Association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease risk: a meta-analysis.

BACKGROUND: The association between the oxidative stress gene polymorphism and chronic obstructive pulmonary disease (COPD) risk has been extensively studied but the results have been controversial. This study aimed to investigate the overall association between the oxidative stress gene including glutathione S-transferase (GST), epoxide hydrolase exon (EPHX), superoxide dismutase (SOD), catalase (CAT), cytochrome P450 system (CYP) and heme oxygenase (HO-1) polymorphism and the risk of COPD. METHODS: We searched the PubMed and EMBASE database to identify studies that investigated the association between the oxidative stress gene polymorphism and risk of COPD. The relevant data were extracted and statistical analyses were performed using the Revman 5.4 and STATA 12 software. Dominant genetic model, recessive model, co-dominant model, heterozygote model, and allele model were analyzed. Venice criteria and publication bias were conducted to access the credibility and reliability. RESULTS: In total, 63 publications including 14,733 patients and 50,570 controls were included in the meta-analysis.15 genetic variants of 6 genes were analyzed, and 7 SNPs in GSTP1, CAT, CYP, SOD were first analyses until now. In our study, EPHX T113C C allele, GSTM1 null, GSTT1 null, GSTP1 A313G G and C341T T allele, CYP1A1 MspI C allele, SOD3 A213G G allele and L type in Ho-1 showed increased COPD risk, especially in Asians. T allele in CAT C262T and C allele in SOD2 Val 9 Ala were associated with decreased COPD risk. To avoid high heterogeneity and publications bias, subgroups analysis was performed in accord with HWE and ethnicity. Publication bias was assessed by Begg's funnel plots and Egger's test, and no publication bias were found for recessive models. 4 variants were identified with strong levels of epidemiological evidence of associations with the COPD risk. CONCLUSIONS: Our results confirm that oxidative stress gene polymorphism was associated with COPD risk. These finding can improve human understanding of this disease gene molecular level and enable early intervention and prevention of COPD. Well-designed studies with large sample sizes are essential to clarify the association of these significant variants with the susceptibility to COPD.

Predictive model based on multiple immunofluorescence quantitative analysis for pathological complete response to neoadjuvant immunochemotherapy in lung squamous cell carcinoma.

Objective: This study aims to establish a prediction model for neoadjuvant immunochemotherapy (NICT) in lung squamous cell carcinoma to guide clinical treatment. Methods: This retrospective study included 50 patients diagnosed with lung squamous cell carcinoma who received NICT. The patients were divided into the pathological complete response (PCR) group and the non-PCR group. HE staining and multiple immunofluorescence (mIF) techniques were utilized to analyze the differences in the immune microenvironment between these groups. LASSO regression and optimal subset regression were employed to identify the most significant variables and construct a prediction model. Results: The PCR group showed higher densities of lymphocyte nuclei and karyorrhexis based on HE staining. Furthermore, based on mIF analysis, the PCR group showed higher cell densities of CD8+, PD-L1+, and CD8+PD-L1+ in the tumor region, while showing lower cell densities of CD3+Foxp3+, Foxp3+, and CD163+. Logistic univariate analysis revealed CD8+PD-L1+, PD-L1+, CD8+, CD4+LAG-3+, lymphocyte nuclei, and karyorrhexis as significant factors influencing PCR. By using diverse screening methods, the three most relevant variables (CD8+, PD-L1+, and CD8+PD-L1+ in the tumor region) were selected to establish the prediction model. The model exhibited excellent performance in both the training set (AUC=0.965) and the validation set (AUC=0.786). In the validation set, In comparison to the conventional TPS scoring criteria, the model attained superior accuracy (0.85), specificity(0.67), and sensitivity (0.92). Conclusion: NICT treatment might induce anti-tumor effects by enriching immune cells and reactivating exhausted T cells. CD8+, PD-L1+, and CD8+PD-L1+ cell abundances within the tumor region have been closely associated with therapeutic efficacy. Incorporating these three variables into a predictive model allows accurate forecasting of treatment outcomes and provides a reliable basis for selecting NICT treatment strategies.

Anoikis and SPP1 in idiopathic pulmonary fibrosis: integrating bioinformatics, cell, and animal studies to explore prognostic biomarkers and PI3K/AKT signaling regulation.

