Comprehensive analysis of m6A methylomes in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a serious and fatal disease. Recently, m6A has been reported to play an important role in the lungs of IPAH patients and experimental pulmonary hypertension models. However, the meaning of m6A mRNAs in the peripheral blood of IPAH patients remains largely unexplored. We aimed to construct a transcriptome-wide map of m6A mRNAs in the peripheral blood of IPAH patients. M6A RNA Methylation Quantification Kit was utilized to measure the total m6A levels in the peripheral blood of IPAH patients. A combination of MeRIP-seq, RNA-seq and bioinformatics analysis was utilized to select m6A-modified hub genes of IPAH. MeRIP-qPCR and RT-qPCR were used to measure the m6A levels and mRNA levels of TP53, RPS27A, SMAD3 and FoxO3 in IPAH patients. Western blot was performed to assess the protein levels of m6A related regulators and m6A related genes in experimental PH animal models, hypoxia-treated and PDGF-BB induced PASMCs. We found that the total m6A levels were increased in peripheral blood of IPAH patients and verified that m6A levels of RPS27A and SMAD3 were significantly elevated and m6A levels of TP53 and FoxO3 were significantly reduced. The mRNA or protein levels of RPS27A, SMAD3, TP53 and FoxO3 were changed in human blood samples, experimental PH animal models and PDGF-BB induced PASMCs. Moreover, METTL3 and YTHDF1 were increased in the hypoxia induced pulmonary hypertension rat model, hypoxia-treated and PDGF-BB induced PASMCs. These finding suggested that m6A may play an important role in IPAH.

Sugar intake and risk of hypertension: a systematic review and dose-response meta-analysis of cohort and cross-sectional studies.

Several epidemiological studies have investigated the association between sugar intake, the levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the risk of hypertension, but findings have been inconsistent. We carried out a systematic review and meta-analysis of observational studies to examine the associations between sugar intake, hypertension risk, and BP levels. Articles published up to February 2, 2021 were sourced through PubMed, EMBASE and Web of Science. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a fixed- or random-effects model. Restricted cubic splines were used to evaluate dose-response associations. Overall, 35 studies were included in the present meta-analysis (23 for hypertension and 12 for BP). Sugar-sweetened beverages (SSBs) and artificially sweetened beverages (ASBs) were positively associated with hypertension risk: 1.26 (95% CI, 1.15-1.37) and 1.10 (1.07-1.13) per 250-g/day increment, respectively. For SBP, only SSBs were significant with a pooled ß value of 0.24 mmHg (95% CI, 0.12-0.36) per 250 g increase. Fructose, sucrose, and added sugar, however, were shown to be associated with elevated DBP with 0.83 mmHg (0.07-1.59), 1.10 mmHg (0.12-2.08), and 5.15 mmHg (0.09-10.21), respectively. Current evidence supports the harmful effects of sugar intake for hypertension and BP level, especially SSBs, ASBs, and total sugar intake.

Shikonin improves pulmonary vascular remodeling in monocrotaline­induced pulmonary arterial hypertension via regulation of PKM2.

Pulmonary arterial hypertension (PAH), a fatal disease with an insidious onset and rapid progression, shows characteristics such as increases in pulmonary circulatory resistance and pulmonary arterial pressure, and progressive right heart failure. Shikonin can reduce right ventricular systolic pressure in chronically hypoxic mice. However, the mechanisms underlying the protective effect of shikonin against PAH pathogenesis have only been sporadically identified. The present study evaluated whether inhibiting the expression of pyruvate kinase M2 (PKM2) contributed to the improvement of pulmonary vascular remodeling in PAH rats induced by monocrotaline (MCT) treatment. Hemodynamic parameters were assessed using echocardiography and right ventricular catheterization. Right ventricular hypertrophy index analysis and hematoxylin and eosin staining were used to evaluate the degree of pulmonary vascular and right heart remodeling. Moreover, PKM2, p­PKM2, ERK, p­ERK, glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) protein expression levels were semi­quantified using western blotting. The expression and distribution of PKM2 were assessed using immunofluorescence microscopy. The present study demonstrated that MCT treatment caused pulmonary arterial hypertension and pulmonary vascular remodeling in experimental rats. Shikonin improved hemodynamics and pulmonary vascular remodeling in MCT­induced PAH rats, decreased aerobic glycolysis and downregulated PKM2, p­PKM2, p­ERK, GLUT 1 and LDHA protein expression levels. Shikonin improved experimental pulmonary arterial hypertension hemodynamics and pulmonary vascular remodeling at least partly through the inhibition of PKM2 and the resultant suppression of aerobic glycolysis. These results provide a novel understanding of possible new treatment targets for PAH.

