Prediction of mortality in pneumonia patients with connective tissue disease treated with glucocorticoids or/and immunosuppressants by machine learning.

Objectives: The assessment of accurate mortality risk is essential for managing pneumonia patients with connective tissue disease (CTD) treated with glucocorticoids or/and immunosuppressants. This study aimed to construct a nomogram for predicting 90-day mortality in pneumonia patients using machine learning. Methods: Data were obtained from the DRYAD database. Pneumonia patients with CTD were screened. The samples were randomly divided into a training cohort (70%) and a validation cohort (30%). A univariate Cox regression analysis was used to screen for prognostic variables in the training cohort. Prognostic variables were entered into the least absolute shrinkage and selection operator (Lasso) and a random survival forest (RSF) analysis was used to screen important prognostic variables. The overlapping prognostic variables of the two algorithms were entered into the stepwise Cox regression analysis to screen the main prognostic variables and construct a model. Model predictive power was assessed using the C-index, the calibration curve, and the clinical subgroup analysis (age, gender, interstitial lung disease, diabetes mellitus). The clinical benefits of the model were assessed using a decision curve analysis (DCA). Similarly, the C-index was calculated and the calibration curve was plotted to verify the model stability in the validation cohort. Results: A total of 368 pneumonia patients with CTD (training cohort: 247; validation cohort: 121) treated with glucocorticoids or/and immunosuppressants were included. The univariate Cox regression analysis obtained 19 prognostic variables. Lasso and RSF algorithms obtained eight overlapping variables. The overlapping variables were entered into a stepwise Cox regression to obtain five variables (fever, cyanosis, blood urea nitrogen, ganciclovir treatment, and anti-pseudomonas treatment), and a prognostic model was constructed based on the five variables. The C-index of the construction nomogram of the training cohort was 0.808. The calibration curve, DCA results, and clinical subgroup analysis showed that the model also had good predictive power. Similarly, the C-index of the model in the validation cohort was 0.762 and the calibration curve had good predictive value. Conclusion: In this study, the nomogram developed performed well in predicting the 90-day risk of death in pneumonia patients with CTD treated with glucocorticoids or/and immunosuppressants.

Identification of a m6A-related ferroptosis signature as a potential predictive biomarker for lung adenocarcinoma.

BACKGROUND: Both N6-methyladenosine (m6A) and ferroptosis-related genes are associated with the prognosis of lung adenocarcinoma. However, the predictive value of m6A-related ferroptosis genes remains unclear. Here, we aimed to identify the prognostic value of m6A-related ferroptosis genes in lung adenocarcinoma. METHODS: Lung adenocarcinoma sample data were downloaded from the University of California Santa Cruz Xena and Gene Expression Omnibus databases. Spearman's correlation analysis was used to screen for m6A-related ferroptosis genes. Univariate Cox regression, Kaplan-Meier, and Lasso analyses were conducted to identify prognostic m6A-related ferroptosis genes, and stepwise regression was used to construct a prognostic gene signature. The predictive value of the gene signature was assessed using a multivariate Cox analysis. In the validation cohort, survival analysis was performed to verify gene signature stability. The training cohort was divided into high- and low-risk groups according to the median risk score to assess differences between the two groups in terms of gene set variation analysis, somatic mutations, and tumor immune infiltration cells. RESULTS: Six m6A-related ferroptosis genes were used to construct a gene signature in the training cohort and a multivariate Cox analysis was conducted to determine the independent prognostic value of these genes in lung adenocarcinoma. In the validation cohort, Kaplan-Meier and receiver operating characteristic analyses confirmed the strong predictive power of this signature for the prognosis of lung adenocarcinoma. Gene set variation analysis showed that the low-risk group was mainly related to immunity, and the high-risk group was mainly related to DNA replication. Somatic mutation analysis revealed that the TP53 gene had the highest mutation rate in the high-risk group. Tumor immune infiltration cell analysis showed that the low-risk group had higher levels of resting CD4 memory T cells and lower levels of M0 macrophages. CONCLUSION: Our study identified a novel m6A-related ferroptosis-associated six-gene signature (comprising SLC2A1, HERPUD1, EIF2S1, ACSL3, NCOA4, and CISD1) for predicting lung adenocarcinoma prognosis, yielding a useful prognostic biomarker and potential therapeutic target.

