[A prospective cohort study of association between early childhood body mass index trajectories and the risk of overweight].

OBJECTIVE: To compare the association between body mass index (BMI) trajectories determined by different methods and the risk of overweight in early childhood in a prospective cohort study, and to identify children with higher risk of obesity during critical growth windows of early childhood. METHODS: A total of 1 330 children from Peking University Birth Cohort in Tongzhou (PKUBC-T) were included in this study. The children were followed up at birth, 1, 3, 6, 9, 12, 18, and 24 months and 3 years of age to obtain their height/length and weight data, and calculate BMI Z-score. Latent class growth mixture modeling (GMM) and longitudinal data-based k-means clustering algorithm (KML) were used to determine the grouping of early childhood BMI trajectories from birth to 24 mouths. Linear regression was used to compare the association between early childhood BMI trajectories determined by different methods and BMI Z-score at 3 years of age. The predictive performance of early childhood BMI trajectories determined by different methods in predicting the risk of overweight (BMI Z-score > 1) at 3 years was compared using the average area under the curve (AUC) of 5-fold cross-validation in Logistic regression models. RESULTS: In the study population included in this research, the three-category trajectories determined using GMM were classified as low, medium, and high, accounting for 39.7%, 54.1%, and 6.2% of the participants, respectively. The two-category trajectories determined using the KML method were classified as low and high, representing 50. 3% and 49. 7% of the participants, respectively. The three-category trajectories determined using the KML method were classified as low, medium, and high, accounting for 31.1%, 47.4%, and 21.5% of the participants, respectively. There were certain differences in the growth patterns reflected by the early childhood BMI trajectories determined using different methods. Linear regression analysis found that after adjusting for maternal ethnicity, educational level, delivery mode, parity, maternal age at delivery, gestational week at delivery, children' s gender, and breastfeeding at 1 month of age, the association between the high trajectory group in the three-category trajectories determined by the KML method (manifested by a slightly higher BMI at birth, followed by rapid growth during infancy and a stable-high BMI until 24 months) and BMI Z-scores at 3 years was the strongest. Logistic regression analysis revealed that the three-category trajectory grouping determined by the KML method had the best predictive performance for the risk of overweight at 3 years. The results were basically consistent after additional adjustment for the high bound score of the child' s diet balanced index, average daily physical activity time, and screen time. CONCLUSION: This study used different methods to identify early childhood BMI trajectories with varying characteristics, and found that the high trajectory group determined by the KML method was better able to identify children with a higher risk of overweight in early childhood. This provides scientific evidence for selecting appropriate methods to define early childhood BMI trajectories.

Administration of A. muciniphila ameliorates pulmonary arterial hypertension by targeting miR-208a-3p/NOVA1 axis.

Pulmonary arterial hypertension (PH) is a chronic disease induced by a progressive increase in pulmonary vascular resistance and failure of the right heart function. A number of studies show that the development of PH is closely related to the gut microbiota, and lung-gut axis might be a potential therapeutic target in the PH treatment. A. muciniphila has been reported to play a critical role in treating cardiovascular disorders. In this study we evaluated the therapeutic effects of A. muciniphila against hypoxia-induced PH and the underlying mechanisms. Mice were pretreated with A. muciniphila suspension (2 × 108 CFU in 200 µL sterile anaerobic PBS, i.g.) every day for 3 weeks, and then exposed to hypoxia (9% O2) for another 4 weeks to induce PH. We showed that A. muciniphila pretreatment significantly facilitated the restoration of the hemodynamics and structure of the cardiopulmonary system, reversed the pathological progression of hypoxia-induced PH. Moreover, A. muciniphila pretreatment significantly modulated the gut microbiota in hypoxia-induced PH mice. miRNA sequencing analysis reveals that miR-208a-3p, a commensal gut bacteria-regulated miRNA, was markedly downregulated in lung tissues exposed to hypoxia, which was restored by A. muciniphila pretreatment. We showed that transfection with miR-208a-3p mimic reversed hypoxia-induced abnormal proliferation of human pulmonary artery smooth muscle cells (hPASMCs) via regulating the cell cycle, whereas knockdown of miR-208a-3p abolished the beneficial effects of A. muciniphila pretreatment in hypoxia-induced PH mice. We demonstrated that miR-208a-3p bound to the 3'-untranslated region of NOVA1 mRNA; the expression of NOVA1 was upregulated in lung tissues exposed to hypoxia, which was reversed by A. muciniphila pretreatment. Furthermore, silencing of NOVA1 reversed hypoxia-induced abnormal proliferation of hPASMCs through cell cycle modulation. Our results demonstrate that A. muciniphila could modulate PH through the miR-208a-3p/NOVA1 axis, providing a new theoretical basis for PH treatment.