Metabolic Score for Visceral Fat: a novel predictor for the risk of type 2 diabetes mellitus.

To investigate the association between the Metabolic Score for Visceral Fat (METS-VF) and risk of type 2 diabetes mellitus (T2DM) and compare the predictive value of the METS-VF for T2DM incidence with other obesity indices in Chinese people. A total of 12 237 non-T2DM participants aged over 18 years from the Rural Chinese Cohort Study of 2007-2008 were included at baseline and followed up during 2013-2014. The cox proportional hazards regression was used to calculate hazard ratios (HR) and 95 % CI for the association between baseline METS-VF and T2DM risk. Restricted cubic splines were used to model the association between METS-VF and T2DM risk. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the ability of METS-VF to predict T2DM incidence. During a median follow-up of 6·01 (95 % CI 5·09, 6·06) years, 837 cases developed T2DM. After adjusting for potential confounding factors, the adjusted HR for the highest v. lowest METS-VF quartile was 5·97 (95 % CI 4·28, 8·32), with a per 1-sd increase in METS-VF positively associated with T2DM risk. Positive associations were also found in the sensitivity and subgroup analyses, respectively. A significant nonlinear dose-response association was observed between METS-VF and T2DM risk for all participants (Pnonlinearity = 0·0347). Finally, the AUC value of METS-VF for predicting T2DM was largest among six indices. The METS-VF may be a reliable and applicable predictor of T2DM incidence in Chinese people regardless of sex, age or BMI.

Fried-food consumption and risk of overweight/obesity, type 2 diabetes mellitus, and hypertension in adults: a meta-analysis of observational studies.

Recent studies have reported conflicting associations of fried-food consumption and risk of overweight/obesity, type 2 diabetes mellitus (T2DM) and hypertension, and a meta-analysis is not available. We aimed to explore the association between fried-food consumption and risk of overweight/obesity, T2DM and hypertension in adults through a meta-analysis. We searched PubMed, EMBASE, and Web of Science for studies published up to 17 June 2020. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated by random-effects models. In comparing the highest to lowest fried-food intake, the pooled RRs (95% CIs) were 1.16 (1.07-1.25; I2 = 71.0%, Pheterogeneity < 0.001) for overweight/obesity (cohort: 1.19 [0.97-1.47], n = 2; cross-sectional: 1.14 [1.03-1.27], n = 9), 1.07 (0.90-1.27; 84.7%) for T2DM (cohort: 1.01 [0.89-1.15], n = 9; case-control: 2.33 [1.80-3.01], n = 1), and 1.20 (1.05-1.38; I2=91.8%) for hypertension (cohort: 1.06 [0.98-1.15], n = 8; cross-sectional: 2.16 [0.59-7.87], n = 3). Our meta-analysis indicates fried-food consumption is associated with increased risk of overweight/obesity and hypertension but not T2DM in adults, but the findings should be interpreted with caution due to high heterogeneity and unstable subgroup analyses of this meta-analysis. More studies are warranted to investigate the total fried-food consumption and these health outcomes.

The progress of pulmonary artery denervation.

Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary arterial pressure and pulmonary arterioles remodeling. Some studies have discovered the relationship between sympathetic nerves (SNs) and pathogenesis of PAH. This review is aimed to illustrate the location and components of SNs in the pulmonary artery, along with different methods and effects of pulmonary artery denervation (PADN). Studies have shown that the SNs distributed mainly around the main pulmonary artery and pulmonary artery bifurcation. And the SNs could be destroyed by three ways: the chemical way, the surgical way and the catheter-based way. PADN can significantly decrease pulmonary arterial pressure rapidly, improve hemodynamic varieties, and then palliate PAH. PADN has been recognized as a prospective and effective therapy for PAH patients, especially for those with medication-refractory PAH. However, further enlarged clinical studies are needed to confirm accurate distribution of SNs in the pulmonary artery and the efficacy of PADN.

Association between shift work and risk of metabolic syndrome: A systematic review and meta-analysis.