OBJECTIVE: This study aims to explore the relevance of anoikis in idiopathic pulmonary fibrosis (IPF) and identify associated biomarkers and signaling pathways. METHOD: Unsupervised consensus cluster analysis was employed to categorize IPF patients into subtypes. We utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and Protein-Protein Interaction network construction to identify anoikis-related modules and key genes. A prognostic signature was developed using Lasso and multivariate Cox regression analysis. Single-cell sequencing assessed hub gene expression in various cell types, and both cell and animal experiments confirmed IPF-related pathways. RESULTS: We identified two distinct anoikis-associated subtypes with differing prognoses. WGCNA revealed essential hub genes, with SPP1 being prominent in the anoikis-related signature. The anoikis-related signature is effective in determining the prognosis of patients with IPF. Single-cell sequencing highlighted significant differences in SPP1 expression, notably elevated in fibroblasts derived from IPF patients. In vivo and in vitro experiments demonstrated that SPP1 enhances fibrosis in mouse lung fibroblasts by regulating p27 through the PI3K/Akt pathway. CONCLUSION: Our research demonstrates a robust prognostic signature associated with anoikis and highlights SPP1 as a pivotal regulator of the PI3K/AKT signaling pathway in pulmonary fibrosis.

Exploring ABHD5 as a Lipid-Related Biomarker in Idiopathic Pulmonary Fibrosis: Integrating Machine Learning, Bioinformatics, and In Vitro Experiments.

Recent studies increasingly suggest a connection between lipids and idiopathic pulmonary fibrosis (IPF). This study was aimed at exploring potential lipid-related biomarkers for IPF and uncovering the mechanisms underlying pulmonary fibrosis. IPF-related datasets were retrieved from the GEO database, and the ComBat algorithm was used to merge multiple datasets and eliminate batch effects. Weighted gene co-expression network analysis (WGCNA) was utilized to identify modules and genes associated with IPF. Potential hub genes were determined by intersecting these genes with lipid-related genes from the GeneCards database. A machine learning-based integrative approach was developed to construct diagnostic and prognostic signatures, which were validated across several datasets. Additionally, single-cell sequencing data was used to validate the expression differences of core IPF-related genes across various cell types. The effect of ABHD5 on fibroblasts was assessed using the cell counting kit-8, 5-ethynyl-2'-deoxyuridine, and cell scratch assays. The expression levels of fibrotic factors were measured using real-time quantitative polymerase chain reaction and western blot analysis. WGCNA identified a red module potentially related to IPF, and the intersection with lipid-related genes yielded 51 hub genes. These genes were used to build diagnostic and prognostic models that demonstrated robust validation capabilities across multiple datasets. Single-cell sequencing analysis revealed low expression of ABHD5 in the lung tissues of IPF patients, with a higher proportion of fibroblasts exhibiting low ABHD5 expression. Cell experiments showed that under the influence of TGF-ß1, knockdown of ABHD5 slightly promoted fibroblast proliferation. Additionally, fibroblasts with low ABHD5 expression exhibited enhanced migratory capabilities and secreted more fibrotic factors. Lipid-related diagnostic and prognostic models for IPF were developed, and ABHD5 may serve as a potential biomarker. Low ABHD5 expression could potentially accelerate the progression of pulmonary fibrosis.

Ox-LDL-induced TGF-ß1 production in human alveolar epithelial cells: involvement of the Ras/ERK/PLTP pathway.

Oxidized-low density lipoprotein (Ox-LDL) has been shown to play an important role in impaired surfactant metabolism and transforming growth factor-ß1 (TGF-ß1) is a critical mediator in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). In this study, we investigated whether Ox-LDL can induce TGF-ß1 protein production, and if so, how it achieves this induction in human alveolar epithelial cells (A549). We show here that Ox-LDL not only caused a dose- and time-dependent up-regulation of TGF-ß1 production, but also increased Smad3 phosphorylation, Ras/extracellular signal-regulated kinase (ERK) activity and phospholipid transfer protein (PLTP) expression in A549 cells. The inhibition of Ras/ERK activity with specific inhibitors significantly suppressed Ox-LDL-induced TGF-ß1 production, Smad3 phosphorylation and PLTP expression. Furthermore, treatment of cells with PLTP siRNA suppressed both TGF-ß1 release and Smad3 activation induced by Ox-LDL, but not the activation of Ras/ERK cascade. Taken together, we provide evidences that induction of TGF-ß1 production and Smad3 phosphorylation by Ox-LDL is mediated by Ras/ERK/PLTP pathway in human alveolar epithelial cells.

