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BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.
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Antibacterianos , Infecciones Comunitarias Adquiridas , Levofloxacino , Quinolonas , Humanos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Levofloxacino/uso terapéutico , Levofloxacino/efectos adversos , Levofloxacino/administración & dosificación , Método Doble Ciego , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Adulto , Anciano , Resultado del Tratamiento , Quinolonas/uso terapéutico , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Administración Intravenosa , Infusiones Intravenosas , Adulto Joven , Neumonía/tratamiento farmacológico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: Paclitaxel exhibits outstanding biological activities in inhibiting cell proliferation and inducing cell apoptosis. However, the effects of paclitaxel on airway smooth muscle cells (ASMCs) have not been reported yet. The purpose of this study is to determine the effects of paclitaxel on the proliferation and apoptosis of ASMCs. METHODS: Rat primary ASMCs were isolated and used in all the experiments. Cell Counting Kit-8 assay and Edu assay were used to analyze the cell viability and proliferation, respectively. Flow cytometry was used to detect the cell cycle and apoptosis. Quantitative real-time PCR (qRT-PCR), western blotting, and immunostaining were used to detect the expression of cyclin-dependent kinase 1 (Cdk1). RESULTS: Our study showed that paclitaxel inhibits the proliferation of ASMCs in a dose- and time-gradient-dependent manner. Further study displayed that cell cycle is arrested at G2/M phase. And Cdk1 was dramatically down-regulated by paclitaxel treatment. Cell morphological analysis showed that ASMCs are elliptical with a larger surface area after paclitaxel treatment. Nucleus morphological analysis showed that the nuclei are in a diffuse state after paclitaxel treatment. However, paclitaxel did not induce the apoptosis of ASMCs. CONCLUSIONS: Our study demonstrated that paclitaxel inhibits the proliferation of ASMCs at least partly by negatively regulating Cdk1-cell cycle axis.
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Background: The deposition of Aß42 has been regarded as one of the important pathological features of Alzheimer's disease (AD). However, drug development for Aß42 toxicity has been progressed slowly. Objective: Our aim was to introduce the effect and related mechanism of trehalose on an Aßarc (arctic mutant Aß42) Drosophila AD model. Methods: The human Aßarc was expressed in Drosophila to construct the AD model. Trehalose was added to the culture vial. The movement ability was determined by detecting climbing ability and flight ability. Enzyme-linked immunosorbent assay was used to detect the levels of Aßarc, ATP, and lactate. Electron microscopy assay, mitochondrial membrane potential assay, and mitochondrial respiration assay were used to assess the mitochondrial structure and function. Results: Trehalose strongly improved the movement ability of Aßarc Drosophila in a concentration gradient-dependent manner. Furthermore, trehalose increased the content of ATP and decreased the content of Aßarc and lactate both in the brain and thorax of Aßarc Drosophila. More importantly, the mitochondrial structure and function were greatly improved by trehalose treatment in Aßarc Drosophila. Conclusion: Trehalose improves movement ability at least partly by reducing the Aßarc level and restoring the mitochondrial structure and function in Aßarc Drosophila.
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BACKGROUND: Spontaneous pneumomediastinum (SPM) was defined by the appearance of free air in the mediastinum that was not preceded by trauma, surgery, or other medical procedures. Among the numerous manifestations of SPM, abdominal pain had seldom been described. CASE PRESENTATION: A 25-year-old man presented to the emergency department with nausea, vomiting, and abdominal pain for 7 days. The presenting clinical features and the radiological results were suggestive of psychogenic vomiting with spontaneous pneumomediastinum in a patient who suffered from abdominal pain. CONCLUSIONS: The special feature of this case was the elucidation of a rare cause of abdominal pain, which should be differentiated in patients with vomiting combined with abdominal pain. The importance of this case was that its recognition may prevent unnecessary procedures to rule out or treat other causes of abdominal pain.
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Enfisema Mediastínico , Masculino , Humanos , Adulto , Enfisema Mediastínico/diagnóstico , Enfisema Mediastínico/diagnóstico por imagen , Radiografía , Vómitos/complicaciones , Dolor Abdominal/etiología , Servicio de Urgencia en HospitalRESUMEN
Asthma is a complex and heterogeneous airway disease caused by genetic, environmental and epigenetic factors treated with hormones and biologics. Irreversible pathological changes to airway smooth muscle cells (ASMCs) such as hyperplasia and hypertrophy can occur in asthmatic patients. Determining the mechanisms responsible is vital for preventing such changes. In recent years, noncoding RNAs (ncRNAs), especially microRNAs, long noncoding RNAs and circular RNAs, have been found to be associated with abnormalities of the ASMCs. This review highlights recent ncRNA research into ASMC pathologies. We present a schematic that illustrates the role of ncRNAs in pathophysiological changes to ASMCs that may be useful in future research in diagnostic and treatment strategies for patients with asthma.
