Hyperoxia Induced Bronchopulmonary Dysplasia-Like Inflammation via miR34a-TNIP2-IL-1ß Pathway.

Lung injury induced by oxygen is a key contributor to the pathogenesis of preterm infant bronchopulmonary dysplasia (BPD). To date, there are comprehensive therapeutic strategy for this disease, but the underlying mechanism is still in progress. By using lentivirus, we constructed microRNA34a (miR34a)-overexpressing or knockdown A549 cell lines, and exposure to hyperoxia to mimic oxygen induce lung injury. In this study, we investigated 4 proinflammatory cytokines, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), angiopoietin-1 (Ang-1), and Cyclooxygenase-2 (COX-2) in the secreted sputum of infants who received mechanical ventilation, and found that IL-1ß was substantially elevated in the first week after oxygen therapy and with no significant decrease until the fourth week, while TNF-α, Ang-1, and COX-2 were increased in the first week but decreased quickly in the following weeks. In addition, in vitro assay revealed that hyperoxia significantly increased the expression of miR-34a, which positively regulated the proinflammatory cytokine IL-1ß in a time- and concentration-dependent manner in A549 cells. Overexpressing or knockdown miR34 would exacerbate or inhibit production of IL-1ß and its upstream NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. Mechanically, it's found that TNFAIP3 interacting protein 2 (TNIP2), an inhibitor of nuclear factor κB (NF-κB), is a direct target of miR34a, negatively regulated activation of NLRP3 inflammasome and the production of IL-1ß. Overexpressing TNIP2 ameliorated hyperoxia-induced production of IL-1ß and cell apoptosis. Our findings suggest that TNIP2 may be a potential clinical marker in the diagnosis of BPD.

Hypertension in adolescents: The role of obesity and family history.

We evaluated the combined effect of obesity and family history (FH) on the risk of hypertension in adolescents. We studied 1288 school-aged adolescents aged 16.0 ± 0.5 years (49.0% males) attending the medical examination for enrollment in the city of Nanning, China. Their blood pressure, weight, and height were measured. A questionnaire was administered to both adolescents and their parents to obtain information on the participants' medical history. Multiple logistic regression analysis, according to bodyweight categories and adjusted for age, gender, and body mass index (BMI), was done to determine the association of FH with hypertension. Hypertension was found in 14.1% of adolescents. The prevalence of hypertension was significantly higher in adolescents with obesity and positive FH than their normal weight and negative FH counterparts. For adolescents with normal weight and waist circumstance (WC), those with a positive FH in parents compared to those without had an significantly increased risk for hypertension (odds ratio [OR], 2.15; 95% confidence interval [CI] 1.28-3.61, and 1.96; 95% CI 1.16-3.32, respectively). These findings were adjusted for age, gender, and BMI. Our study showed that routine screening for pediatric hypertension should be performed in adolescents who are overweight and obese. Furthermore, parental FH of hypertension played an important role in predicting the hypertension phenotype among adolescents with normal weight.

Overexpression of KDM4D promotes acute myeloid leukemia cell development by activating MCL-1.

Acute myeloid leukemia (AML) is regarded as a fatal cancer in the world. The overall survival in adult patients with AML is still poor. As lysine demethylases, the KDM4 family is found highly expressed in many kinds of tumors. In this study, we demonstrate that KDM4D is overexpressed in AML and knockdown of KDM4D not only inhibits the proliferation of AML cells, but also induces cell cycle arrest and apoptosis. Furthermore, our research shows that KDM4D can regulate the expression of MCL-1 by demethylating H3K9me3 at the promoter region in AML cells. Besides, we find that high expression of KDM4D is correlated with poor overall survival in AML patients. Taken together, our study demonstrated that KDM4D can promote MCL-1 expression in AML and may serve as a novel target for the treatment of AML.

Lifestyle Clusters and Cardiometabolic Risks in Adolescents: A Chinese School-Based Study Using a Latent Class Analysis Approach.

