Identification and validation of potential biomarkers related to oxidative stress in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia with a poor prognosis and a pathogenesis that has not been fully elucidated. Oxidative stress is closely associated with IPF. In this research, we aimed to identify reliable diagnostic biomarkers associated with the oxidative stress through bioinformatics techniques. The gene expression profile data from the GSE70866 dataset was retrieved from the gene expression omnibus (GEO) database. We extracted 437 oxidative stress-related genes (ORGs) from gene set enrichment analysis (GSEA). The GSE141939 dataset was used for single-cell RNA-seq analysis to identify the expression of diagnostic genes in different cell clusters. A total of 10 differentially expressed oxidative stress-related genes (DE-ORGs) were screened. Subsequently, SOD3, CD36, ACOX2, RBM11, CYP1B1, SNCA, and MPO from the 10 DE-ORGs were identified as diagnostic genes based on random forest algorithm with randomized least absolute shrinkage and selection operator (LASSO) regression. A nomogram was constructed to evaluate the risk of disease. The decision curve analysis (DCA) and clinical impact curves indicated that the nomogram based on these seven biomarkers had extraordinary predictive power. Immune cell infiltration analysis results revealed that DE-ORGs were closely related to various immune cells, especially CYP1B1 was in positive correlation with monocytes and negative correlation with macrophages M1. Single-cell RNA-seq analysis showed that CYP1B1 was mainly associated with macrophages, and SNCA was mainly associated with basal cells. CYP1B1 and SNCA were diagnostic genes associated with oxidative stress in IPF.

Repeated pulmonary nodules as the primary symptom of familial hemophagocytic lymphohistiocytosis in adults: a case report and review.

Pulmonary nodules are usually considered to be associated with malignant tumors and benign lesions, such as granuloma, pulmonary lymph nodes, fibrosis, and inflammatory lesions. Clinical cases of pulmonary nodules associated with hemophagocytic lymphohistiocytosis have rarely been reported. Therefore, when patients develop pulmonary nodules, the possibility of developing hemophagocytic lymphohistiocytosis is often not considered. We report the first case of familial hemophagocytic lymphohistiocytosis with recurrent pulmonary nodules as the first symptom. Our findings will hopefully provide new ideas for the diagnosis and treatment of pulmonary nodules in the future.

Exploration and Validation of Potential Biomarkers and Therapeutic Targets in Ferroptosis of Asthma.

Purpose: Asthma is a chronic inflammatory airway disease involving multiple mechanisms, of which ferroptosis is a form of programmed cell death. Recent studies have shown that ferroptosis may play a crucial role in the pathogenesis of asthma, but no specific ferroptosis gene has been found in asthma, and the exact mechanism is still unclear. The present study aimed to screen ferroptosis genes associated with asthma and find therapeutic targets, in order to contribute a new clue for the diagnosis and therapy of asthma. Methods: Ferroptosis-related differentially expressed genes (FR-DEGs) in asthma were selected by the GSE41861, GSE43696 and ferroptosis datasets. Next, the FR-DEGs were subjected by GO and KEGG enrichment, and the mRNA-miRNA network was constructed. Then, GSEA and GSVA enrichment analysis and Immune infiltration analysis were performed, followed by targeted drug prediction. Finally, the expression of FR-DEGs was confirmed using GSE63142 dataset and RT-PCR assay. Results: We found 13 FR-DEGs by the GSE41861, GSE43696 and ferroptosis database. Functional enrichment analysis revealed that the 13 FR-DEGs were enriched in oxidative stress, immune response, ferroptosis, lysosome, necrosis, apoptosis etc. Moreover, our results revealed the mRNA-miRNA network of the FR-DEGs and identified candidate drugs. Also, immune infiltration revealed that ELAVL1, CREB5, CBR1 and NR1D2 are associated with the immune cells and may be potential targets in asthma. Finally, 10 FR-DEGs were validated by the GSE63142 database. It was verified that 7 FR-DEGs were differentially expressed by collecting asthma patients and healthy controls. Conclusion: This study ultimately identified 7 FR-DEGs for the diagnosis and therapy of asthma. These 7 FR-DEGs contribute to oxidative stress and immune responses. This study provides potential therapeutic targets and biomarkers for asthma patients, shedding further light on the pathogenesis of asthma as well as providing new insights into the treatment of asthma.