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Asma , MicroARNs , Humanos , Células Cultivadas , Asma/diagnóstico , Asma/genética , Asma/patología , Miocitos del Músculo Liso/patología , MicroARNs/genética , Proliferación CelularRESUMEN
Nowadays, the diagnosis and treatment of COPD are often based on the results of lung function tests. Certain individuals, however, are not candidates for lung function testing due to pulmonary bullae, cardiac failure, low lung function, and other factors. Therefore, we evaluated whether serum tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein ß (14-3-3ß) could be a biomarker for the diagnosis of stable COPD patients. The expression of serum 14-3-3ß protein was evaluated by an enzyme-linked immunosorbent assay. The association between its concentrations and clinical parameters of stable COPD patients were analyzed by correlation analysis and ROC curve. The results before propensity score matching (PSM) showed that serum 14-3-3ß protein concentrations (ng/ml) in stable COPD patients were significantly higher than in healthy controls (P < 0.001). Furthermore, serum 14-3-3ß protein concentrations were higher in GOLD 3&4 COPD patients compared with healthy participants, GOLD 1 and GOLD 2 COPD patients (P < 0.05), which shows that the concentration of 14-3-3ß protein correlates with disease severity in stable COPD patients. After 1:1 PSM, there was also a statistically significant rise in 14-3-3 protein levels in stable COPD patients compared to healthy controls (P < 0.01). Serum 14-3-3ß protein levels were positively correlated with blood neutrophil levels (P < 0.05), and negatively related to lung function parameters in stable COPD patients (P < 0.01). When the cutoff value was set at 29.53 ng/ml, the ROC curve yielded a sensitivity of 84.9% and a specificity of 68.3% for diagnosing stable COPD. The 14-3-3ß protein may be a potential serum biomarker for the diagnosis of stable COPD patients, which is associated with disease severity, systemic inflammation, and small airway obstruction.
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Proteínas 14-3-3 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Proteínas 14-3-3/metabolismo , Relevancia Clínica , Estudios de Casos y Controles , BiomarcadoresRESUMEN
BACKGROUND: Pleural effusion is a common clinical condition caused by several respiratory diseases, including tuberculosis and malignancy. However, rapid and accurate diagnoses of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remain challenging. Although monocytes have been confirmed as an important immune cell in tuberculosis and malignancy, little is known about the role of monocytes subpopulations in the diagnosis of pleural effusion. METHODS: Pleural effusion samples and peripheral blood samples were collected from 40 TPE patients, 40 MPE patients, and 24 transudate pleural effusion patients, respectively. Chemokines (CCL2, CCL7, and CX3CL1) and cytokines (IL-1ß, IL-17, IL-27, and IFN-γ) were measured by ELISA. The monocytes phenotypes were analyzed by flow cytometry. The chemokines receptors (CCR2 and CX3CR1) and cytokines above in different monocytes subsets were analyzed by real-time PCR. Receiver operating characteristic curve analysis was performed for displaying differentiating power of intermediate and nonclassical subsets between tuberculous and malignant pleural effusions. RESULTS: CCL7 and CX3CL1 levels in TPE were significantly elevated in TPE compared with MPE and transudate pleural effusion. Cytokines, such as IL-1ß, IL-17, IL-27, and IFN-γ, in TPE were much higher than in other pleural effusions. Moreover, CD14+ CD16++ nonclassical subset frequency in TPE was remarkably higher than that in MPE, while CD14++ CD16+ intermediate subset proportion in MPE was found elevated. Furthermore, CX3CL1-CX3CR1 axis-mediated infiltration of nonclassical monocytes in TPE was related to CX3CL1 and IFN-γ expression in TPE. Higher expression of cytokines (IL-1ß, IL-17, IL-27, and IFN-γ) were found in nonclassical monocytes compared with other subsets. Additionally, the proportions of intermediate and nonclassical monocytes in pleural effusion have the power in discriminating tuberculosis from malignant pleural effusion. CONCLUSIONS: CD14 and CD16 markers on monocytes could be potentially used as novel diagnostic markers for diagnosing TPE and MPE.