A Methylation Diagnostic Model Based on Random Forests and Neural Networks for Asthma Identification.

Background: Asthma significantly impacts human life and health as a chronic disease. Traditional treatments for asthma have several limitations. Artificial intelligence aids in cancer treatment and may also accelerate our understanding of asthma mechanisms. We aimed to develop a new clinical diagnosis model for asthma using artificial neural networks (ANN). Methods: Datasets (GSE85566, GSE40576, and GSE13716) were downloaded from Gene Expression Omnibus (GEO) and identified differentially expressed CpGs (DECs) enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Random forest (RF) and ANN algorithms further identified gene characteristics and built clinical models. In addition, two external validation datasets (GSE40576 and GSE137716) were used to validate the diagnostic ability of the model. Results: The methylation analysis tool (ChAMP) considered DECs that were up-regulated (n =121) and down-regulated (n =20). GO results showed enrichment of actin cytoskeleton organization and cell-substrate adhesion, shigellosis, and serotonergic synapses. RF (random forest) analysis identified 10 crucial DECs (cg05075579, cg20434422, cg03907390, cg00712106, cg05696969, cg22862094, cg11733958, cg00328720, and cg13570822). ANN constructed the clinical model according to 10 DECs. In two external validation datasets (GSE40576 and GSE137716), the Area Under Curve (AUC) for GSE137716 was 1.000, and AUC for GSE40576 was 0.950, confirming the reliability of the model. Conclusion: Our findings provide new methylation markers and clinical diagnostic models for asthma diagnosis and treatment.

Clinical evaluation of prone position ventilation in the treatment of acute respiratory distress syndrome induced by sepsis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an acute, diffuse, inflammatory lung injury. Previous studies have shown prone position ventilation (PPV) to be associated with improvement in oxygenation. However, its role in patients with ARDS caused by sepsis remains unknown. AIM: To analyze the clinical effects of PPV in patients with ARDS caused by sepsis. METHODS: One hundred and two patients with ARDS were identified and divided into a control group (n = 55) and a PPV treatment group (n = 47). Outcomes included oxygenation index, lung compliance (Cst) and platform pressure (Pplat), which were compared between the two groups after ventilation. Other outcomes included heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), left ventricular ejection fraction (LVEF), the length of mechanical ventilation time and intensive care unit (ICU) stay, and levels of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) after ventilation. Finally, mortality rate was also compared between the two groups. RESULTS: On the first day after ventilation, the oxygenation index and Cst were higher and Pplat level was lower in the PPV group than in the conventional treatment group (P < 0.05). There were no significant differences in oxygenation index, Cst, and Pplat levels between the two groups on the 2nd, 4th, and 7th day after ventilation (P > 0.05). There were no significant differences in HR, MAP, CVP, LVEF, duration of mechanical ventilation and ICU stay, and the levels of CRP, PCT, and IL-6 between the two groups on the first day after ventilation (all P > 0.05). The mortality rates on days 28 and 90 in the PPV and control groups were 12.77% and 29.09%, and 25.53% and 45.45%, respectively (P < 0.05). CONCLUSION: PPV may improve respiratory mechanics indices and may also have mortality benefit in patients with ARDS caused by sepsis. Finally, PPV was not shown to cause any adverse effects on hemodynamics and inflammation indices.

Drp1-dependent mitochondrial fission mediates corneal injury induced by alkali burn.

