELISA）. The amount of ascites was measured， and the dry-wet weight ratios of pancreatic and lung tissue were determined. Pancreatic and lung tissue was taken for hematoxylin-eosin （HE） staining to observe pathological changes and then scored. The protein expression levels of FPR1， FPR2， and NLRP3 in lung tissue were detected by the immunohistochemical method. Western blot was used to detect the expression of FPR1， FPR2， and NLRP3 in lung tissue. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of FPR1， FPR2， and NLRP3 in lung tissue. ResultsCompared with the sham group， the SAP-ALI model group showed significantly decreased dry-wet weight ratio of lung tissue （P<0.01）， serious pathological changes of lung tissue， a significantly increased pathological score （P<0.01）， and significantly increased protein and mRNA expression levels of FPR1， FPR2， and NLRP3 in lung tissue （P<0.01）. After BOC2 intervention， the above detection indicators were significantly reversed （P<0.01）. After treatment with XBJ， the groups of different XBJ doses achieved results consistent with BOC2 intervention. ConclusionXBJ can effectively improve the inflammatory response of the lungs in SAP-ALI rats and reduce damage. The mechanism may be related to inhibiting the expression of FPRs and NLRP3 in lung tissue， which thereby reduces IL-1β and simultaneously antagonize the release of inflammatory factors IL-6 and TNF-α.

OBJECTIVE To evaluate the cost-effectiveness of finerenone combined with standard treatment regimen in the treatment of diabetic nephropathy （DN）. METHODS From the perspective of healthcare service providers， a Markov model was established to simulate the dynamic changes of each stage in DN patients who received finerenone combined with the standard treatment regimen or the standard treatment regimen alone based on the phase Ⅲ clinical trial study of finerenone for DN. Markov model was used to perform the cost-effectiveness of long-term effects and the costs of the two therapies with a simulation cycle of 4 months， a simulation period of 15 years and an annual discount rate of 5%. At the same time， one-way sensitivity analysis and probability sensitivity analysis were performed， and the stability of the results was validated. RESULTS Accumulative cost of the standard treatment regimen was 579 329.54 yuan， and the accumulative utility was 8.052 4 quality-adjusted life year （QALYs）； the accumulative cost of finerenone combined with the standard treatment regimen was 332 520.61 yuan， and the accumulative utility was 8.187 4 QALYs. Finerenone combined with the standard treatment regimen was more cost-effective. The results of one-way sensitivity analysis showed that dialysis status utility value， DN stage 3 utility value and DN stage 4 utility value had a great influence on the incremental cost-effectiveness ratio， but did not affect the robustness of the model. The results of probability sensitivity analysis showed that finerenone combined with the standard treatment regimen was more cost-effective with 100% probability. CONCLUSIONS For DN patients， finerenone combined with the standard treatment regimen is more cost-effective as an absolute advantage option.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

OBJECTIVES: Ruptured abdominal aortic aneurysm (rAAA) is a life-threatening vascular emergency with extremely high in-hospital mortality. Open surgical repair (OSR) was historically the only treatment option but is associated with substantial trauma and perioperative risk. In recent years, endovascular repair (EVAR) has gained widespread use due to its minimally invasive nature and faster recovery, becoming the preferred option for anatomically suitable patients in many centers. However, controversy remains regarding the long-term survival benefits of EVAR compared with OSR and key prognostic factors affecting outcomes. This study aims to evaluate the clinical efficacy of OSR and EVAR for rAAA and identify independent predictors of postoperative survival to guide clinical decision-making. METHODS: A retrospective analysis was conducted on 83 patients diagnosed with rAAA and treated surgically in the Department of Vascular Surgery, the Second Xiangya Hospital of Central South University, between January 2013 and December 2022. Patients were divided into an OSR group and an EVAR group based on surgical approach. Baseline clinical characteristics, perioperative data, and follow-up outcomes were compared between groups. Long-term survival was analyzed, and univariate and multivariate Cox proportional hazards regression models were used to determine independent prognostic factors. RESULTS: Among the 83 patients, 32 (38.6%) underwent OSR and 51 (61.4%) received EVAR, with the proportion of EVAR steadily increasing to nearly 80% in the most recent 5 years. Patients in the EVAR group were older [(68.76±8.57) years vs (60.59±13.24) years, P=0.012], and had a lower proportion of males (76.5% vs 96.9%, P=0.013). EVAR significantly reduced operating time [(181.86±69.87) min vs (291.09±60.33) min] and hospital stay [(12.14±6.31) days vs (16.22±7.89) days (P<0.05)], but total hospitalization costs were markedly higher [(208 735.84±101 394.19) yuan vs (84 893.35±40 668.56) yuan, P<0.001]. There were no significant differences between groups in 30-day mortality (15.6% vs 15.7%), aneurysm-related mortality (9.4% vs 11.7%), overall mortality (28.1% vs 29.4%), or re-intervention rate (0 vs 5.9%) (P>0.05). The median follow-up time was 54.6 months (range, 12-144 months). Kaplan-Meier survival analysis showed comparable cumulative survival rates between OSR and EVAR (82.7% vs 76.2%, P=0.420). Cox regression identified hyperlipidemia [hazard ratio (HR)=2.32, 95% confidence interval (CI) 1.28 to 4.19, P=0.005] and elevated preoperative serum creatinine (HR=3.33, 95% CI 1.69 to 6.55, P<0.001) as significant predictors of poor prognosis. Both factors remained independently associated with mortality in the multivariate model (hyperlipidemia: HR=2.02, 95% CI 1.10 to 3.70; elevated serum creatinine: HR=2.77, 95% CI 1.40 to 5.47; P<0.05). CONCLUSIONS EVAR offeres advantages in operative and recovery times, though its long-term survival outcomes are comparable to OSR. A history of hyperlipidemia and elevated preoperative creatinine levels are independent predictors of poor prognosis. Surgical approach should be chosen based on anatomical feasibility and patient condition, with close management of lipid levels and renal function to improve outcomes.
Humans ; Aortic Aneurysm, Abdominal/mortality* ; Endovascular Procedures/methods* ; Retrospective Studies ; Male ; Female ; Prognosis ; Aged ; Aortic Rupture/mortality* ; Middle Aged ; Treatment Outcome ; Aged, 80 and over