Predictors of COVID-19 Severity in Elderly Patients Infected by Omicron in China, 18 December 2022-5 February 2023.

Purpose: To analyze the clinical characteristics and prognosis of patients hospitalized with non-severe, severe pneumonia and death in Omicron COVID-19. Patients and Methods: We collected clinical data from 118 patients with COVID-19 in China from 18 December, 2022 and 5 February, 2023. According to the outcome, the patients were divided into non-severe group, severe group and death group. Subsequently, we statistically analyzed the general condition, clinical manifestations, laboratory parameters, NLR, MLR, PLR and HALP of these groups. We also retrospectively analyzed the possible factors affecting the prognostic regression of patients with COVID-19. Results: A total of 118 COVID-19 patients were enrolled in this study, including 64 non-severe patients, 38 severe patients and 16 death patients. Compared with the non-severe group, T lymphocytes, B lymphocytes, Th1, Th2, Th17, Treg cells, IgA, IgG, IgM in the severe and death groups decreased more significantly (P<0.05). The levels of myocardial markers, ALT, AST, BUN, Cr, D-dimer, fibrinogen, NLR, MLR and PLR in the severe and death groups were significantly higher than those in the non-severe group (P<0.05). The level of HALP was significantly lower than that of non-severe group (P<0.05). MLR is not only an independent risk factor for the transition from non-severe to severe disease, but also an independent risk factor for predicting the possibility of death in COVID-19 patients. Conclusion: The analysis of COVID-19 patients in China showed that severe patients were older, more likely to have related complications, lower lymphocyte count, liver and kidney function disorder, glucose and lipid metabolism disorders, myocardial injury, and abnormal coagulation function, suggesting the need for early anticoagulant therapy. In addition, NLR, MLR, PLR and HALP can be used as biomarkers to evaluate the severity and prognosis of COVID-19 patients.

Targeted inhibition of ß-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-ß1.

BACKGROUND: TGF-ß1 is a key cytokine involved in both airway inflammation and airway remodeling in asthma because of its anti-inflammatory and profibrotic effect. In our previous study, we found that knockdown of cytosolic ß-catenin alleviated the profibrogenic effect of TGF-ß1 without influencing its anti-inflammatory effect. However, the exact role of targeting ß-catenin in asthma is not yet fully demonstrated. In the present study, we investigated the effect and mechanism of targeting ß-catenin in OVA-challenged asthmatic rats with airway inflammation and remodeling features. METHODS: We integrated experimental asthma model and asthma related cell model to explore the effect of targeting ß-catenin on airway inflammation and remodeling of asthma. RESULTS: Blocking ß-catenin with ICG001, a small molecule inhibitor of ß-catenin/TCF via binding to cAMP-response elementbinding protein, attenuated airway inflammation by increasing levels of anti-inflammation cytokines IL-10, IL-35 and decreasing levels of T helper (Th)2 cells and Th17 cytokine. Suppressing ß-catenin by ICG001 inhibited airway remodeling via reducing the level of TGF-ß1 and the expressions of Snail, MMP-7, MMP-9 and, up-regulating expression of E-cadherin, down-regulating expressions of α-SMA and Fn. Inhibition of ß-catenin with ICG001 suppressed TGF-ß1 induced proliferation and activation of CCC-REPF-1, blocked TGF-ß1 induced epithelial-mesenchymal transition (EMT) of RLE-6TN. CONCLUSION: Blockade of ß-catenin/TCF not only prevents TGF-ß1 induced EMT and profibrogenic effects involved in pathological remodeling of airway, but also alleviates airway inflammation in asthma by balancing pro-inflammatory and anti-inflammatory cytokine. In conclusion, targeting ß-catenin specifically via inhibition of ß-catenin/TCF might be a new therapeutic strategy for asthma.The reviews of this paper are available via the supplemental material section.