Background: Unhealthy dietary and lifestyle behaviors are associated with a higher prevalence of non-communicable chronic diseases and higher mortality in adults. However, there remains some uncertainty about the magnitude of the associations between lifestyle behaviors and cardiovascular factors in adolescents. Methods: We conducted a school-based cross-sectional study of 895 Chinese adolescents aged 15-19 years. They participated in a questionnaire survey, physical examination, and blood sample collection. Latent class analysis (LCA) was used to identify heterogeneous subgroups of lifestyle behaviors. A set of 12 latent class indicators, which reflected lifestyle behaviors including dietary habits, physical activity, sleep duration, screen time, and pressure perception, were included in the analysis. Logistic regression analysis was performed to determine whether the derived classes were related to a cardiometabolic risk. Results: In total, 13.7 and 5.6% of the participants were overweight and obese, respectively, and 8.4 and 14.1% reported having pre-hypertension and hypertension, respectively. A two-class model provided the best fit with a healthy lifestyle pattern (65.8%) and a sub-healthy lifestyle pattern (34.2%). There were more female participants with a healthy lifestyle (56.2 vs. 43.8%), whereas there were more males with a sub-healthy lifestyle (45.4 vs. 54.6%), (all P = 0.002). Increased risk of cardiometabolic abnormality (BMI categories, blood pressure and lipids) was not significant across lifestyle patterns, except for waist circumference (70.5 vs 69.1 cm, P = 0.044). There was no significant difference in physical activity and intake of fruit and vegetable between the two patterns. Conclusion: Primary prevention based on lifestyle modification should target patterns of behaviors at high risk in adolescents. Due to the complex effect of lifestyle clusters on cardiometabolic risks, well-designed and prospective studies in adolescents are needed in the future.

Bovine surfactant in the treatment of pneumonia-induced-neonatal acute respiratory distress syndrome (NARDS) in neonates beyond 34 weeks of gestation: a multicentre, randomized, assessor-blinded, placebo-controlled trial.

Neonatal acute respiratory distress syndrome (NARDS) reflects pulmonary surfactant dysfunction, and the usage of bovine surfactant (Calsurf) supplement may therefore be beneficial. To determine whether bovine surfactant given in NARDS can improve oxygenation and survival rate, we conducted a multicenter, randomized trial between January 2018 and June 2019, and we compared Calsurf treatment to controls in neonates with pneumonia accompanied by NARDS. Neonates who met the Montreux criteria definition of NARDS were included, and those with congenital heart and lung malformations were excluded. Primary outcomes were oxygenation index (OI) after Calsurf administration, and secondary outcomes were mortality, and duration of ventilator and oxygen between the two groups, and also other morbidities. Cumulatively, 328 neonates were recruited and analyzed, 162 in the control group, and 166 in the Calsurf group. The results shows that OI in the Calsurf group were significantly lower than that in the control group at 4 h (7.2 ± 2.7 and 11.4 ± 9.1, P = 0.001); similarly, OI in the Calsurf group were significantly lower than in the control group at 12 h ( 7.5 ± 3.1 and 11.2 ± 9.2, P = 0.001). Mortality and duration of ventilator support or oxygen use between the two groups were not significantly different.Conclusion: Calsurf acutely improved OI immediately after administration in pneumonia-induced NARDS; although, we observed no significant decrease in mortality, duration of ventilator or oxygen, or major morbidity. What is known: • The definition proposed as the Monteux criteria for neonatal acute respiratory distress syndrome (NARDS). • Surfactant acutely improved oxygenation and significantly decreased mortality in children and adolescents with acute lung injury. What is new: • This is the first large randomized controlled trail to study on surfactant treatment of neonates with acute respiratory distress syndromes. • Surfactant acutely improved oxygenation immediately after administration in pneumonia-induced NARDS at a gestational age beyond 34 weeks.

Silencing of Long Non-Coding RNA X Inactive Specific Transcript (Xist) Contributes to Suppression of Bronchopulmonary Dysplasia Induced by Hyperoxia in Newborn Mice via microRNA-101-3p and the transforming growth factor-beta 1 (TGF-ß1)/Smad3 Axis.