Prevalence of neutropenia in US residents: a population based analysis of NHANES 2011-2018.

AIMS: Neutrophils play a pivotal in immunity and inflammation. We aim to investigate the prevalence of neutropenia in the United States. METHODS: In this cross-sectional study, participants from the National Health and Nutrition Examination Survey (NHANES) (2011-2018) were enrolled. Demographic information, hematologic measurements, smoking status of all participants were collected for all participants. All statistical analyses were performed utilizing the NHANES survey weights. Covariate-adjusted linear regression was used to compare hematologic indices in different population grouped by age, sex, ethnicity, and smoking. We also employed multivariate-logistic regression to estimate the weighted odds ratio with a 95% confidence interval and predict the neutropenia risk among. RESULTS: 32,102 participants from NHANES survey were included, represented 286.6 million multiracial population in the United States. Black participants had lower mean leukocyte count (mean difference (MD): 0.71 × 109/L; P < 0.001) and lower neutrophil count (MD: 0.83 × 109/L; P < 0.001) compared with white participants after adjusting for age and sex. Furthermore, t a notable observation was the significant downward shift in the distribution curves of leukocyte count and neutrophil count among black participants. Smokers had a higher mean leukocyte count (MD: 1.10 × 109 cells/L; P < 0.001) and a higher mean neutrophil count (MD: 0.75 × 109 cells/L; P < 0.001) comparing with nonsmokers. The estimated prevalence of neutropenia was 1.24% (95% CI: 1.11 - 1.37%), which corresponds to approximately 35.5 million individuals in the United States. The prevalence of neutropenia in black participants was significantly higher than other races. Results of logistic regression analysis showed that black individuals, male individuals, and children younger than 5 years had a higher risk of neutropenia. CONCLUSIONS: Neutropenia is more common in the general population than we thought, especially in black individuals and children. More attention should be paid to neutropenia.

Development and evaluation of a meat mitochondrial metagenomic (3MG) method for composition determination of meat from fifteen mammalian and avian species.

BACKGROUND: Bioassessment and biomonitoring of meat products are aimed at identifying and quantifying adulterants and contaminants, such as meat from unexpected sources and microbes. Several methods for determining the biological composition of mixed samples have been used, including metabarcoding, metagenomics and mitochondrial metagenomics. In this study, we aimed to develop a method based on next-generation DNA sequencing to estimate samples that might contain meat from 15 mammalian and avian species that are commonly related to meat bioassessment and biomonitoring. RESULTS: In this project, we found the meat composition from 15 species could not be identified with the metabarcoding approach because of the lack of universal primers or insufficient discrimination power. Consequently, we developed and evaluated a meat mitochondrial metagenomics (3MG) method. The 3MG method has four steps: (1) extraction of sequencing reads from mitochondrial genomes (mitogenomes); (2) assembly of mitogenomes; (3) mapping of mitochondrial reads to the assembled mitogenomes; and (4) biomass estimation based on the number of uniquely mapped reads. The method was implemented in a python script called 3MG. The analysis of simulated datasets showed that the method can determine contaminant composition at a proportion of 2% and the relative error was < 5%. To evaluate the performance of 3MG, we constructed and analysed mixed samples derived from 15 animal species in equal mass. Then, we constructed and analysed mixed samples derived from two animal species (pork and chicken) in different ratios. DNAs were extracted and used in constructing 21 libraries for next-generation sequencing. The analysis of the 15 species mix with the method showed the successful identification of 12 of the 15 (80%) animal species tested. The analysis of the mixed samples of the two species revealed correlation coefficients of 0.98 for pork and 0.98 for chicken between the number of uniquely mapped reads and the mass proportion. CONCLUSION: To the best of our knowledge, this study is the first to demonstrate the potential of the non-targeted 3MG method as a tool for accurately estimating biomass in meat mix samples. The method has potential broad applications in meat product safety.