Identification of hub genes and key pathways in the emphysema phenotype of COPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition associated with high morbidity and mortality. This study aimed to use weighted gene co-expression network analysis (WGCNA) to explore the molecular pathogenesis of the emphysema phenotype of COPD. After obtaining lung mRNA expression profiles from ten patients with the emphysema phenotype of COPD and eight controls, emphysema-associated gene modules were identified with WGCNA. Among 13 distinct modules, the green-yellow and brown modules showed the strongest correlations with emphysema severity and lung function and were thus selected as hub modules. On gene ontology analysis, these two modules were mainly enriched in immune response, B cell receptor (BCR) signaling pathway, extracellular matrix (ECM) organization, and collagen fibril organization. Pathway analysis primarily showed enrichment in BCR signaling pathways, ECM receptor interaction, and NF-κB and TGF-ß signaling pathways for the two hub modules. Several genes, including FCRLA, MS4A1, CD19, FKBP10, C1S and HTRA1, among others, were identified as hub genes. Our results shed light on the potential genetic mechanisms underlying the pathogenesis of the emphysema phenotype of COPD. However, further research will be needed to confirm the involvement of the identified genes and to determine their therapeutic relevance.

Mitochondrial-Targeting Antioxidant SS-31 Suppresses Airway Inflammation and Oxidative Stress Induced by Cigarette Smoke.

This study investigated whether the mitochondrial-targeted peptide SS-31 can protect against cigarette smoke- (CS-) induced airway inflammation and oxidative stress in vitro and in vivo. Mice were exposed to CS for 4 weeks to establish a CS-induced airway inflammation model, and those in the experimental group were pretreated with SS-31 1 h before CS exposure. Pathologic changes and oxidative stress in lung tissue, inflammatory cell counts, and proinflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. The mechanistic basis for the effects of SS-31 on CS extract- (CSE-) induced airway inflammation and oxidative stress was investigated using BEAS-2B bronchial epithelial cells and by RNA sequencing and western blot analysis of lung tissues. SS-31 attenuated CS-induced inflammatory injury of the airway and reduced total cell, neutrophil, and macrophage counts and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and matrix metalloproteinase (MMP) 9 levels in BALF. SS-31 also attenuated CS-induced oxidative stress by decreasing malondialdehyde (MDA) and myeloperoxidase (MPO) activities and increasing that of superoxide dismutase (SOD). It also reversed CS-induced changes in the expression of mitochondrial fission protein (MFF) and optic atrophy (OPA) 1 and reduced the amount of cytochrome c released into the cytosol. Pretreatment with SS-31 normalized TNF-α, IL-6, and MMP9 expression, MDA and SOD activities, and ROS generation in CSE-treated BEAS-2B cells and reversed the changes in MFF and OPA1 expression. RNA sequencing and western blot analysis showed that SS-31 inhibited CS-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway in vitro and in vivo. Thus, SS-31 alleviates CS-induced airway inflammation and oxidative stress via modulation of mitochondrial function and regulation of MAPK signaling and thus has therapeutic potential for the treatment of airway disorders caused by smoking.

The Association and Influencing Factors between Antipsychotics Exposure and the Risk of VTE and PE: A Systematic Review and Meta-analysis.

BACKGROUND: Different clinical studies have given inconsistent results on whether the use of antipsychotics increases the risk of thromboembolism. In this paper, we reviewed all relevant literature to provide suggestions for clinical diagnosis and treatment. METHODS: PubMed, Web of Science, EMBASE, MEDLINE, Cochrane and Scopus databases were thoroughly searched up to June 2019. Two researchers independently searched the literature, extracted data. Data were analyzed by Stata 12.0 software. RESULTS: A total of 22 studies involving 31514226 subjects were included. This meta-analysis showed that patients taking the first- or second-generation antipsychotics had a higher risk of venous thromboembolism and pulmonary embolism than those who did not, and low potency first-generation agents increased the risk of venous thromboembolism more than high potency antipsychotics, and olanzapine, clozapine, haloperidol, perphenazine and risperidone also significantly increased the risk of it. The risk of venous thrombosis in obese people was higher than that in overweight people, patients not less than 65 years old had an increased risk compared with younger patients. In addition, women taking antipsychotics had a higher risk of pulmonary embolism than men. CONCLUSION: The use of antipsychotics will increase the risk of venous thromboembolism and pulmonary embolism, which will be affected by the type of antipsychotics and patient characteristics.