Fractional flow reserve (FFR), an established modality for functionally assessing coronary artery disease, is increasingly applied to diagnose and manage lower extremity arterial disease. By incorporating functional parameters, FFR enhances revascularization precision by quantifying the hemodynamic impact of stenotic lesions, thereby overcoming limitations of conventional imaging. Key clinical applications in lower extremity disease include functional assessment in moderate intermittent claudication, post-vascular preparation strategy optimization, and predicting revascularization outcomes and complications. Advances in pressure wire and microcatheter systems, alongside non-invasive imaging-derived FFR techniques, are improving its feasibility and applicability. However, widespread adoption is challenged by the complex anatomy of the lower extremity arterial system, frequent severe calcification and diffuse disease, and a current lack of standardized FFR cutoff values. Promoting the standardized use of FFR is crucial for shifting the clinical management paradigm from anatomy-based repair toward functional reconstruction.
Humans ; Lower Extremity/blood supply* ; Peripheral Arterial Disease/diagnosis* ; Fractional Flow Reserve, Myocardial ; Endovascular Procedures/methods* ; Intermittent Claudication/physiopathology*

The incomplete degradation of tumour cells by macrophages (Mϕ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mϕ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mϕ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mϕ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mϕ phagosomes, causing Mϕ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mϕ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mϕ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mϕ to degrade tumour cells by suppressing NOX2.

Objective To investigate the prognostic value of M2 macrophage-related genes(MRG)in hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC).Methods The transcriptome data of 73 patients with HBV-related HCC were obtained from TCGA database,and the MRG modules were identified by WGCNA.The MRG-based risk scoring model was constructed by LASSO regression analysis and validated using an external dataset.The correlation of the risk score with immune cell infiltration and drug sensitivity of HCC were analyzed with CIBERSORT and R.pRRophetic.The signaling pathways of the differential genes between the high-and low-risk groups were investigated using GSVA and GSEA enrichment analyses,and MRG expressions at the single cell level were validated using R.Seurat.The cell interaction intensity was analyzed by R.Cellchat to identify important cell types related to HCC progression.MRG expression levels were detected by RT-qPCR in THP-1 cells with HCC-conditioned medium-induced M2 polarization and in HBV-positive HCC cells.Results A high M2 macrophage infiltration level was significantly correlated with a poor prognosis of HCC,and 5 hub MRG(VTN,GCLC,PARVB,TRIM27,and GMPR)were identified.The overall survival of HCC patients was significantly lower in the high-risk than in the low-risk group.The high-and the low-risk groups showed significant enrichment of M2 macrophages and na?ve B cells,respectively,and were sensitive to BI.2536 and to AG.014699,AKT.inhibitor.Ⅷ,AZD.0530,AZD7762,and BMS.708163,respectively.The proliferation-related and metabolism-related pathways were enriched in the high-risk group,where monocytes showed the most active cell interactions during HCC progression.VTN was significantly upregulated in HCC cell lines,while GCLC,PARVB,TRIM27,and GMPR were upregulated in M2 THP-1 cells.Conclusion The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients.

Background::Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model.Methods::Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan–Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. Results::HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days ( P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4 + and CD8 + T cells in the spleen ( P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes ( CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF) -β pathway-related genes and Treg signature genes ( CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4 + Foxp3 + cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. Conclusions::HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

Objective To investigate the prognostic value of M2 macrophage-related genes(MRG)in hepatitis B virus(HBV)-related hepatocellular carcinoma(HCC).Methods The transcriptome data of 73 patients with HBV-related HCC were obtained from TCGA database,and the MRG modules were identified by WGCNA.The MRG-based risk scoring model was constructed by LASSO regression analysis and validated using an external dataset.The correlation of the risk score with immune cell infiltration and drug sensitivity of HCC were analyzed with CIBERSORT and R.pRRophetic.The signaling pathways of the differential genes between the high-and low-risk groups were investigated using GSVA and GSEA enrichment analyses,and MRG expressions at the single cell level were validated using R.Seurat.The cell interaction intensity was analyzed by R.Cellchat to identify important cell types related to HCC progression.MRG expression levels were detected by RT-qPCR in THP-1 cells with HCC-conditioned medium-induced M2 polarization and in HBV-positive HCC cells.Results A high M2 macrophage infiltration level was significantly correlated with a poor prognosis of HCC,and 5 hub MRG(VTN,GCLC,PARVB,TRIM27,and GMPR)were identified.The overall survival of HCC patients was significantly lower in the high-risk than in the low-risk group.The high-and the low-risk groups showed significant enrichment of M2 macrophages and na?ve B cells,respectively,and were sensitive to BI.2536 and to AG.014699,AKT.inhibitor.Ⅷ,AZD.0530,AZD7762,and BMS.708163,respectively.The proliferation-related and metabolism-related pathways were enriched in the high-risk group,where monocytes showed the most active cell interactions during HCC progression.VTN was significantly upregulated in HCC cell lines,while GCLC,PARVB,TRIM27,and GMPR were upregulated in M2 THP-1 cells.Conclusion The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients.

BACKGROUND: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. METHODS: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. RESULTS: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05). CONCLUSIONS The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; China ; Prognosis ; Transcription Factors