Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling.

Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.

Mechanisms regarding cardiac toxicity triggered by up-regulation of miR-144 in larval zebrafish upon exposure to triclosan.

Although triclosan (TCS) is ubiquitously detected in environmental media and organisms, little information is available on its cardiotoxicity and underlying mechanisms. Herein, acute TCS exposure (0.69-1.73 µM) to zebrafish from embryos (6 hpf) to larvae (72 hpf) resulted in cardiac development defects, including increased angle between atrium and ventricle, prolonged SV-BA distance, linearized heart and pericardial cyst in 72-hpf larvae. These malformations resulted from interfered oxidative-stress pathways, reflecting in accumulated ROS and MDA and inhibited SOD and CAT activities. By RT-qPCR, the transcription levels of four cardiac development-related marker genes were significantly up-regulated except for gata4. Besides, miR-144 was identified as a regulatory molecule of TCS-induced cardiac defects by integrating analyses of artificial intervene expression and RNA-Seq data. Interestingly, the target genes of miR-144 were found and interacted with the above marker genes through constructing protein-protein interaction networks. After intervening the expression of miR-144 by microinjecting and activating Wnt pathway by an agonist BML-284, we confirmed that up-regulated miR-144 suppressed the expression of angiogenesis-related genes and negatively regulated Wnt pathway, further triggering angiogenesis disorders and cardiac phenotypic malformation. These findings unravel the underlying molecular mechanisms regarding TCS-induced cardiac development toxicity, and contribute to early warning and risk management of TCS.

Triclosan targets miR-144 abnormal expression to induce neurodevelopmental toxicity mediated by activating PKC/MAPK signaling pathway.

Although the previous research confirmed that triclosan (TCS) induced an estrogen effect by acting on a novel G-protein coupled estrogen-membrane receptor (GPER), the underlying mechanisms by which downstream pathways induce neurotoxicity remain unclear after TCS activation of GPER. By employing a series of techniques (Illumina miRNA-seq, RT-qPCR, and artificial intervention of miRNA expression), we screened out four important miRNAs, whose target genes were directly/indirectly involved in neurodevelopment and neurobehavior. Especially, the miR-144 up-regulation caused vascular malformation and severely affected hair-cell development and lateral-line-neuromast formation, thereby causing abnormal motor behavior. After microinjecting 1-2-cell embryos, the similar phenotypic malformations as those induced by TCS were observed, including aberrant neuromast, cuticular-plate development and motor behavior. By KEGG pathway enrichment analysis, these target genes were demonstrated to be mainly related to the PKC/MAPK signaling pathway. When a PKC inhibitor was used to suppress the PKC/MAPK pathway, a substantial alleviation of TCS-induced neurotoxicity was observed. Therefore, TCS acts on GPER to activate the downstream PKC/MAPK signaling pathway, further up-regulating miR-144 expression and causing abnormal modulation of these nerve-related genes to trigger neurodevelopmental toxicity. These findings unravel the molecular mechanisms of TCS-induced neurodegenerative diseases, and offer theoretical guidance for TCS-pollution early warning and management.

Correlation of Clinical Symptoms and Sputum Inflammatory Markers with Air Pollutants in Stable COPD Patients in Beijing Area.

Short-term exposure to major air pollutants can increase the risk of acute exacerbation in chronic obstructive pulmonary disease (COPD) patients. However, evidence on the mechanism of acute exacerbation of COPD (AECOPD) caused by air pollutants is still limited. A total of 78 patients with stable COPD and 58 healthy controls were recruited in Peking University Third Hospital in China from December 2014 to January 2015. The correlation and lag effect over 7 days (lag1-7) of 6 air pollutants with clinical symptoms and inflammatory markers in induced sputum were analyzed. PM2.5, NO2 and CO were positively correlated with the COPD assessment test (CAT) score at lag 5, PM10 was positively correlated with the CAT score at lag 3, MMP-9 and IL-8 were positively correlated with PM2.5, PM10 and NO2 at lag 2, and CO was positively correlated with each other marker at lag 4. Short-term exposure to PM2.5, PM10, NO2, and CO can cause a neutrophil-mediated airway inflammatory response, followed by increased clinical symptoms. If the PM2.5, PM10, NO2 and CO exposure levels increase during air pollution monitoring, the early usage of medication or reduction of exposure to pollutants can effectively reduce the clinical symptoms of patients.