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Interleucina-27 , Derrame Pleural Maligno , Derrame Pleural , Tuberculosis , Biomarcadores , Exudados y Transudados/metabolismo , Humanos , Interleucina-17 , Monocitos/metabolismo , Derrame Pleural/diagnóstico , Derrame Pleural/metabolismo , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Tuberculosis/diagnósticoRESUMEN
Asthma is a chronic inflammatory disease that involves complex gene-environment interactions. Methylation of nucleotides, such as 5-methylcytosine (5mC) in DNA and N6-methyladenosine (m6A) in mRNA, carries important information for gene regulation. Our study screened m6A genes and genes associated with asthma from the Gene Expression Omnibus (GEO) databases GSE63383, GSE119580, GSE38003, GSE34313, GSE13168, and GSE35643. GSE52778, GSE35643, GSE40996, and GSE64744), and DNA methylation data from GSE85568 and GSE146377. We screened out 6 m6A related genes (FTO, IGF2BP2, RBM15, RBMX, WTAP, and YTHDC1) that were significantly dysregulated in asthma or proinflammatory conditions. A correlation study showed a high correlation between m6A genes and gene pairs such as WTAP, IL7R, and TLR2; RBMX, SLC22A4, IL33, TNC, FLG, and IL6R (|r| ≥ 0.8). Following DNA methylation dataset analysis, we proposed several DNA methylation-m6A modification asthma-related gene axes such as cg19032951/cg15153914-IGF2BP2-SMAD3. Interestingly, several target genes, such as SMAD3, possess the ability to participate in DNA methylation processes, which may reciprocally regulate the expression of m6A genes and form a closed-loop regulation axis. Some classic DNA methylation-related genes, such as TET1, UHRF1, and ZBTB4, were also involved. We identified an integrated profile of m6A gene expression in asthma and proposed a novel potential interplay between DNA methylation and m6A modification in asthma pathogenesis. Using the CMAP database, we found that resveratrol may target these dysregulated m6A genes, and therefore may serve as a potential therapeutic agent for asthma.
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Asma , Metilación de ADN , Adenosina/genética , Adenosina/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Asma/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Análisis de Datos , Expresión Génica , Humanos , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al ARN/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
OBJECTIVES: The purpose of this study was to clarify the relationship between obstructive sleep apnea (OSA) and oxidative stress markers in blood. METHODS: We conducted a systematic literature search on databases including Pubmed and Embase for studies reporting circulating oxidative stress markers in patients with OSA and controls that were published between 1988 and June 2019. Standardized mean differences (SMDs) and 95% confidence intervals (95%CI) were calculated. RESULTS: Of the 2226 articles initially retrieved, 52 were included in our meta-analysis, covering a total of 12 oxidative stress markers. The concentrations of malondialdehyde (SMD = 1.18; 95%CI: 0.87, 1.49; p < 0.001), thiobarbituric acid reactive substances (SMD = 1.82; 95%CI: 0.79, 2.86; p = 0.001), advance oxidative protein products (SMD = 0.68; 95%CI: 0.14, 1.23; p = 0.014), total oxidant capacity (SMD = 1.32; 95%CI: 0.33, 2.31; p = 0.009), and asymmetric dimethylarginine (SMD = 0.32; 95%CI: 0.16, 0.47; p < 0.001) in the blood of patients with OSA were higher than those of the control group, whereas the concentrations of thiols (SMD = - 0.37; 95%CI: - 0.60, - 0.15; p = 0.001) and nitric oxide (SMD = - 2.61; 95%CI: - 4.02, - 1.21; p < 0.001) were lower than those of the control group. CONCLUSIONS: The oxidative stress markers in the blood of patients with OSA were aberrant, indicating an imbalanced state of oxidation and antioxidation in OSA.