1α, 25-dihydroxyvitamin D3 inhibits transforming growth factor ß1-induced epithelial-mesenchymal transition via ß-catenin pathway.

BACKGROUND: The transforming growth factor ß1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) has been proven associated with the pathogenesis of asthmatic airway remodeling, in which the Wnt/ß-catenin pathway plays an important role, notably with regard to TGF-ß1. Recent studies have shown that 1α, 25-dihydroxyvitamin D3(1α, 25(OH)2D3) inhibits TGF-ß1-induced EMT, although the underlying mechanism have not yet been fully elucidated. METHODS: Alveolar epithelial cells were exposed to 1α, 25(OH)2D3, ICG-001, or a combination of both, followed by stimulation with TGF-ß1. The protein expression of E-cadherin, α-smooth muscle actin, fibronectin, and ß-catenin was analyzed by western blotting and immunofluorescence analysis. The mRNA transcript of Snail was analyzed using RT-qPCR, and matrix metalloproteinase 9 (MMP-9) activity was analyzed by gelatin zymogram. The activity of the Wnt/ß-catenin signaling pathway was analyzed using the Top/Fop flash reporters. RESULTS: Both 1α, 25(OH)2D3 and ICG-001 blocked TGF-ß1-induced EMT in alveolar epithelial cells. In addition, the Top/Fop Flash reporters showed that 1α, 25(OH)2D3 suppressed the activity of the Wnt/ß-catenin pathway and reduced the expression of target genes, including MMP-9 and Snail, in synergy with ICG-001. CONCLUSION: 1α, 25(OH)2D3 synergizes with ICG-001 and inhibits TGF-ß1-induced EMT in alveolar epithelial cells by negatively regulating the Wnt/ß-catenin signaling pathway.

Bacillus Calmette-Guerin alleviates airway inflammation and remodeling by preventing TGF-ß1 induced epithelial-mesenchymal transition.

Bacillus Calmette-Guerin (BCG) is a potent agent for the prevention of tuberculosis. Current studies have regarded BCG as an immunomodulator. However, there is little information on whether it can be used to inhibit airway inflammation and airway remodeling caused by asthma. Therefore, in this study, we investigate the role of epithelial-mesenchymal transition (EMT) in airway inflammation and airway remodeling as well as the possible therapeutic mechanism of BCG for the treatment of asthma. Wistar rats were sensitized and challenged by ovalbumin for 2 weeks or 8 weeks. BCG was subcutaneously administered daily before every ovalbumin challenge to determine its therapeutic effects. The 2 weeks model group showed extensive eosinophilia, chronic inflammatory responses, bronchial wall thickening, airway epithelium damage, increased levels of transforming growth factor ß 1 (TGF-ß1) in both bronchoalveolar lavage fluid and sera, decreased expression of epithelial marker E-cadherin, and increased expressions of mesenchymal markers α-smooth muscle actin (α-SMA) and Fibronectin (Fn). Except for inflammatory responses, all responses were more significant in the 8 weeks model group which displayed characteristics of airway remodeling including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. When compared with the model groups, BCG administration inhibited airway inflammation and airway remodeling, decreased TGF-ß1 levels, upregulated expression of E-cadherin, and downregulated expression of α-SMA and Fn. The present study suggests for the first time that increased secretion of TGF- ß1 induced by asthmatic chronic inflammation may result in EMT, which is one of the most important mechanisms of airway inflammation and airway remodeling seen with asthma. BCG alleviates airway inflammation and airway remodeling by preventing TGF-ß1 induced EMT, therefore BCG may be a new therapy for treating asthma.