Ciprofibrate attenuates airway remodeling in cigarette smoke-exposed rats.

Airway remodeling is a key pathological lesion in chronic obstructive pulmonary disease (COPD), and it leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective at controlling airway remodeling. To address this issue, we queried the Connectivity Map (cMap) database to screen for drug candidates that had the potential to dilate the bronchus and inhibit airway smooth muscle (ASM) proliferation. We identified ciprofibrate as a drug candidate. Ciprofibrate inhibited cigarette smoke extract-induced rat ASM cell contraction and proliferation in vitro. We exposed Sprague-Dawley (SD) rats to clean air or cigarette smoke (CS) and treated the rats with ciprofibrate. Ciprofibrate improved pulmonary function, inhibited airway hypercontraction, and ameliorated morphological small airway remodeling, including airway smooth muscle proliferation, in CS-exposed rats. Ciprofibrate also significantly reduced IL-1ß, IL-12p70, IL-17A and IL-18 expression, which are related to airway remodeling, in the sera of CS-exposed rats. These findings indicate that ciprofibrate could attenuate airway remodeling in CS-exposed rats.

Disruption of histidine and energy homeostasis in chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range. Methods: We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student's t-test with Welch correction or ANOVA with post-hoc Tukey's test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation. Results: Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD. Conclusion: COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.Trial registration www.clinicaltrials.gov, NCT03310177.

Serum amino acid concentrations and clinical outcomes in smokers: SPIROMICS metabolomics study.

Metabolomics is an emerging science that can inform pathogenic mechanisms behind clinical phenotypes in COPD. We aimed to understand disturbances in the serum metabolome associated with respiratory outcomes in ever-smokers from the SPIROMICS cohort. We measured 27 serum metabolites, mostly amino acids, by 1H-nuclear magnetic resonance spectroscopy in 157 white ever-smokers with and without COPD. We tested the association between log-transformed metabolite concentrations and one-year incidence of respiratory exacerbations after adjusting for age, sex, current smoking, body mass index, diabetes, inhaled or oral corticosteroid use, study site and clinical predictors of exacerbations, including FEV1% predicted and history of exacerbations. The mean age of participants was 53.7 years and 58% had COPD. Lower concentrations of serum amino acids were independently associated with 1-year incidence of respiratory exacerbations, including tryptophan (ß = -4.1, 95% CI [-7.0; -1.1], p = 0.007) and the branched-chain amino acids (leucine: ß = -6.0, 95% CI [-9.5; -2.4], p = 0.001; isoleucine: ß = -5.2, 95% CI [-8.6; -1.8], p = 0.003; valine: ß = -4.1, 95% CI [-6.9; -1.4], p = 0.003). Tryptophan concentration was inversely associated with the blood neutrophil-to-lymphocyte ratio (p = 0.03) and the BODE index (p = 0.03). Reduced serum amino acid concentrations in ever-smokers with and without COPD are associated with an increased incidence of respiratory exacerbations.

Symptom-related sputum microbiota in stable chronic obstructive pulmonary disease.

Background: The role of airway microbiota in COPD is highly debated. Symptomology assessment is vital for the management of clinically stable COPD patients; however, the link between symp toms and the airway microbiome is currently unknown. Purpose: The present study aimed to evaluate the relationship among stable COPD patients. Patients and methods: We conducted pyrosequencing of bacterial 16S rRNA using induced sputum samples in a Han Chinese cohort that included 40 clinically stable COPD patients and 19 healthy controls. Results: Alterations in community composition and core bacte rial taxa (Neisseria subflava, etc.) were observed in patients with severe symptoms compared with controls. The co-occurrence network indicated that the key microbiota enriched in COPD patients showed higher expression in patients with severe symptoms. The association pattern of symptoms with the sputum microbiome was obviously different from that of lung function in COPD patients. Conclusion: These findings broaden our insights into the relationship between the sputum microbiota and the symptom severity in COPD patients, emphasizing the role of symptoms in the airway microbiome, independent of lung function.

Characterization of throat microbial flora in smokers with or without COPD.