Corneal alkali burn, one of the most serious ophthalmic emergencies, is difficult to be cured by conservative treatments. It is well known that oxidative stress, inflammation and neovascularization are the main causes of corneal damage after alkali burn, but its underlying mechanism remains to be elucidated. Here, we reported that the expression and phosphorylation (Ser616) of mitochondrial fission protein Drp1 were up-regulated at day 3 after alkali burn, while mitochondrial fusion protein Mfn2 was down-regulated. The phosphorylation of ERK1/2 in corneas was increased at day 1, 3, 7 and peaked at day 3 after alkali burn. In human corneal epithelial cells (HCE-2), NaOH treatment induced mitochondrial fission, intracellular ROS production and mitochondrial membrane potential disruption, which was prevented by Drp1 inhibitor Mdivi-1. In corneas, Mdivi-1 or knockdown of Drp1 by Lenti-Drp1 shRNA attenuated alkali burn-induced ROS production and phosphorylation of IκBα and p65. In immunofluorescence staining, it was detected that Mdivi-1 also prevented NaOH-induced nuclear translocation of p65 in HCE-2 cells. Moreover, the expression of NADPH oxidase NOX2 and NOX4 in corneas peaked at day 7 after alkali burn. Mdivi-1, Lenti-Drp1 shRNA or the mitochondria-targeted antioxidant mito-TEMPO efficiently alleviated activation of NF-κB, expression of NOX2/4 and inflammatory cytokines including IL-6, IL-1ß and TNF-α in corneas after alkali burn. In pharmacological experiments, both Mdivi-1 and NADPH oxidases inhibitor Apocynin protected the corneas against alkali burn-induced neovascularization. Intriguingly, the combined administration of Mdivi-1 and Apocynin had a synergistic inhibitory effect on corneal neovascularization after alkali burn. Taken together, these results indicate that Drp1-dependent mitochondrial fission is involved in alkali burn-induced corneal injury through regulating oxidative stress, inflammatory responses and corneal neovascularization. This might provide a novel therapeutic target for corneal injury after alkali burn in the future.

Blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß1­42­induced degeneration.

Alzheimer's disease (AD), one of the most common types of chronic neurodegenerative diseases, is pathologically characterized by the formation of amyloid ß (Aß) peptide­containing plaques and neurofibrillary tangles. Among Aß peptides, Aß1­42 induces neuronal toxicity and neurodegeneration. In our previous studies, Cdk5 was found to regulate Aß1­42­induced mitochondrial fission via the phosphorylation of dynamin­related protein 1 (Drp1) at Ser579. However, whether blockage of Drp1 phosphorylation at Ser579 protects neurons against Aß1­42­induced degeneration remains to be elucidated. Thus, the aim the present study was to examine the effect of mutant Drp1­S579A on neurodegeneration and its underlying mechanism. First, the phosphorylation­defect (phospho­defect) mutant, Lenti­Drp1­S579A was constructed. Phospho­defect Drp1­S579A expression was detected in primary cultures of mouse cortical neurons infected with Lenti­Drp1­S579A using western blotting and it was found to successfully attenuate the phosphorylation of endogenous Drp1 at Ser579. In primary neuronal cultures, the neuronal processes were evaluated under microscopy. Treatment with 10 µM Aß1­42 significantly decreased dendritic density and length, spine outgrowth and synapse number. As expected, infection of neurons with Lenti­Drp1­S579A efficiently alleviated the inhibitory effect of Aß1­42 on neurite outgrowth and synapse density. In addition, infection with Lenti­Drp1­S579A abolished the cleavage of caspase­3 and apoptosis in neurons exposed to Aß1­42. Thus, the current data demonstrated that blockage of Drp1 phosphorylation at Ser579 may be an effective strategy to protect neurons against Aß1­42­induced degeneration and apoptosis. These findings underline the therapeutic potential of targeting Drp1 in the treatment of AD.

Mitochondrial Dynamics Mediated by DRP1 and MFN2 Contributes to Cisplatin Chemoresistance in Human Ovarian Cancer SKOV3 cells.