BACKGROUND Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly affecting premature infants. Long non-coding RNA (lncRNA) X inactive specific transcript (Xist) is actively involved in pulmonary disease development. The present study explored the potential mechanism of Xist in BPD development. MATERIAL AND METHODS First, newborn BPD mouse models were successfully established. lncRNAs and genes with differential expression were identified using microarray analysis. Various injuries and radial alveolar counts of lung tissues of BPD mice were detected by hematoxylin-eosin staining. Functional assays were utilized to detect alterations of superoxide dismutase (SOD), malondialdehyde (MDA), vascular endothelial growth factor, collagen I, alpha-smooth muscle Actin, TGF-ß1, and Smad3. Then, dual-luciferase reporter gene assay and RNA pull-down assay were performed to clarify the targeting relationship between Xist and miR-101-3p and between miR-101-3p and high-mobility group protein B3 (HMGB3). RESULTS In BPD mice, radial alveolar counts value and SOD activity declined while MDA level increased. Results of microarray analysis found that Xist and HMGB3 were highly expressed in BPD mice. Next, silenced Xist alleviated lung damage in BPD mice. Xist competitively bound to miR-101-3p to activate HMGB3, and overexpressed miR-101-3p mitigated lung damage in BPD mice. Additionally, silenced Xist downregulated the TGF-ß1/Smad3 axis. CONCLUSIONS Our study demonstrated that silencing of Xist suppressed BPD development by binding to miR-101-3p and downregulating HMGB3 and the TGF-b1/Smad3 axis. Our results may provide novel insights for BPD treatment.

[Change of Thrombelastography in Children's DIC and Analysis of Its Sensitivity and Specificity for Diagnosis of DIC].

OBJECTIVE: To investigate the influence of thrombelastography index changes on its sensitivity and specificity for diagnosis of disseminated intravascular coagulation (DIC) in children. METHODS: A total of 149 children with DIC in our hospital from June 2013 to June 2016 were selected in DIC group, while 106 cases of non-DIC, including healthy children and children with diseases easily confused with DIC, were selected as non-DIC(control) group. The thrombelastography, D-dimer, coagulation functions including prothrombintime (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and fibin degradation product (FDP), congental coagulation disorders and platelet count were detected in DIC and non-DIC groups; the statistics of data was performed and the sensitivity and specificity of thromelastraphy indexes such as R time, α angle MA value and A value were evaluated; the relationship of DIC with indexes was analyzed. Moreover, the result difference of thromelastography and routine coagulation function test was compared at diagnosis of DIC. RESULTS: According to statistical analysis of clinical data in 2 groups, the average R time in non-DIC group was significantly less than that in DIC group (P<0.05); the average α angle in non-DIC group was larger than that in DIC group (P<0.05), both the MA and A values in the non-DIC group were significantly higher than those in DIC group (P<0.05). The specificity of routine coagulation function test for diagnosis of DIC was as follow: PT-27.2%, APTT-42.2%, international normalized ratio(INR)-47.9%, FIB-44.4%, FDP-42.7% and D-dimer-68.3%, which were significantly lower than that of R time,α angle and MA value for diagnosis of DIC (85.1%, 74.1% and 73%). The α angle and MA value of healthy children were greater than those of children with severe liver disease(P<0.05). while the average R time of healthy children was less than that of children with severe liver disease(P<0.05), but the difference of A value between them did not statistically significant (P>0.05) . The average R time of healthy children was less than that of children with congenital coagulation disorders (P<0.05). but there was no significant differences in α angle MA and Avalues between them. CONCLUSION: As compared with routine coagulation function test, the thrombelastography shows more high specificity for diagnosis of DIC, and can more precisely diagnose the DIC; moreover, the thrombelastography combined with roatime coagulation function test can more early find and diagnose the DIC in children, therefore it can improve the survival rate of children with DIC.

Synergetic effect of α-lipoic acid with keratinocyte growth factor on protecting alveolar epithelial type II cells of rat fetus from hyperoxia -induced injury.