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Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/diagnóstico , Biomarcadores , Estrés Oxidativo , Malondialdehído , Óxido NítricoRESUMEN
Background: Cigarette smoking and Th2-inflammation are both crucial in the pathogenesis of asthma. However, it is unknown whether smoking can affect the association between Th2-inflammation and small airway obstruction in adults with asthma. Methods: Adults diagnosed with asthma by a pulmonologist according to Global Initiative for Asthma guidelines were recruited from September 2016 to April 2018 to participate in this study. Participants were divided into two groups, the small airway obstruction group (those with FEF25-75% predicted value ≤ 65%) and the normal small airway function group (those with FEF25-75% predicted value > 65%). Final data analysis included 385 and 93 people in the Obstructive Group and the Normal Group, respectively. Total serum IgE level and blood eosinophil count were used as biomarkers of the Th2 phenotype. Results: The Obstructive Group had a larger fraction of smokers, higher blood eosinophil count, and lower lung function than the Normal Group. Current-smoking status was associated with an increased risk of small airway obstruction (adjusted odds ratio = 4.677, 95% confidence interval [1.593-13.730]); and log-IgE level was associated with a decreased risk of small airway obstruction (0.403 [0.216-0.754]). Smoking status stratified analysis showed an association between log-IgE level and a decreased risk of small airway obstruction only in never-smoker asthmatics (0.487 [0.249-0.954]). Conclusions: Current-smoking status and total serum IgE are, respectively, associated with small airway obstruction. Smoking status modifies the relationship between Th2 biomarkers and small airway function. These findings contribute to the understanding of risk factors associated with asthma endotyping.
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Obstrucción de las Vías Aéreas , Asma , Obstrucción de las Vías Aéreas/epidemiología , Asma/epidemiología , Biomarcadores , Eosinófilos , Humanos , FumarRESUMEN
Trehalose is a disaccharide with multiple important biological activities. In many cell types, Trehalose regulates the physiological behaviors of proliferation, apoptosis and autophagy. But the effects of trehalose on ASMCs have never been reported. Here, we showed that trehalose activated autophagy of ASMCs at low dose, inhibited proliferation and induced apoptosis of ASMCs at high dose. Further study, we found the cell cycle was arrested in S and G2\M phases, the expression of CyclinA1 and CyclinB1 decreased. Then, we investigated the ratio of Bcl-2/Bax was drastically reduced. Next, we detected an important transcription factor TFEB, which is closely related to autophagy. We found TFEB was highly activated with trehalose treatment. And many downstream autophagy-related genes of TFEB were also up-regulated. In summary, trehalose plays an important role on the regulation of proliferation, apoptosis and autophagy of ASMCs.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Sistema Respiratorio/metabolismo , Trehalosa/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The determination of systemic inflammatory markers is one of the important directions to study the pathogenesis of asthma and improve the diagnosis of asthma. Current studies have found that the 14-3-3 protein family subtypes interact with target proteins to participate in the pathogenesis of a variety of immune inflammatory diseases. However, studies on serum tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein ß (14-3-3ß) in asthma are scarce. This study aimed to assess the clinical significance of 14-3-3ß in asthmatic patients. METHODS: We recruited 54 asthmatic patients with acute exacerbation and 50 asthmatic patients with chronic persistent. The normal control group included 54 healthy individuals. Clinical characteristics, clinical indicators [fractional expiratory nitric oxide (FeNO), eosinophil count, forced vital capacity (FVC), percent of predicted FVC (FVC% predicted), forced expiratory volume in one second (FEV1), percent of predicted FEV1 (FEV1% predicted), the ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and serum 14-3-3ß levels were measured to compare among each group. Spearman's rank correlation coefficient was used to evaluate the correlation between 14-3-3ß and clinical indicators. Finally, Receiver-operating characteristic (ROC) curves analysis was used to determine the sensitivity and specificity of 14-3-3ß. RESULTS: Our results showed that median (interquartile range) of serum 14-3-3ß concentration (ng/mL) in acute exacerbation group of asthma (41.18 [33.06-51.76]) was much higher than that in normal control group (24.99 [17.43-29.91]; P < 0.001) and chronic persistent group of asthma (25.88 [21.03-34.55]; P < 0.001). Spearman's correlation coefficient shows that the serum 14-3-3ß level was positively correlated with FeNO (r = - 0.292, P = 0.032) and peripheral blood eosinophil count (r = 0.328, P = 0.016), and was negatively related to FEV1/FVC (r = - 0.293, P = 0.031) in the acute exacerbation group of asthma. At the same time, the serum 14-3-3ß level was also negatively associated with FEV1 (r = - 0.297, P = 0.036) in the chronic persistent group of asthma. ROC curve analysis comparing acute exacerbation group of asthma with normal control group demonstrated a significant (P < 0.001) AUC of 0.90 (95% CI 0.85-0.96). CONCLUSION: The serum 14-3-3ß protein may become a potential biomarker in asthmatic patients with acute exacerbation.