The study aimed to determine the relationship between throat microbiome and COPD. Sixty-five Chinese males (n=20, smokers without COPD; n=45 smokers with COPD) were included. Nonmetric multidimensional scaling indicated differences of microbiome between COPD and controls, but no difference was observed between COPD patients with differing degrees of lung function or disease severity. Rarefaction analyses suggested that operational taxonomic units (OTUs, species-level) richness decreased in COPD. The dominant taxa between COPD and controls were similar, but the proportions of taxonomic distribution were different. The dominant phyla were Bacteroidetes, Proteobacteria, Firmicutes and Fusobacteria. The dominant genera were Haemophilus, Leptotrichia, Porphyromonas, Fusobacterium, Veillonella, Streptococcus, Neisseria and Prevotella. Two dominant OTUs, otu3 (Veillonella_dispar) and otu4 (Streptococcus_unclassified), were identified. Otu3 and its father-level taxa, which were negatively correlated with predicted percent of forced expiratory volume in a second (FEV1%pred), were increased in COPD. By contrast, otu4 and its father-level taxa, which were positively correlated with FEV1%pred, were decreased in COPD. Otu4 also showed a slight potential as a COPD biomarker. To conclude, the throat microbiome was different between smokers with or without COPD, which is similar to findings from the lower respiratory tract. This study may strengthen our understanding of the relationship between microbiomes of different airway sites and COPD.

Identification of thyroxine-binding globulin as a candidate plasma marker of chronic obstructive pulmonary disease.

Biomarkers for the management of chronic obstructive pulmonary disease (COPD) are limited. The aim of this study was to explore new plasma biomarkers in patients with COPD. Thyroxine-binding globulin (THBG) was initially identified by proteomics in a discovery panel and subsequently verified by enzyme-linked immunosorbent assay in another verification panel with a 1-year follow-up. THBG levels were elevated in patients with COPD (9.2±2.3 µg/mL) compared to those of the controls (6.6±2.0 µg/mL). Receiver operating characteristic curves suggested that THBG was able to slightly differentiate between patients with COPD and controls (area under the curve [AUC]: 0.814) and performed better if combined with fibrinogen (AUC: 0.858). THBG was more capable of distinguishing Global Initiative for Obstructive Lung Disease stages I-III and IV (AUC: 0.851) compared with fibrinogen (AUC 0.582). THBG levels were negatively associated with predicted percentage forced expiratory volume in 1 s and positively related to predicted percentage residual volume, RV/percentage total lung capacity, and percentage low-attenuation area. COPD patients with higher baseline THBG levels had a greater risk of acute exacerbation (AE) than those with lower THBG levels (P=0.014, by Kaplan-Meier curve; hazard ratio: 4.229, by Cox proportional hazards model). In summary, THBG is a potential plasma biomarker of COPD and can assist in the management of stable stage and AEs in COPD patients.

Effect of Dermabrasion and ReCell® on Large Superficial Facial Scars Caused by Burn, Trauma and Acnes△.

Objective To explore the effects of dermabrasion combined with ReCell® on large superficial facial scars caused by burn, trauma and acnes.Methods Nineteen patients with large superficial facial scars were treated by the same surgeon with dermabrasion combined with ReCell®. According to the etiology, patients were classified into post-burning group (n=5), post-traumatic group (n=7) and post-acne group (n=7). Fifteen patients completed the follow-ups, 5 patients in each group. Healing time, complication rate, the preoperative and 18-month-post-operative assessments using Patient Satisfaction Score (PSS), Vancouver Scar Scale (VSS), and Patient and Observer Scar Assessment Scale (POSAS) of each group were analyzed to compare the effect of the combined therapy on outcomes.Results The healing time of post-burning group (19.6±4.0 days), post-traumatic group (15.8±2.6 days), and post-acne group (11.4±3.1 days) varied remarkably (F=7.701, P=0.007). The complication rates were 60%, 20%, and 0 respectively. The post-operative POSAS improved significantly in all groups (P<0.05), where the most significant improvement was shown in the post-acne group (P<0.05). The post-operative PSS and VSS improved only in the post-traumatic group and post-acne group (all P<0.05), where the more significant improvement was also shown in the post-acne group (P<0.05).Conclusions The combined treatment of dermabrasion and ReCell® has remarkable effect on acne scars, moderate effect on traumatic scars and is not suggested for burn scars. POSAS should be applied to assess the therapeutic effects of treatments for large irregular scars.