Individual and joint effects of prenatal green spaces, PM2.5 and PM1 exposure on BMI Z-score of children aged two years: A birth cohort study.

BACKGROUND: Few studies examined the association of prenatal exposure to green spaces with children's body mass index (BMI) Z-score, and no study evaluated the joint effect of prenatal green spaces and PM2.5 or PM1 exposure on children's BMI Z-score. We aimed to assess the individual and joint effects of prenatal green spaces, PM2.5, and PM1 exposure on BMI Z-score of children aged two years. METHODS: The study was based on a birth cohort in Beijing, China, in which 13,253 mothers (LMP from 2014 to 2017) and their children were included. We estimated prenatal green spaces exposure by calculating average normalized difference vegetation index with 500 m buffers (NDVI-500), prenatal PM2.5 and PM1 exposure based on maternal residential addresses. Weight and height of children were measured at 2 years old. We calculated children's BMI Z-score based on the WHO Standards. Generalized linear regression was used to examine the individual and joint effects of prenatal NDVI-500, PM2.5 and PM1 exposure on children's BMI Z-score. RESULTS: A 0.1 increase in prenatal NDVI-500 exposure, a 10 µg/m3 decrease in PM2.5, a 10 µg/m3 decrease in PM1 were associated with 0.185 [95% confidence interval (95%CI): 0.155, 0.216], 0.034 (95%CI: 0.015, 0.052) and 0.041 (95%CI: 0.020, 0.061) increase of children's BMI Z-score, respectively. Compared with those exposed to low-level NDVI-500 (not greater than median) and high-level PM2.5 (greater than median), the BMI Z-score was higher in children whose mother exposed to high-level of NDVI-500 and low-level PM2.5 [ß:0.172 (95%CI: 0.131, 0.214), Pinteraction = 0.003]. Compared with those exposed to low-level NDVI-500 and high-level PM1, the BMI Z-score was higher in children whose mother exposed to high-level of NDVI-500 and low-level PM1 [ß:0.169 (95%CI: 0.127, 0.210), Pinteraction<0.001]. In the trimester-specific analysis, NDVI-500 and PM exposure during the second trimester have a consistent individual effect, together with a joint effect, on child growth. CONCLUSION: The study suggested the beneficial effect of prenatal exposure to green spaces on child growth and its interaction with PM2.5 and PM1, especially in the second trimester. The findings call for developing public health policy to improve green infrastructure and control PM2.5 and PM1 concentrations, in order to promote child growth.

Nucleo-cytoplasmic RNA distribution responsible for maintaining neuroinflammatory microenvironment.

Subcellular localization of transcripts is highly associated with regulation of gene expression, synthesis of protein, and also the development of the human brain cortex. Although many mechanisms are prevalent in the occurrence of neuroinflammation, the mechanisms based on differences in subcellular localization of transcripts have not been explored. To characterize the dynamic profile of nuclear and cytoplasmic transcripts during the progress of haemorrhage-induced neuroinflammation, we isolated nucleo-cytoplasmic RNA fractions of oxyhaemoglobin (oxy-Hb) treated microglia cells and sequenced both fractions. We discovered that cytoplasmic retained genes were the major forces to maintain the neuroinflammatory microenvironment with 10 hub genes and 40 conserved genes were identified. Moreover, antisense RNA Gm44096 and lincRNA Gm47270, which co-expressed with a crowd of inflammatory genes in the cytoplasm, were discovered as regulatory strategies for sustaining the neuroinflammatory microenvironment. Thus, our study provides a new perspective on understanding haemorrhage-induced neuroinflammation and also reveals a mechanism of lncRNA responsible for maintaining the neuroinflammatory microenvironment.