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BACKGROUND: Although studies have identified hundreds of genetic variants associated with asthma risk, a large fraction of heritability remains unexplained, especially in Chinese individuals. METHODS: To identify genetic risk factors for asthma in a Han Chinese population, 211 asthma-related genes were first selected based on database searches. The genes were then sequenced for subjects in a Discovery Cohort (284 asthma patients and 205 older healthy controls) using targeted next-generation sequencing. Bioinformatics analysis and statistical association analyses were performed to reveal the associations between rare/common variants and asthma, respectively. The identified common risk variants underwent a validation analysis using a Replication Cohort (664 patients and 650 controls). RESULTS: First, we identified 18 potentially functional rare loss-of-function (LOF) variants in 21/284 (7.4%) of the asthma cases. Second, using burden tests, we found that the asthma group had nominally significant (p < 0.05) burdens of rare nonsynonymous variants in 10 genes. Third, 23 common single-nucleotide polymorphisms were associated with the risk of asthma, 7/23 (30.4%) and 9/23 (39.1%) of which were modestly significant (p < 9.1 × 10-4 ) in the Replication Cohort and Combined Cohort, respectively. According to our cumulative risk model involving the modestly associated alleles, middle- and high-risk subjects had a 2.0-fold (95% CI: 1.621-2.423, p = 2.624 × 10-11 ) and 6.0-fold (95% CI: 3.623-10.156, p = 7.086 × 10-12 ) increased risk of asthma, respectively, compared with low-risk subjects. CONCLUSION: This study revealed novel rare and common genetic risk factors for asthma, and provided a cumulative risk model for asthma risk prediction and stratification in Han Chinese individuals.
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Asma/genética , Asma/patología , Biomarcadores/metabolismo , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asma/epidemiología , Biomarcadores/análisis , Estudios de Casos y Controles , Niño , Preescolar , China/epidemiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. Hyaluronidase 1 (HYAL1) was found to be upregulated in fibroblasts from IPF patients, and overexpression of HYAL1 could prevent human fetal lung fibroblast proliferation. However, the genetic correlation between the HYAL1 and IPF or connective tissue diseases related interstitial lung disease (CTD-ILD) has not been determined. METHODS: A two-stage study was conducted in Southern Han Chinese population. We sequenced the coding regions and flanking regulatory regions of HYAL1 in stage one (253 IPF cases and 125 controls). A statistically significant variant was further genotyped in stage two (162 IPF cases, 182 CTD-ILD cases, and 225 controls). RESULTS: We identified a nonsynonymous polymorphism (rs117179004, T392M) significantly associated with increased IPF risk (dominant model: OR = 2.239, 95% CI = 1.212-4.137, p = 0.010 in stage one; OR = 2.383, 95% CI = 1.376-4.128, p = 0.002 in stage two). However, we did not observe this association in CTD-ILD (OR = 1.401, 95% CI = 0.790-2.485, p = 0.248). CONCLUSION: Our findings suggest that the nonsynonymous polymorphism (rs117179004, T392M) may confer susceptibility to IPF in Southern Han Chinese, but is not associated with susceptibility to CTD-ILD.
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Hialuronoglucosaminidasa/genética , Fibrosis Pulmonar Idiopática/genética , Polimorfismo de Nucleótido Simple , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Pulmonares Intersticiales/genética , Masculino , Persona de Mediana EdadRESUMEN
Inhibition of activated macrophages is an alternative therapeutic strategy for asthma. We investigated whether a coumarin compound, osthole, isolated from Cnidium monnieri (L.) Cuss, alleviated macrophage activation in vivo and in vitro. Osthole could reduce expression of a marker of activated macrophages, cluster of differentiation (CD)206, in an ovalbumin-challenge model of asthma in mice. Osthole could also inhibit infiltration of inflammatory cells, collagen deposition and production of proinflammatory cytokines [interleukin (IL)-1ß, tumor necrosis factor-É, macrophage migration inhibitory factor (MIF)] in asthmatic mice. In vitro, expression of phosphorylated-IĸBÉ, MIF and M2 cytokines (Ym-1, Fizz-1, arginase-1) in IL-4-induced macrophages decreased upon exposure to the NF-ĸB inhibitor MG-132. In our short hairpin (sh)RNA-MIF-knockdown model, reduced expression of M2 cytokines was detected in the IL-4 + shRNA-MIF group. Osthole could attenuate the proliferation and migration of an IL-4-induced rat alveolar macrophages line (NR8383). Osthole could reduce IL-4-induced translocation of nuclear factor-kappa B (NF-ĸB) in NR8383 cells. Collectively, our results suggest that osthole ameliorates macrophage activation in asthma by suppressing the NF-ĸB/MIF signaling pathway, and might be a potential agent for treating asthma.