Cisplatin (DDP) is the first-line chemotherapeutic agent for ovarian cancer. However, the development of DDP resistance seriously influences the chemotherapeutic effect and prognosis of ovarian cancer. It was reported that DDP can directly impinge on the mitochondria and activate the intrinsic apoptotic pathway. Herein, the role of mitochondrial dynamics in DDP chemoresistance in human ovarian cancer SKOV3 cells was investigated. In DDP-resistant SKOV3/DDP cells, mitochondrial fission protein DRP1 was down-regulated, while mitochondrial fusion protein MFN2 was up-regulated. In accordance with the expression of DRP1 and MFN2, the average mitochondrial length was significantly increased in SKOV3/DDP cells. In DDP-sensitive parental SKOV3 cells, downregulation of DRP1 and upregulation of mitochondrial fusion proteins including MFN1,2 and OPA1 occurred at day 2~6 under cisplatin stress. Knockdown of DRP1 or overexpression of MFN2 promoted the resistance of SKOV3 cells to cisplatin. Intriguingly, weaker migration capability and lower ATP level were detected in SKOV3/DDP cells. Respective knockdown of DRP1 in parental SKOV3 cells or MFN2 in SKOV3/DDP cells using siRNA efficiently reversed mitochondrial dynamics, migration capability and ATP level. Moreover, MFN2 siRNA significantly aggravated the DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3/DDP cells. In contrast, DRP1 siRNA alleviated DDP-induced ROS production, mitochondrial membrane potential disruption, expression of pro-apoptotic protein BAX and Cleaved Caspase-3/9 in SKOV3 cells. Thus, these results indicate that mitochondrial dynamics mediated by DRP1 and MFN2 contributes to the development of DDP resistance in ovarian cancer cells, and will also provide a new strategy to prevent chemoresistance in ovarian cancer by targeting mitochondrial dynamics.

The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI.

Monocytes and macrophages are the two major cell types involved in innate immunity. Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing proteins, mRNAs, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs). However, it is still unclear whether monocyte-derived exosomes are involved in the communication between monocytes and macrophages. In this study, we analyzed the differentially expressed lncRNA profiles in monocytes isolated from blood samples of healthy controls and acute lung injury (ALI) patients. We focused our study on investigating the signaling downstream of CLMAT3 (colorectal liver metastasis-associated transcript 3), a lncRNA that regulated proinflammatory cytokine genes. We revealed that CLMAT3 specifically targeted CtBP2 (C-terminal binding protein 2) and repressed its expression. Elevated CtBP2 acted as a coactivator to assemble a transcriptional complex with histone acetyltransferase p300 and NF-κB (nuclear factor κB) subunits. In vitro coculture and in vivo injection of ALI monocyte-derived exosomes increased the production of proinflammatory cytokines. Importantly, the administration of two CtBP2 inhibitors, NSC95397 and MTOB, could significantly reverse CtBP2-mediated transactivation. Collectively, our results support a model in which monocyte-derived exosomal CLMAT3 activates the CtBP2-p300-NF-κB complex to induce proinflammatory cytokines, thus contributing to the pathogenesis of ALI.

Relationship of Blood Eosinophils with Fractional Exhaled Nitric Oxide and Pulmonary Function Parameters in Chronic Obstructive Pulmonary Disease (COPD) Exacerbation.

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease Report reveals that the blood eosinophil count could forecast the risk of flare-ups. This study explored the correlations of blood eosinophils with fractional exhaled nitric oxide (FeNO) and pulmonary function parameters in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS The data of patients with AECOPD at our hospital admitted between July 2018 and June 2019 were retrospectively analyzed. All patients were stratified into an eosinophilic group (≥2%) or a noneosinophilic group (<2%) based on the peripheral eosinophil count per centum. Cross-sectional analysis was performed to compare clinical characteristics, percentage of eosinophils, FeNO, and pulmonary function between the 2 groups. RESULTS After applying the inclusion/exclusion criteria, 247 patients were included. FeNO values were higher in eosinophilic group (n=97) than in noneosinophilic group (n=150) (P=0.005). The forced expiratory volume in 1 second% predicted (FEV1% predicted), FEV1, and forced vital capacity (FVC) were higher in the eosinophilic group than in the noneosinophilic group (P=0.043; P=0.040; and P=0.011, respectively). Blood eosinophilia showed positive correlations with FeNO (P=0.004) and spirometry variables (FEV1 [% predicted], P=0.003; FEV1, P<0.001; and FVC, P<0.001). An FeNO level of 22.5 ppb was the best cutoff value to predict blood eosinophilia (P=0.000). CONCLUSIONS Blood eosinophil count is a likely biomarker that can predict positive relationship with FeNO values and pulmonary function parameters.

Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1.

Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. In vitro lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslated region (3'-UTR) of NLRP1 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 1), a critical member of inflammasomes. Ectopic overexpression or downregulation of miR-199a-3p resulted in the repression or induction of NLRP1, respectively, thereby downregulating or activating its downstream events. Moreover, transcription factor FOXP3 (forkhead box P3) was able to specifically bind to the promoter of miR-199a-3p. Knockdown or overexpression of FOXP3 resulted in a decrease or induction miR-199a-3p expression, respectively. Using immunoprecipitation (IP), mass spectrometry and co-IP assays, we found that FOXP3 formed a transcriptional complex with HDAC1 (histone deacetylase 1) and CtBP2 (C-terminal-binding protein 2). Collectively, our results suggested that the CtBP2-HDAC1-FOXP3 transcriptional complex (CHFTC) could specifically bind to the promoter of miR-199a-3p and repress its expression. Downregulation of miR-199a-3p eliminated its inhibition of NLRP1, causing activation of NLRP1 and cleavage of pro-IL-1ß and pro-IL-18 mediated by Caspase-1. The secretion of IL-1ß and IL-18 further aggravated the inflammatory response and resulted in the occurrence of ALI.

HSDL2 Promotes Bladder Cancer Growth In Vitro and In Vivo.

Bladder cancer is a common malignant urinary tumor, and patients with bladder cancer have poor prognosis. Abnormal lipid metabolism in peroxisomes is involved in tumor progression. Hydroxysteroid dehydrogenase-like 2 (HSDL2) localized in peroxisomes regulates fatty acid synthesis. In the present study, we reported that HSDL2 was upregulated in two human bladder cancer cell lines 5637 and T24 compared to normal human urothelial cells. Furthermore, lentiviral-mediated HSDL2 knockdown inhibited the proliferation and colony formation while promoted the apoptosis of human bladder cancer T24 cells in vitro. In nude mice HSDL2 knockdown inhibited the growth of T24 derived xenografts in vivo. In conclusion, our results suggest that HSDL2 plays an oncogenic role in bladder cancer and might serve as a potential target for bladder cancer therapy.

Risks of budesonide/formoterol for the treatment of stable COPD: a meta-analysis.

Purpose: The aim of this study was to investigate the comparative risks of budesonide/formoterol, versus placebo or monotherapies, for the treatment of patients with stable COPD. Materials and methods: We undertook a systematic search of the literature in PubMed, Embase, and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing budesonide/formoterol with control regimens for the treatment of patients with stable COPD and at least 12 weeks of follow-up, meeting the inclusion criteria. Studies were reviewed, and OR with corresponding 95% CI was used to pool the results. Results: A total of eight studies involving 9,254 patients met the inclusion criteria of this meta-analysis. Compared with placebo, combination therapy with budesonide/formoterol was associated with a significantly higher risk of adverse effects including oral candidiasis (OR: 3.09, 95% CI: 1.95-4.91) and dysphonia (OR: 2.76, 95% CI: 1.40-5.44), but not pneumonia (OR: 0.94, 95% CI: 0.64-1.37) or bronchitis (OR: 1.36, 95% CI: 0.95-1.95). A similar pattern was also evident for the comparison of formoterol with budesonide/formoterol, with increased occurrence of oral candidiasis (OR: 2.72, 95% CI: 1.33-5.58) and dysphonia (OR: 4.13, 95% CI: 1.95-8.76); however, there were no significant differences in pneumonia (OR: 1.31, 95% CI: 0.98-1.74) or bronchitis (OR: 1.05, 95% CI: 0.83-1.31). In contrast, compared with budesonide, combined budesonide/formoterol was associated with similar risks of adverse effects, including pneumonia (OR: 1.20, 95% CI: 0.60-2.39), bronchitis (OR: 0.95, 95% CI: 0.41-2.20), oral candidiasis (OR: 0.79, 95% CI: 0.41-1.53), and dysphonia (OR: 1.00, 95% CI: 0.40-2.47). Conclusion: Combination therapy does not cause more adverse events, including pneumonia and bronchitis, than control (placebo, formoterol, or budesonide) treatment in patients with stable COPD, while there were higher risks of oral candidiasis and dysphonia compared with the non-inhaled corticosteroid group (placebo, formoterol).