AIMS: A comprehensive assessment of the association of shift work with risk of metabolic syndrome (MetS) through a systematic review and meta-analysis has not been reported. We aimed to evaluate the relationship from observational studies. DATA SYNTHESIS: We searched PubMed, Embase, and Web of Science databases from inception to December 16, 2020. Articles were chosen according to established inclusion criteria. Studies with data on men and women and different types of shift work were treated as independent studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using random-effects models with heterogeneity (I2) > 50%; otherwise, a fixed-effects model was used. A total of 7192 articles was searched from PubMed, Embase and Web of science. Finally, we included 23 articles (38 studies) in this meta-analysis. The pooled RRs and 95% CI of MetS risk with shift work, 1-shift work, 2-shift work, and 3-shift work versus non-shift work were 1.30 (95% CI 1.19-1.41), 0.95 (95% CI 0.82-1.11), 1.19 (95% CI 0.91-1.56) and 1.17 (95% CI 1.00-1.37), respectively. The results from subgroup analyses stratified by sex, age, and region supported our overall findings that shift work is a risk factor for MetS. CONCLUSIONS: This meta-analysis suggests that shift work increases risk of MetS. Higher risk of MetS was found in the shift workers who were 2-shift or 3-shift or women or Asian workers.

Long-term association of ambient air pollution and hypertension in adults and in children: A systematic review and meta-analysis.

AIMS: The association of long-term ambient air pollution and hypertension has been inconsistently reported. We performed an updated systematic review and meta-analysis to assess the association between long-term exposure to ambient air pollution and risk of hypertension in adults and in children. METHODS: PubMed, EMBASE, and Web of Science were searched up to August 7, 2020 for published articles examining the association of long-term exposure to ambient air pollution, including particulate matter (PM; ultrafine particles, PM1, PM1-2.5, PM2.5, PM2.5-10 and PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and hypertension. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for hypertension with each 10-µg/m3 increase in air pollutants were calculated by random-effects models. RESULTS: We included 57 studies (53 of adults and 4 of children) in the meta-analysis. Risk of hypertension was significantly increased in adults with each 10-µg/m3 increase in exposure to PM2.5 (OR 1.10, 95% CI 1.07-1.14; I2 = 93.1%; n = 37), PM10 (1.04, 1.02-1.07; I2 = 44.8%; n = 22), and SO2 (1.21, 1.08-1.36; I2 = 96.6%; n = 3). Hypertension was not significantly associated with PM1 (n = 2), PM2.5-10 (n = 16), NO2 (n = 27), or NOx (n = 17). In children, the summary ORs (95% CIs) for each 10-µg/m3 increase in PM2.5, PM10, SO2 and O3 were 2.82 (0.51-15.68; I2 = 83.8%; n = 2), 1.15 (1.01-1.32; I2 = 0; n = 2), 8.57 (0.13-575.58; I2 = 94.2%; n = 2), and 1.26 (0.81-1.09, I2 = 91.6%; n = 2), respectively. CONCLUSIONS: Long-term ambient air pollution is a potential risk factor for hypertension in adults. More studies are needed to explore the effects of long-term air pollution on hypertension in children.

Integrated analysis of m6A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension.

BACKGROUND: N6-methyladenosine (m6A) modification is one of the most common chemical modifications of eukaryotic mRNAs, which play an important role in tumors and cardiovascular disease through regulating mRNA stability, splicing and translation. However, the changes of m6A mRNA and m6A-related enzymes in pulmonary arterial hypertension (PAH) remain largely unexplored. METHODS: MeRIP-seq was used to identify m6A methylation in lung tissues from control and MCT-PAH rats. Western blot and immunofluorescence were used to evaluate expression of m6A-related enzymes. RESULTS: Compared with control group, m6A methylation was mainly increased in lung tissues from MCT-PAH rats. The up-methylated coding genes in MCT-PAH rats were primarily enriched in processes associated with inflammation, glycolysis, ECM-receptor interaction and PDGF signal pathway, while genes with down-methylation were enriched in processes associated with TGF-ß family receptor members. The expression of FTO and ALKBH5 downregulated, METTL3 and YTHDF1 increased and other methylation modification-related proteins was not significantly changed in MCT-PAH rats lung tissues. Immunofluorescence indicated that expression of FTO decreased and YTHDF1 increased in small pulmonary arteries of MCT-PAH rats. CONCLUSION: m6A levels and the expression of methylation-related enzymes were altered in PAH rats, in which FTO and YTHDF1 may play a crucial role in m6A modification.