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Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has one of the poorest prognosis. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined that IL-24, an IL-20 subfamily cytokine member, was increased both in the serum of IPF patients and the bronchoalveolar lavage fluid (BALF) of mice following bleomycin (BLM)-induced pulmonary fibrosis. As a result, IL-24 deficiency protected mice from BLM-induced lung injury and fibrosis. Specifically, loss of IL-24 significantly attenuated transforming growth factor ß1 (TGF-ß1) production and reduced M2 macrophage infiltration in the lung of BLM-induced mice. Mechanistically, IL-24 alone did not show a perceptible impact on the induction of M2 macrophages, but it synergized with IL-4 to promote M2 program in macrophages. IL-24 suppressed IL-4-induced expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, through which it enhanced signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma (STAT6/PPARγ) signaling, thereby promoting IL-4-induced production of M2 macrophages. Collectively, our data support that IL-24 synergizes with IL-4 to promote macrophage M2 program contributing to the development of pulmonary fibrosis.
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Bleomicina/efectos adversos , Interleucina-4/metabolismo , Interleucinas/deficiencia , Macrófagos/metabolismo , Fibrosis Pulmonar/prevención & control , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
PURPOSE: Recent studies have demonstrated that macrophage migration inhibitory factor (MIF) is of importance in asthmatic inflammation. The role of MIF in modulating airway remodeling has not yet been thoroughly elucidated to date. In the present study, we hypothesized that MIF promoted airway remodeling by intensifying airway smooth muscle cell (ASMC) autophagy and explored the specific mechanisms. METHODS: MIF knockdown in the lung tissues of C57BL/6 mice was conducted by instilling intratracheally adeno-associated virus (AAV) vectors (MIF-mutant AAV9) into mouse lung tissues. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) was used to detect the role of autophagy in ovalbumin (OVA)-asthmatic murine models. Moreover, to block the expression of MIF and CD74 in vitro models, inhibitors, antibodies and lentivirus transfection techniques were employed. RESULTS: First, MIF knockdown in the lung tissues of mice showed markedly reduced airway remodeling in OVA murine mice models. Secondly, ASMC autophagy was increased in the OVA-challenged models. Mice genetically deficient in the autophagy marker ATG5 (ATG5+/-) that were primed and challenged with OVA showed lower airway remodeling than genetically wild-type asthmatic mice. Thirdly, MIF can induce ASMC autophagy in vitro. Moreover, the cellular source of MIF which promoted ASMC autophagy was macrophages. Finally, MIF promoted ASMC autophagy in a CD74-dependent manner. CONCLUSIONS: MIF can increase asthmatic airway remodeling by enhancing ASMC autophagy. Macrophage-derived MIF can promote ASMC autophagy by targeting CD74.
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Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.
Asunto(s)
COVID-19/metabolismo , Proteínas de Unión al ADN/metabolismo , Macrófagos/metabolismo , Fibrosis Pulmonar/metabolismo , Animales , Bleomicina/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Fibrosis , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Liposomas/química , Enfermedades Pulmonares Intersticiales/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibrosis Pulmonar/virología , ARN Interferente Pequeño/metabolismo , Esclerodermia Sistémica/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
AIM: To evaluate the overall diagnostic performance of 14-3-3 η protein in patients with rheumatoid arthritis (RA). METHODS: PubMed, EMBASE, and Web of Science were searched to acquire eligible studies. Articles published in English before 20 February 2020 were included. Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate the risk of bias and application concern of the included articles. Pooled analysis of diagnostic indicators of 14-3-3 η protein for RA was conducted by using a random effects model. Subgroup analysis was used to explore the sources of heterogeneity. Deeks' funnel plot asymmetry test was used to evaluate for the presence of publication bias. RESULTS: A total of 13 studies (1554 positive and 1934 negative participants) were included. The pooled sensitivity and specificity were 0.73 (95% CI 0.71-0.75) and 0.88 (95% CI 0.87-0.90), respectively. The pooled positive/negative likelihood were 5.98 (95% CI 4.39-8.14) and 0.28 (95% CI 0.21-0.37), respectively. In addition, the pooled diagnostic odds ratio was 23.48 (95% CI 13.76-40.08) and the area under curve was 0.9245. The results of subgroup analysis indicated that ethnicity and control group might be the source of heterogeneity. The results of sensitivity analysis were stable. No significant publication bias was found. CONCLUSIONS: The current evidence indicated that 14-3-3 η protein has moderate accuracy for the diagnosis of RA.