Fetuin-B (FETUB): a Plasma Biomarker Candidate Related to the Severity of Lung Function in COPD.

Biomarkers for the progression of lung function in COPD are currently scarce. Plasma fetuin-B (FETUB) was identified by iTRAQ-based proteomics and was verified by ELISA in another group. Information regarding acute exacerbation (AE) was collected in a one-year follow-up programme. FETUB concentrations (1652 ± 427 ng/ml) were greater in COPD patients than in controls (1237 ± 77 ng/ml). The concentrations of FETUB in GOLD II (1762 ± 427 ng/ml), III (1650 ± 375 ng/ml) and IV (1800 ± 451 ng/ml) groups were greater than those in the controls (1257 ± 414 ng/ml) and the GOLD I (1345 ± 391 ng/ml) group. ROCs indicated that FETUB distinguished COPD patients from controls (AUC 0.747, 95% CI: 0.642-0.834) and also GOLD II, III and IV from GOLD I COPD patients (AUC: 0.770, 95% CI: 0.634-0.874). The combination of FETUB and fibrinogen performed better (AUC: 0.804, 95% CI: 0.705-0.881). FETUB also predicted the occurrence of AE (AUC: 0.707, 95% CI: 0.566-0.824) or frequent AE (AUC: 0.727, 95% CI: 0.587-0.840). FETUB concentrations were negatively correlated with FEV1%pred (r = -0.446, p = 0.000) and positively correlated with RV%pred (r = 0.317, p = 0.004), RV/TLC% (r = 0.360, p = 0.004), CT emphysema% (r = 0.322, p = 0.008) and grades of lung function (r = 0.437, p = 0.000). In conclusion, FETUB is likely to assist the diagnosis and management of COPD as a complement for other markers.

A Successfully Treated Metastatic Choriocarcinoma Coexistent With Pregnancy: A Case Report of a 4-Year Follow-Up.

Gestational choriocarcinoma ended with a successful parturition is extremely rare, especially in cases where multiple metastases occurred.A 29-year-old Chinese primigravida was admitted with vaginal bleeding at 32 gestational week, and diagnosed with gestational choriocarcinoma with vaginal, pulmonary, and cerebral metastasis after pathological, and imaging examination. At 33 gestational week, a healthy infant was delivered by cesarean section. Although no evidence of choriocarcinoma or any other forms of gestational trophoblastic diseases was found in the placenta and uterine curettages, the patient was given 7 cycles of postpartum chemotherapy. Her serum beta-human chorionic gonadotropin level fell to the normal range, and the metastatic lesions reduced. The baby is still free from diseases, and the patient reports no clinical manifestation 4 years after the hospital discharge.Despite its rapid metastases and complications, gestational choriocarcinoma still can be successfully treated by postpartum chemotherapy with the least delay.

Comparison of clinical efficacy and complications between Q-switched alexandrite laser and Q-switched Nd:YAG laser on nevus of Ota: a systematic review and meta-analysis.

Although the application of Q-switched lasers on nevus of Ota (OTA) is well demonstrated, debates about clinical option between Q-switched alexandrite laser (QSA) and Q-switched Nd:YAG laser (QSNY) still remain. This systematic review and meta-analysis estimated the overall successful rate of OTA pigment clearance and complication rate of QSA and QSNY and evaluated which laser could produce a better result. English articles evaluating pigment clearance and complications of QSA and/or QSNY on OTA were screened through predetermined inclusion and exclusion criteria and analyzed. The successful rate of pigment clearance and complication rate of QSA and QSNY were respectively calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies. The successful rate and complication rate of QSA and QSNY were compared statistically. Of the 140 articles searched, 13 met inclusion criteria. Totally, 2153 OTA patients treated by QSA and 316 patients treated by QSNY were analyzed. In QSA and QSNY groups, respectively, the successful rate of OTA pigment clearance was 48.3% (95% confidence interval (CI) 19.9-76.8%) and 41% (95% CI 9.7-72.2%), while the complication rate was 8.0% (95% CI 3.9-12.2%) and 13.4% (95% CI 7.7-19.0%). When compared with QSNY, QSA had a significantly higher successful rate (P = 0.017), and a lower complication rate (P = 0.000). According to this review, QSA may surpass QSNY in treatment for OTA as it had a superior successful rate of pigment clearance and a lower complication rate than QSNY did.