Advances in the Study of Metabolomics and Metabolites in Some Species Interactions.

In the natural environment, interactions between species are a common natural phenomena. The mechanisms of interaction between different species are mainly studied using genomic, transcriptomic, proteomic, and metabolomic techniques. Metabolomics is a crucial part of system biology and is based on precision instrument analysis. In the last decade, the emerging field of metabolomics has received extensive attention. Metabolomics not only provides a qualitative and quantitative method for studying the mechanisms of interactions between different species, but also helps clarify the mechanisms of defense between the host and pathogen, and to explore new metabolites with various biological activities. This review focuses on the methods and progress of interspecies metabolomics. Additionally, the prospects and challenges of interspecies metabolomics are discussed.

Vitamin D Alleviates Cognitive Dysfunction by Activating the VDR/ERK1/2 Signaling Pathway in an Alzheimer's Disease Mouse Model.

OBJECTIVE: Vitamin D (Vit D), a steroid hormone, has been linked to cognitive impairment and dementia, such as Alz-heimer's disease (AD). 1, 25(OH)2D3 is the biologically active form of Vit D, which has been shown to have neuroprotective effects. This compound is being evaluated as an emerging therapeutic treatment in models of AD. MATERIAL AND METHODS: The present study was designed to investigate whether Vit D could alleviate cognitive impairment in an AD rat model by regulating the VDR/ERK1/2 signaling pathway. Adult male APPswe/PS1ΔE9 rats (n = 40) were randomly divided into 2 groups: the AD group and the Vit D + AD group (20 mice per group), and 40 C57BL/6J age-matched mice were separated into the control (CON) group and the Vit D + CON group (20 mice per group). The Morris water maze and object recognition tests were used to evaluate learning and memory functions of the mice. Hematoxylin and eosin staining was used to evaluate morphological changes in hippocampal neurons. Western blotting was used to evaluate the proteins responsible for these changes. RESULTS: We found that Vit D improved learning and memory abilities and morphological defects in hippocampal neurons. Vit D decreased the gene expression of caspase-3 and Bax and increased the expression of Bcl-2. Vit D also increased the protein expression of VDR and p-ERK1 protein in AD mice. CONCLUSION: This study provides new clues about the mechanism by which Vit D exerts neuroprotective effects in an AD mouse model.

Tea consumption and colorectal cancer risk: a meta-analysis of prospective cohort studies.

PURPOSE: Data from in vitro and animal studies support the preventive effect of tea (Camellia sinensis) against colorectal cancer. Further, many epidemiologic studies evaluated the association between tea consumption and colorectal cancer risk, but the results were inconsistent. We conducted a meta-analysis of prospective cohort studies to systematically assess the association between tea consumption and colorectal cancer risk. METHODS: A comprehensive literature review was conducted to identify the related articles by searching PubMed and Embase up to June, 2019. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a fixed effect model. RESULTS: Twenty cohort articles were included in the present meta-analysis involving 2,068,137 participants and 21,437 cases. The combined RR of colorectal cancer for the highest vs. lowest tea consumption was determined to 0.97 (95% CI 0.94-1.01) with marginal heterogeneity (I2 = 24.0%, P = 0.093) among all studies. This indicated that tea consumption had no significant association with colorectal cancer risk. Stratified analysis showed that no significant differences were found in all subgroups. We further conducted the gender-specific meta-analysis for deriving a more precise estimation. No significant association was observed between tea consumption and colorectal cancer risk in male (combined RR = 0.97; 95% CI 0.90-1.04). However, tea consumption had a marginal significant inverse impact on colorectal cancer risk in female (combined RR = 0.93; 95% CI 0.86-1.00). Further, we found a stronger inverse association between tea consumption and risk of colorectal cancer among the female studies with no adjustment of coffee intake (RR: 0.90; 95% CI 0.82-1.00, P < 0.05) compared to the female studies that adjusted for coffee intake (RR = 0.97; 95% CI 0.87-1.09, P > 0.05). CONCLUSIONS: Our finding indicates that tea consumption has no significant impact on the colorectal cancer risk in both genders combined, but gender-specific meta-analysis shows that tea consumption has a marginal significant inverse impact on colorectal cancer risk in female.

