Homeobox B4 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on endotoxin-associated acute lung injury in rats.

BACKGROUND: Alveolar capillary endothelial cell (EC) injury has a pivotal role in driving acute respiratory distress syndrome (ARDS) progression and maintaining endothelial homeostasis. A previous ex vivo study revealed that overexpression of homeobox B4 (HOXB4) in bone marrow mesenchymal stem cells (BMSCs) enhanced protection against lipopolysaccharide (LPS)-induced EC injury by activating the Wnt/ß-catenin pathway. This in vivo study was performed to verify whether BMSCs overexpressing HOXB4 exert similar protective effects on LPS-induced acute lung injury (ALI) in an animal model. METHODS: The ALI rat model was established by intraperitoneal injection of LPS. Wildtype BMSCs or BMSCs overexpressing HOXB4 were then injected via the tail vein. The lung characteristics of rats were visualized by computed tomography. Lung histopathological characteristics and collagen deposition were assessed by hematoxylin-eosin and Masson's staining, respectively, which were combined with the lung wet/dry ratio and proinflammatory factor levels in bronchoalveolar lavage fluid to further evaluate therapeutic effects. Expression of ß-catenin and VE-cadherin was assessed by western blotting and immunofluorescence. RESULTS: Compared with wildtype BMSCs, overexpression of HOXB4 optimized the therapeutic effects of BMSCs, which manifested as improvements in lung exudation and histopathological features, reduced lung collagen deposition, amelioration of lung permeability, attenuation of lung inflammation, and enhanced expression of ß-catenin and VE-cadherin proteins. CONCLUSIONS: HOXB4-overexpressing BMSCs optimized the protective effect against LPS-induced ALI by partially activating Wnt/ß-catenin signaling.

Overexpression of Wnt5a promoted the protective effect of mesenchymal stem cells on Lipopolysaccharide-induced endothelial cell injury via activating PI3K/AKT signaling pathway.

BACKGROUND: Lung endothelial barrier injury plays an important role in the pathophysiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) therapy has shown promise in ARDS treatment and restoration of the impaired barrier function. It has been reported that Wnt5a shows protective effects on endothelial cells. Therefore, the study aimed to investigate whether overexpression of Wnt5a could promote the protective effects of MSCs on Lipopolysaccharide (LPS)-induced endothelial cell injury. METHODS: To evaluate the protective effects of MSCs overexpressing Wnt5a, we assessed the migration, proliferation, apoptosis, and angiogenic ability of endothelial cells. We assessed the transcription of protective cellular factors using qPCR and determined the molecular mechanism using Western blot analysis. RESULTS: Overexpression of Wnt5a upregulated the transcription of protective cellular factors in MSCs. Co-culture of MSCWnt5a promoted endothelial migration, proliferation and angiogenesis, and inhibited endothelial cell apoptosis through the PI3K/AKT pathway. CONCLUSIONS: Overexpression of Wnt5a promoted the therapeutic effect of MSCs on endothelial cell injury through the PI3K/AKT signaling. Our study provides a novel approach for utilizing genetically modified MSCs in the transplantation therapy for ARDS.

Association between red blood cell distribution width-to-platelet ratio and post-discharge readmission rate in patients with heart failure: A retrospective cohort study.

Background: To date, no studies have investigated the association between red blood cell distribution width (RDW)-to-platelet ratio (RPR) and readmission rates among patients with heart failure (HF). As such, the present study aimed to examine the relationship between RPR and readmission rates in patients with HF. Methods: Data for this study were obtained from the Fourth People's Hospital (Zigong, Sichuan Province, China). Patients were diagnosed with HF in accordance with European Society of Cardiology criteria. The primary outcome was the 28-day readmission rate. Various logistic regression models were constructed to explore the association between RPR and the 28-day readmission rate. Results: The study comprised 1978 patients with HF, with a 28-day readmission rate of 6.98%. RPR emerged as an independent risk factor for 28-day readmission, evidenced by consistent results across the various regression-adjusted models. The covariate-adjusted propensity score model demonstrated that every 0.1 increase in RPR was associated with an 8.2% increase in 28-day readmission rate (odds ratio [OR] 1.082 [95% confidence interval (CI) 1.012-1.158]; P = 0.0212). Similarly, each 0.1 change in RPR was associated with a 9.8% (OR 1.098 [95% CI 1.014-1.188]) and 7.3% (OR 1.073 [95% CI 0.991-1.161]) increase in 3- and 6-month readmission rates, respectively. However, RPR was not statistically associated with the 6-month readmission rate. Curve fit plots illustrated a nonlinear positive correlation between RPR and 28-day, and 3- and 6-month readmissions. Moreover, the effects of RPR on 28-day, and 3- and 6-month readmission rates remained robust across subgroup variables in stratified analysis. Finally, the effect sizes of pooled multiply imputed data were consistent with the original data, suggesting robust results. Conclusion: RPR was an independent risk factor for 28-day readmission among patients with HF and also demonstrated modest predictive value for readmissions at 3 and 6 months, despite being non-significant for the 6-month readmission rate. Early identification of patients with HF with elevated RPR would facilitate management and may confer favorable effects on prognosis.