Comparative Efficacy of Budesonide/Formoterol with Budesonide, Formoterol or Placebo for Stable Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease publication suggested that the combination of bronchodilator therapy of inhaled glucocorticoid/long-acting ß2 adrenoceptor agonist is more effective in improving pulmonary function and health status in the treatment of patients with acute exacerbations than the individual components; however, it is not known whether this also the case for stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to evaluate the effectiveness of budesonide/formoterol in the maintenance and relief therapy of patients with stable COPD. MATERIAL AND METHODS An electronic search of the literature in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials was undertaken to identify published randomized controlled trials (RCTs) of ≥12 weeks duration comparing the budesonide/formoterol, with budesonide, formoterol, or placebo in the treatment of patients with stable COPD. The identified RCTs were reviewed. The mean difference (MD) with corresponding 95% confidence interval (CI) was used to pool the results. RESULTS Seven high quality studies with RCTs met the inclusion criteria for meta-analysis. Compared with budesonide alone, the combination therapy of budesonide/formoterol showed significant improvement in the following spirometric indices: pre-dose forced expiratory volume in 1 second (FEV1) (SMD: 0.26, 95% CI: 0.18, 0.34; P=0.000). In addition, versus formoterol alone, budesonide/formoterol was associated with a significant increase in pre-dose FEV1 (SMD: 0.12, 95% CI: 0.07, 0.17; P=0.000). A similar pattern was also evident in the comparison to placebo, where budesonide/formoterol yielded greater increase in pre-dose FEV1 (SMD: 0.24, 95% CI: 0.18, 0.30; P=0.000). Moreover, compared with other controls, the combination of budesonide-formoterol significantly improved morning peak expiratory flow and evening peak expiratory flow, significantly reduced the total score of St. George's Respiratory Questionnaire. CONCLUSIONS For stable COPD patients, compared with controls (monocomponents or placebo), budesonide/formoterol improved pulmonary function and health status. Future larger long-term RCTs are warranted to assess the beneficial clinical efficacy of budesonide/formoterol in COPD patients.

Alterations of resting-state functional network centrality in patients with asthma: evidence from a voxel-wise degree centrality analysis.

Several previous studies have reported that asthma patients have abnormal brain activities, whereas alterations in the resting-state network still remain unknown. The aim of this study was to investigate the changes in functional network centrality in asthma patients using voxel-wise degree centrality (DC) method. Asthma patients and healthy controls (HCs) were matched closely in age, sex, and education of participants. The DC method was used to evaluate the functional network centrality. The receiver operating characteristic curve was used to distinguish the asthma group from the HCs group. The Pearson correlation coefficient was used to explore the relationship between the observed mean values of DC in different brain areas and the behavioral performance. Compared with HCs, DC values were significantly decreased in the right middle temporal gyrus and the right putamen of asthma patients. In contrast, in asthma patients, DC values were markedly increased in the right posterior lobe of the cerebellum, right inferior temporal gyrus, left superior frontal gyrus, left postcentral gyrus and inferior parietal lobule, left middle frontal gyrus, and left postcentral gyrus. However, there was no relationship between the observed mean DC values in different brain areas and the behavioral performance. The results showed that the DC values were altered in various brain regions of asthma patients, which were related to default mode network, the cortex-basal ganglia network, the frontoparietal network, and the sensorimotor network, leading to some useful information for clinical studies in asthma patients.

[Mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice].

OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 µg/g). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at 24 hours after the last challenge, and the total number of cells and percentage of eosinophils in BALF were calculated. Pathological staining was performed to observe histopathological changes in lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression of E-cadherin and vimentin during epithelial-mesenchymal transition (EMT). RESULTS: Compared with the control group, the OVA group had marked infiltration of inflammatory cells in the airway, thickening of the airway wall, increased secretion of mucus, and increases in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the OVA group, the JQ1+OVA group had significantly alleviated airway inflammatory response and significant reductions in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the control group, the OVA group had significant reductions in the mRNA and protein expression of E-cadherin and significant increases in the mRNA and protein expression of vimentin (P<0.01); compared with the OVA group, the JQ1+OVA group had significant increases in the mRNA and protein expression of E-cadherin and significant reductions in the mRNA and protein expression of vimentin (P<0.01); there were no significant differences in these indices between the JQ1+OVA group and the control group (P>0.05). CONCLUSIONS: Mice with OVA-induced asthma have airway remodeling during EMT. BET bromodomain inhibitor JQ1 can reduce airway inflammation, inhibit EMT, and alleviate airway remodeling, which provides a new direction for the treatment of asthma.

Exhaled Air Molecules and Chronic Obstructive Pulmonary Disease.

Chronic airway inflammation,a main pathologic process of chronic obstructive pulmonary disease (COPD),can trigger inflammation cells and airway structure cells to produce bioactive molecules,which play key roles in the pathogenesis of COPD and are also an efficient indicators for the diagnosis and treatment of COPD. This article reviews the important roles of these exhaled air molecules in the diagnosis and treatment of COPD,with an attempt to offer new strategies in the management of COPD.

[Immunological mechanism of wheezing attack in children with cytomegalovirus infection].

OBJECTIVE: To study the possible immunological mechanism of wheezing attack in children with cytomegalovirus (CMV) infection. METHODS: A total of 25 under-5-year-old children with wheezing following CMV infection were enrolled. The expression of serum regulatory T cells (Treg)/T helper 17 (Th17) cytokines interleukin (IL)-10, IL-6, and IL-17, and peripheral blood lymphocyte subsets were determined. Twenty age-matched healthy children were selected as the control group. RESULTS: The wheezing group had a significantly reduced serum IL-10 level, significantly increased IL-6 and IL-17 levels, significantly reduced levels of natural killer cells, and significantly increased levels of CD8+ T cells and CD19+ B cells, as compared with the control group. CONCLUSIONS: Wheezing children with CMV infection have Treg/Th17 imbalance and cellular immune dysfunction, which may be an important immunological mechanism of the development of wheezing in children after CMV infection.

Proteomic analysis of NGF-induced transdifferentiation of adrenal medullary cells.

Nerve growth factor (NGF) is a polypeptide growth factor with specific trophic function in nerve cells and was initially investigated for its role as a key player in the regulation of peripheral innervations. The aim of this study was to examine the NGF-induced transdifferentiation of adrenal medullary cells, and to screen the major candidate differentially expressed proteins involved in the transdifferentiation. NGF was used to treat primary cultures of neonatal calf adrenal medullary cells and the effects of transdifferentiation were determined in association with cellular morphology, ultrastructure and changes in endocrine function. Differentially expressed proteins were screened and identified through two-dimensional gel electrophoresis and mass spectrometry. The protein spots showing differential expression were verified by western blot analysis. We observed neurite outgrowth in the adrenal medullary cells treated with NGF under a phase contrast microscope. Ultrastructure analysis revealed that there were rich drumstick-like and villiform processes on the cell membranes and vesicles were formed near the cell membranes. The cytoplasm was rich in mitochondria and the secretion of epinephrine was decreased. Two-dimensional gel electrophoresis revealed that among the differentially expressed proteins, 48 protein spots showed an upregulated expression and 37 protein spots showed a downregulated expression, and no 'all-or-none' spots with significant differences in expression were found. Fourteen protein spots with an upregulated expression and 6 with a downregulated expression were randomly selected for identification by mass spectrometry. Western blot analysis revealed that ras homologus oncogene (Rho) GDP dissociation inhibitor α (RhoGDIα) protein expression was significantly downregulated and peripherin protein expression was significantly upregulated. In brief, our data demonstrate that NGF can induce the differentiation of adrenal medullary cells into neurons, and that RhoGDIα and peripherin may play important roles in this process.