Myocardial injury and pericarditis after combined left atrial and coronary sinus ablation in Wolff-Parkinson-White syndrome: a case report.

BACKGROUND: Radiofrequency catheter ablation is an established procedure with a high success rate for treating Wolff-Parkinson-White (WPW) syndrome. Rare complications post-ablation may nonetheless occur particularly associated with coronary sinus. Identifying and avoiding these complications remains a challenge. CASE PRESENTATION: A 66-year-old woman with WPW syndrome was admitted to the hospital due to frequent attacks of paroxysmal tachycardia. During electrophysiological study, an accessory pathway was thought to connect the posterior wall of the left ventricle. The patient underwent Radiofrequency (RF) catheter ablation. The procedure was time-consuming because of combined left atrial and coronary sinus ablation. The total amount of radiofrequency application energy in the coronary sinus was 6800 J. After the operation, widespread concave ST-segment elevation, significantly increased value of serum troponin I and mild pericardial effusion were identified, but the patient did not show any symptoms. Therefore, the patient was suspected to have myocardial injury and pericarditis caused by ablation-related injury. The patient was uneventfully discharged five days after the procedure with a significantly decreased value of troponin I. The reexamined electrocardiogram was normal after three weeks. CONCLUSIONS: To the best of our knowledge, this is the first study to report on myocardial injury and pericarditis after combined left atrial and coronary sinus ablation in WPW syndrome. Our findings underscore the need for detailed mapping and careful ablation with low energy, as well as the merits of identifying myocardial infarction after coronary sinus ablation.

The preablation monocyte/ high density lipoprotein ratio predicts the late recurrence of paroxysmal atrial fibrillation after radiofrequency ablation.

BACKGROUND: The monocyte/high-density lipoprotein ratio (MHR) has emerged as a promising alternative biomarker in the fields of cardiovascular disease and atrial fibrillation (AF). This retrospective study was aimed to explore the predictive value of the MHR for the late recurrence of AF after radiofrequency ablation. METHODS: From April 2015 to October 2018, patients with paroxysmal AF who had undergone radiofrequency catheter ablation at Subei People's Hospital of Jiangsu Province were enrolled in our study. All the participants were observed until November 2019 after the procedure. During the postoperative follow up, the patients were categorized into the recurrence group and maintenance of sinus rhythm group based on who had experienced AF recurrence. RESULTS: One hundred twenty-five patients were diagnosed with paroxysmal AF, with an average age of 61.2 ± 9.3 years. Forty-seven patients had developed late recurrence during a mean follow up of 25.1 ± 12.0 months. The AF recurrence event rates were significantly increased in the highest MHR tertile compared with those in the lowest MHR tertile (22.0% vs. 57.1%; P < 0.05). On multivariate logistic regression analysis, the preablation MHR (OR = 1.34; 95% CI = 1.12 ~ 1.60; P = 0.001) and left atrial diameter (LAD) (OR = 1.21, 95% CI = 1.08 ~ 1.35; P = 0.001) were independent risk factors predicting the recurrence of AF after radiofrequency ablation. Furthermore, receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of the MHR was 0.712 (95% CI = 0.618 ~ 0.806; P = 0.000) and that of LAD was 0.739 (95% CI = 0.653 ~ 0.814; P = 0.000). Z-test found no significant difference between the MHR and LAD regarding the AUC (Z = 0.451; P = 0.652). CONCLUSION: An elevated preablation MHR was associated with an increased risk of the postoperative recurrence of AF. Additionally, the MHR independently predicted the late recurrence of paroxysmal AF after radiofrequency ablation, with the same predictive value as LAD.