Causal association of circulating cytokines with sepsis: a Mendelian randomization study.

Background: Observational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR). Methods: We performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Results: We found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (ß-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. Conclusion: This MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and ß-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.

Association between ICU admission (neutrophil + monocyte)/lymphocyte ratio and 30-day mortality in patients with sepsis: a retrospective cohort study.

BACKGROUND: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. METHODS: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P = 0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P = 0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P < 0.0001). CONCLUSION: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.

Association Between ICU admission (Neutrophil + Monocyte)/Lymphocyte Ratio And 30-Day Mortality in Patients with Sepsis: A Retrospective Study from MIMIC-IV.

Background: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. Methods: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P=0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P=0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P<0.0001). Conclusion: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.

Overexpression of FoxM1 Enhanced the Protective Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Lipopolysaccharide-Induced Acute Lung Injury through the Activation of Wnt/ß-Catenin Signaling.

Background: Mesenchymal stem cell- (MSC-) based cell and gene therapies have made remarkable progress in alleviating acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the benefits of Forkhead box protein M1 (FoxM1) gene-modified MSCs in the treatment of ALI have not been studied. Methods: We evaluated the therapeutic effects of FoxM1-modified MSCs in ALI mice induced by lipopolysaccharide (LPS) by quantifying the survival rate, lung weight ratio (wet/dry), and contents of bronchoalveolar lavage fluid. In addition, microcomputed tomography, histopathology, Evans Blue assay, and quantification of apoptosis were performed. We also explored the underlying mechanism by assessing Wnt/ß-catenin signaling following the treatment of mice with FoxM1-modified MSCs utilizing the Wnt/ß-catenin inhibitor XAV-939. Results: Compared with unmodified MSCs, transplantation of FoxM1-modified MSCs improved survival and vascular permeability; reduced total cell counts, leukocyte counts, total protein concentrations, and inflammatory cytokines in BALF; attenuated lung pathological impairments and fibrosis; and inhibited apoptosis in LPS-induced ALI/ARDS mice. Furthermore, FoxM1-modified MSCs maintained vascular integrity during ALI/ARDS by upregulating Wnt/ß-catenin signaling, which was partly reversed via a pathway inhibitor. Conclusion: Overexpression of FoxM1 optimizes the treatment action of MSCs on ALI/ARDS by inhibiting inflammation and apoptosis and restoring vascular integrity partially through Wnt/ß-catenin signaling pathway stimulation.

USP22 promotes development of lung adenocarcinoma through ubiquitination and immunosuppression.

Ubiquitin-specific protease 22 (USP22) expresses highly in lung adenocarcinoma (LUAD), which are associated with poor overall survival (OS). Microarray processing was performed to determine gene expression profiling, in which it was found that knocking down USP22 resulted in abnormal expression of a large number of genes. Differentially expressed genes (DEGs)-based protein-protein interaction (PPI) network was organized into 9 functional modules. These functional modules participated significantly in protein modification-related biological process and were involved in cancer-related pathways. The network was constructed to describe the global regulation of USP22-TF/pivot-module-pathway. It suggested that knocking down USP22 may up-regulate the expression of UBC to promote the pathways of cell cycle and ubiquitin-mediated proteolysis in the development of LUAD. More than that, knocking down USP22 can up-regulate STAT1 to activate JAK1-STAT1-caspase pathway, and promote apoptosis of tumor cell. Receiver operating characteristic (ROC) curve analysis suggested that E2F3, H2AFX, TFAP2A, PITX1, IRF7, and FOXM1 may be the potential diagnosis biomarkers for LUAD. On the other hand, BRCA1, FOXM1 and TFAP2A may be prognostic biomarkers of LUAD. In conclusion, we constructed a global regulation network to show that USP22 may promote the development of LUAD through ubiquitination and immunosuppression.