AIM: To explore the potential mechanism of the synergetic effect of α-lipoic acid with keratinocyte growth factor (KGF) on protecting alveolar epithelial type II cells (ATIICs) from hyperoxia-induced injury. METHODS: Primary culture of ATIICs from the Sprague-Dawley rat fetuses was examined under room air and 95% of O2. Various KGF concentrations (0 to 100 ng/mL) and 0.5 mM of α-lipoic were added into the cell culture. Levels of intracellular reactive oxygen species, necrosis, and proliferation of ATIICs were measured using flow cytometry, ELISA, and MTT assays, respectively. RT-PCR was performed to detect KGFR mRNA expression. Western blot was employed to detect the expression of KGFR, phospho-p53, HDAC1, and acetylated H3 and H4. RESULTS: KGF promoted the proliferation and inhibited the apoptosis of ATIICs in room air or under temporary exposure to hyperoxia. However, the resistance of ATIICs to KGF was observed after prolonged exposure. Further investigation demonstrated that down-regulation of KGF receptor via activation of p53 and recruitment of HDAC1 induced by oxidative stress contributed to KGF resistance. This resistance could be attenuated by α-lipoic acid, a powerful antioxidant. CONCLUSION: Application of KGF combined with α-lipoic acid could inhibit KGF resistance to provide maximum protection to ATIICs from hyperoxic injury.

GSTM1 and GSTT1 gene polymorphisms as major risk factors for bronchopulmonary dysplasia in a Chinese Han population.

Bronchopulmonary dysphasia (BPD) is a complex multifactorial disease with an obvious genetic predisposition. Oxidative stress plays an important role in its pathogenesis. Glutathione S-transferases (GSTs) detoxify metabolites produced by oxidative stress within the cell and protect the cells against injury. In the present study, the hypothesis that polymorphisms in the GSTM1 and GSTT1 genes are associated with BPD in Chinese Han infants was examined. Sixty infants with BPD and 100 gestational age and birth weight-matched preterm infants without BPD were recruited. Genotyping for GSTM1 and GSTT1 was performed by multiplex polymerase chain reaction (PCR). The GSTM1 null genotype was more prevalent in BPD infants (65.0%) than in the control subjects (48.0%), which yielded higher risk towards BPD (odds ratio (OR): 2.012, 95% confidence interval (CI)=1.040-3.892, p=0.037). There was no statistically significant association of GSTT1 genotype with BPD (OR: 1.691, 95% CI=0.884-3.236, p=0.111), although the frequency of GSTT1 null genotype was higher among the BPD subjects (60.0%) than in the control patients (47.0%). GSTM1 and GSTT1 double null genotype was also higher in BPD group (38.3%) than in controls (21.0%) with a higher risk towards BPD (OR: 2.338, 95%CI=1.151-4.751, p=0.017). The results suggest that null genotypes of GSTM1 and GSTT1 genes may contribute to the development of BPD in our Chinese Han population.

Association of surfactant protein B gene polymorphisms (C/A-18, C/T1580, intron 4 and A/G9306) and haplotypes with bronchopulmonary dysplasia in chinese han population.

This study aimed to investigate the association between surfactant protein B (SP-B) polymorphisms and bronchopulmonary dysplasia (BPD) in Chinese Han infants. We performed a casecontrol study including 86 infants with BPD and 156 matched controls. Genotyping was performed by sequence specific primer-polymerase chain reaction (PCR) and haplotypes were reconstructed by the fastPHASE software. The results showed that significant differences were detected in the genotype distribution of C/A-18 and intron 4 polymorphisms of SP-B gene between cases and controls. No significant differences were detected in the genotype distribution of C/T1580 or A/G9306 between the two groups. Haplotype analysis revealed that the frequency of A-del-C-A haplotype was higher in case group (0.12 to 0.05, P=0.003), whereas the frequency of C-inv-C-A haplotype was higher in control group (0.19 to 0.05, P=0.000). In addition, a significant difference was observed in the frequency of C-inv-T-A haplotype between the two groups. It was concluded that the polymorphisms of SP-B intron 4 and C/A-18 could be associated with BPD in Chinese Han infants, and the del allele of intron 4 and A allele of C/A-18 might be used as markers of susceptibility in the disease. Haplotype analysis indicated that the gene-gene interactions would play an important part in determining susceptibility to BPD.