Can men with atrial fibrillation really rest easy with a CHA2DS2-VASc score of 0?

BACKGROUND: Atrial fibrillation (AF) significantly increases the risk of ischemic stroke depending on various risk factors. The CHA2DS2-VASc score is used widely to improve stratification of AF-related stroke to identify for whom anticoagulation could be safely withheld. As upstream therapy, the management of lifestyle for AF and related stroke prevention has been ongoing for past decades. CASE PRESENTATION: A 56-year-old male was taken to our hospital because of acute ischemic stroke. Without intracranial vascular malformation and angiostenosis, two small emboli were successfully taken out from the left middle cerebral artery by mechanical thrombectomy. During the hospitalisation, no apparent abnormalities were found in various laboratory tests, echocardiogram or the coronary computed tomography angiography. However, asymptomatic paroxysmal AF was first diagnosed and was presumed to be responsible for his stroke. Noticeable, he was always in good fitness benefiting from the formed good habits of no smoking and drinking. With a CHA2DS2-VASc score of 0, he had no history of any known diseases or risk factors associated with AF and related stroke. Instead of lacking exercise, he persisted in playing table tennis faithfully 3-4 times a week and 2-3 h each time over the past 30 years, and, in fact, has won several amateur table tennis championships. CONCLUSION: In view of the possible pathophysiological mechanisms resulting from the long-term vigorous endurance exercise, it may be a potential risk factor for developing AF and even for subsequent stroke. Not merely should strengthen the screening for AF in specific individuals as sports enthusiasts, but the necessity of oral anticoagulant for those with a CHA2DS2-VASc score of 0 might deserve the further investigation.

Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury.

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.

A Novel Multi-Angle SAR Imaging System and Method Based on an Ultrahigh Speed Platform.

Considering the difficulty of pulse repetition frequency (PRF) design in multi-angle SAR when using ultra-high speed platforms, a multi-angle SAR imaging system in a unified coordinate system is proposed. The digital multi-beamforming is used in the system and multi-angle SAR data can be obtained in one flight. Therefore, the system improves the efficiency of data recording. An improved range migration algorithm (RMA) is used for data processing, and imaging is made in a unified imaging coordinate system. The resolution of different view images is the same, and there is a fixed delay between the images. On this basis, the SAR image fusion is performed after image matching. The results of simulation and measured data confirm the effectiveness of the system and the method.

Role of AGEs in the progression and regression of atherosclerotic plaques.

The formation of advanced glycation end-products(AGEs) is an important cause of metabolic memory in diabetic patients and a key factor in the formation of atherosclerosis(AS) plaques in patients with diabetes mellitus. Related studies showed that AGEs could disrupt hemodynamic steady-state and destroy vascular wall integrity through the endothelial barrier damage, foam cell(FC) formation, apoptosis, calcium deposition and other aspects. At the same time, AGEs could initiate oxidative stress and inflammatory response cascade via receptor-depended and non-receptor-dependent pathways, promoting plaques to develop from a steady state to a vulnerable state and eventually tend to rupture and thrombosis. Numerous studies have confirmed that these pathological processes mentioned above could lead to acute coronary heart disease(CHD) and other acute cardiovascular and cerebrovascular events. However, the specific role of AGEs in the progression and regression of AS plaques has not yet been fully elucidated. In this paper, the formation, source, metabolism, physical and chemical properties of AGEs and their role in the migration of FCs and plaque calcification are briefly described, we hope to provide new ideas for the researchers that struggling in this field.

Bcl-2 inhibitors reduce steroid-insensitive airway inflammation.