Association between the Lymphotoxin-α A252g Gene Polymorphism and the Risk of Sepsis and Mortality: A Meta-Analysis.

BACKGROUND: The association between the lymphotoxin-α (LTA) A252G polymorphism and sepsis risk has been extensively studied, but the results have been controversial. This study is aimed at investigating the overall association between the LTA A252G polymorphism and the risk of sepsis/septic shock and sepsis-related mortality. METHODS: We searched the PubMed and EMBASE databases to identify studies that investigated the association between the LTA A252G polymorphism and risks of sepsis, septic shock, and mortality. The relevant data were extracted, and statistical analyses were performed using the Revman 5.0 and STATA 12 software. RESULTS: A total of 32 publications were included in the meta-analysis. The results demonstrated that the LTA A252G polymorphism showed no significant association with sepsis risk (GG+GA vs. AA: OR = 0.92, 95%CI = 0.79-1.07, p = 0.27) or with sepsis shock risk (GG+GA vs. AA: OR = 1.01, 95%CI = 0.84-1.22, p = 0.91). However, in the subgroup analyzed by ethnicity, the LTA A252G polymorphism significantly decreased sepsis risk in the Asian population for the recessive model [GG vs. GA+AA: OR = 0.82, 95%CI = 0.68-0.99, p = 0.04] but not in the Caucasian population. Moreover, comparisons between sepsis patients who survived and those who did not suggested that the LTA A252G polymorphism decreases the risk of mortality [GG+GA vs. AA: OR = 0.57, 95%CI = 0.41-0.80, p < 0.01]. CONCLUSION: Our results suggested that the A252G polymorphism in the LTA gene decreased the risk of sepsis in Asians and may reduce mortality in septic individuals.

COVID-19 Is Distinct From SARS-CoV-2-Negative Community-Acquired Pneumonia.

Background: Corona virus disease (COVID-19) is an infectious respiratory disease that has spread rapidly across the world. Many studies have already evaluated the clinical features of COVID-19, but how it compares with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative community-acquired pneumonia (SN-CAP) is still unclear. Moreover, COVID-19 mortality is correlated with disease severity, but indicators for severity grading have not been specified. We aimed to analyze the clinical characteristics of COVID-19 in comparison with SN-CAP and find indicators for disease severity in COVID-19. Methods: Patients diagnosed with COVID-19 and SN-CAP were enrolled. Clinical, radiological, and laboratory data were analyzed. Results: The numbers of COVID-19 and SN-CAP patients enrolled were 304 and 138, respectively. The age of the patients was not significantly different between the groups. Compared with SN-CAP, COVID-19 patients had more symptoms of fever and dyspnea; and showed significant difference in blood count results. Computed tomography (CT) imaging of COVID-19 patients showed patchy ground-glass opacities that correlated with disease severity, whereas the CT imaging of SN-CAP patients showed patchy high-density shadows. COVID-19 patients were classified into moderate, severe, and critically severe groups. The severe and critically severe groups had elevated levels of white blood cells (WBC), neutrophils, platelets, C-reaction protein (CRP), lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), troponin-I, creatinine, and blood urea nitrogen (BUN). However, they had decreased levels of lymphocytes, lymphocyte ratio, and albumin. Compared with the younger patients, the older COVID-19 individuals had more chronic diseases and significantly elevated levels of WBC, neutrophil, and CRP levels. Conclusion: SN-CAP showed more inflammatory reaction than COVID-19. Old people with chronic diseases are more susceptible to COVID-19 and have a high likelihood of developing severe and critically severe infection. Levels of WBC, lymphocytes, neutrophils, CRP, NLR, PLR, troponin-I, creatinine, and BUN are important indicators for severity grading in COVID-19.

Evaluation of ghrelin level and appetite regulation in patients with acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD. METHODS: Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD. RESULTS: Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge. CONCLUSION: We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.