Efficacy of 23-valent pneumococcal polysaccharide vaccine in preventing community-acquired pneumonia among immunocompetent adults: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Data on the efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV-23) in preventing adult community-acquired pneumonia (CAP) among the target population of individuals aged over 65 years and high-risk individuals aged 19-64 years are conflicting. As the Advisory Committee on Immunization Practices (ACIP) has recently demonstrated PPV-23 is likely beneficial to immunocompromised adults by the Grading, Assessment, Development, and Evaluation (GRADE) framework, we conducted meta-analysis to examine its efficacy in an immunocompetent population. METHODS: We searched the PUBMED, EMBASE, and Cochrane Library databases for randomized trials. Overall relative risks (RRs) with 95% confidential intervals (CIs) were calculated, and the Cochrane Q test (p, I(2)) was performed. Outcomes were assessed by the GRADE framework. RESULTS: Seven randomized trials involving 156,010 participants were included in this meta-analysis. High-quality evidence revealed that PPV-23 was weakly associated with the prevention of all-cause pneumonia ([RR] 0.87, [95%CI] 0.76-0.98, p=0.11, I(2)=43%), especially among the target population ([RR] 0.72, [95%CI] 0.69-0.94, p=0.58 I(2)=0%), the elderly group aged over 40 years ([RR] 0.80, [95%CI] 0.69-0.94) and the Japanese population ([RR] 0.72, [95%CI] 0.59-0.88, p=0.24, I(2)=30%). The target population included adults aged over 65 years and patients at high risk of pneumonia due to chronic lung disease, chronic obstructive pulmonary disease or living in a nursing home. Protective trends of PPV-23 in the outcomes of pneumococcal pneumonia ([RR] 0.54, [95%CI] 0.18-1.65, p=0.01, I(2)=77%) and mortality due to pneumonia ([RR] 0.67, [95%CI] 0.43-1.04, p=0.67, I(2)=0%) were observed, although the results were statistically insignificant, possibly due to the small number of trials included. PPV-23 did not prevent all-cause mortality ([RR] 1.04, [95%CI] 0.87-1.24, p=0.95, I(2)=0%). CONCLUSIONS: PPV-23 provided weak protection against all-cause pneumonia in an immunocompetent population, especially among the target population. The additional benefit of PPV-23 in preventing CAP further supports its application in the target population.

A successful pregnancy and parturition in a patient with anuria undergoing maintenance hemodialysis for 6 years: a case report of a 3-year-follow-up.

BACKGROUND: Pregnancies in hemodialysis patients are uncommon and difficult to study. Although the chance of a successful pregnancy and parturition in hemodialysis women has increased over the years, it still remains extremely low with a high maternal and fetal mortality and morbidity rate. CASE PRESENTATION: We reported a case of successful pregnancy and parturition in a 22-year-old Chinese female in uremic stage of chronic renal failure and undergoing maintenance hemodialysis (three sessions a week) for 6 years. At the 22nd gestational week, she was diagnosed as pregnant by ultrasound, and started an enhanced hemodialysis routine (Five sessions a week). At the 32nd gestational week, she got hospitalized and received hemodialysis more frequently (seven sessions a week). Based on the initial diagnoses, including uremic stage of chronic renal failure, stage-3 hypertension, single pregnancy of 32nd gestational week, single umbilical artery and polyhydramnios, a drug therapy consisting of compound amino acid, fructosediphosphate sodium, 10% L-carnitine, erythropoietin, polyferose, amlodipine, isosorbidedinitrate, low-molecular weight-heparin, multivitamins and folic acid was given, and daily examination of the mother and fetus was performed. Under the joint efforts of various departments, the patient underwent caesarean section at the 34th gestational week due to progressive uterine contraction and gave birth to a female, well-being baby weighing 1470 g. It has been more than 3 years since the parturition. The mother has returned to the previous hemodialysis routine, and the child has been growing up healthily. CONCLUSION: Although pregnancy in hemodialysis patients is rare, with a high rate of risks. Patients could still gain a good outcome, if we intensify hemodialysis and enhance the collaboration between the patient, nephrologists, obstetricians, neonatologist, nutritionists, and other departments.