BACKGROUND: Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies. OBJECTIVE: We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma. METHODS: Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness. RESULTS: Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17 cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis ex vivo from patients with severe asthma. CONCLUSION: Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.

The circ_0003928/miR-31-5p/MAPK6 cascade affects high glucose-induced inflammatory response, fibrosis and oxidative stress in HK-2 cells.

BACKGROUND: Diabetic nephropathy (DN) is a severe diabetic complication disorder. Circular RNAs (circRNAs) actively participate in DN pathogenesis. In this report, we sought to define a new mechanism of circ_0003928 in regulating high glucose (HG)-induced HK-2 cells. METHODS: To construct a DN cell model, we treated HK-2 cells with HG. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. The inflammatory cytokines were quantified by ELISA. Protein analysis was performed by immunoblotting, and mRNA expression was detected by quantitative PCR. The circ_0003928/miR-31-5p and miR-31-5p/MAPK6 relationships were validated by RNA pull-down and luciferase assays. RESULTS: HG promoted HK-2 cell apoptosis, fibrosis and oxidative stress. Circ_0003928 and MAPK6 levels were enhanced and miR-31-5p level was decreased in HK-2 cells after HG treatment. Circ_0003928 disruption promoted cell growth and inhibited apoptosis, inflammatory response, fibrosis and oxidative stress in HG-induced HK-2 cells. Circ_0003928 targeted miR-31-5p, and MAPK6 was a target of miR-31-5p. Circ_0003928 regulated MAPK6 expression through miR-31-5p. The functions of circ_0003928 disruption in HG-induced HK-2 cells were reversed by miR-31-5p downregulation or MAPK6 upregulation. CONCLUSION: Circ_0003928 exerts regulatory impacts on HG-induced apoptosis, inflammation, fibrosis and oxidative stress in human HK-2 cells by the miR-31-5p/MAPK6 axis.

The efficacy of sorafenib against hepatocellular carcinoma is enhanced by 5-aza-mediated inhibition of ID1 promoter methylation.

Sorafenib resistance greatly restricts its clinical application in patients with hepatocellular carcinoma (HCC). Numerous studies have reported that ID1 exerts a crucial effect in cancer initiation and development. Our previous research revealed an inhibitory role of ID1 in sorafenib resistance. However, the upstream regulatory mechanism of ID1 expression is unclear. Here, we discovered that ID1 expression is negatively correlated with promoter methylation, which is regulated by DNMT3B. Knockdown of DNMT3B significantly inhibited ID1 methylation status and resulted in an increase of ID1 expression. The demethylating agent 5-aza-2'-deoxycytidine (5-aza) remarkably upregulated ID1 expression. The combination of 5-aza with sorafenib showed a synergistic effect on the inhibition of cell viability.

A poor prognostic male choriocarcinoma with multiple systemic metastases: a case report and the literature review.

Background: Non-gestational choriocarcinoma, also known as primary choriocarcinoma, is extremely rare in men, manifesting with specific signs such as breast feminization, testicular atrophy, and loss of libido. The presentation typically includes elevated serum ß-hCG levels, widespread metastatic disease, and a rapid progression of the condition. Case report: We present a rare case of a 41-year-old man diagnosed with choriocarcinoma, exhibiting a unique combination of multiple metastases, including lung, brain, bone, and retroperitoneal lymph node metastases, as confirmed by 18F-FDG PET/CT imaging. The patient was treated with aggressive chemotherapy and pembrolizumab, and the prognosis remained poor. The patient's overall survival was a mere 5 months following diagnosis. Conclusion: Non-gestational choriocarcinoma represents a rare entity in clinical practice and should be considered in young men presenting with gynaecomastia and elevated ß-hCG levels alongside normal gonads. Thus, we advocate for a more comprehensive inquiry into medical history and a systematic examination. The 18F-FDG PET/CT examination not only visually delineates the lesion's location and extent but also serves as a cornerstone for clinical tumor staging, providing valuable support for treatment monitoring and subsequent follow-up.