Luteolin Ameliorates Experimental Pulmonary Arterial Hypertension via Suppressing Hippo-YAP/PI3K/AKT Signaling Pathway.

Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.

Air pollution and DNA methylation in adults: A systematic review and meta-analysis of observational studies.

This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies. PubMed, Web of Science and Embase databases were systematically searched for available studies on the association between air pollution and DNA methylation published up to March 9, 2021. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). Meta-analysis was used to summarize the combined estimates for the association between air pollutants and global DNA methylation levels. Heterogeneity was assessed with the Cochran Q test and quantified with the I2 statistic. In total, 38 articles were included in this study: 16 using global methylation, 18 using candidate genes, and 11 using EWAS, with 7 studies using more than one approach. Meta-analysis revealed an imprecise but inverse association between exposure to PM2.5 and global DNA methylation (for each 10-µg/m3 PM2.5, combined estimate: 0.39; 95% confidence interval: 0.97 - 0.19). The candidate-gene results were consistent for the ERCC3 and SOX2 genes, suggesting hypermethylation in ERCC3 associated with benzene and that in SOX2 associated with PM2.5 exposure. EWAS identified 201 CpG sites and 148 differentially methylated regions that showed differential methylation associated with air pollution. Among the 307 genes investigated in 11 EWAS, a locus in nucleoredoxin gene was found to be positively associated with PM2.5 in two studies. Current meta-analysis indicates that PM2.5 is imprecisely and inversely associated with DNA methylation. The candidate-gene results consistently suggest hypermethylation in ERCC3 associated with benzene exposure and that in SOX2 associated with PM2.5 exposure. The Kyoto Encyclopedia of Genes and Genomes (KEGG) network analyses revealed that these genes were associated with African trypanosomiasis, Malaria, Antifolate resistance, Graft-versus-host disease, and so on. More evidence is needed to clarify the association between air pollution and DNA methylation.

Fried-food consumption and risk of cardiovascular disease and all-cause mortality: a meta-analysis of observational studies.

OBJECTIVE: We performed a meta-analysis, including dose-response analysis, to quantitatively determine the association of fried-food consumption and risk of cardiovascular disease and all-cause mortality in the general adult population. METHODS: We searched PubMed, EMBASE and Web of Science for all articles before 11 April 2020. Random-effects models were used to estimate the summary relative risks (RRs) and 95% CIs. RESULTS: In comparing the highest with lowest fried-food intake, summary RRs (95% CIs) were 1.28 (1.15 to 1.43; n=17, I2=82.0%) for major cardiovascular events (prospective: 1.24 (1.12 to 1.38), n=13, I2=75.7%; case-control: 1.91 (1.15 to 3.17), n=4, I2=92.1%); 1.22 (1.07 to 1.40; n=11, I2=77.9%) for coronary heart disease (prospective: 1.16 (1.05 to 1.29), n=8, I2=44.6%; case-control: 1.91 (1.05 to 3.47), n=3, I2=93.9%); 1.37 (0.97 to 1.94; n=4, I2=80.7%) for stroke (cohort: 1.21 (0.87 to 1.69), n=3, I2=77.3%; case-control: 2.01 (1.27 to 3.19), n=1); 1.37 (1.07 to 1.75; n=4, I2=80.0%) for heart failure; 1.02 (0.93 to 1.14; n=3, I2=27.3%) for cardiovascular mortality; and 1.03 (95% CI 0.96 to 1.12; n=6, I2=38.0%) for all-cause mortality. The association was linear for major cardiovascular events, coronary heart disease and heart failure. CONCLUSIONS: Fried-food consumption may increase the risk of cardiovascular disease and presents a linear dose-response relation. However, the high heterogeneity and potential recall and misclassification biases for fried-food consumption from the original studies should be considered.

CD38: A Potential Therapeutic Target in Cardiovascular Disease.

Substantial research has demonstrated the association between cardiovascular disease and the dysregulation of intracellular calcium, ageing, reduction in nicotinamide adenine dinucleotide NAD+ content, and decrease in sirtuin activity. CD38, which comprises the soluble type, type II, and type III, is the main NADase in mammals. This molecule catalyses the production of cyclic adenosine diphosphate ribose (cADPR), nicotinic acid adenine dinucleotide phosphate (NAADP), and adenosine diphosphate ribose (ADPR), which stimulate the release of Ca2+, accompanied by NAD+ consumption and decreased sirtuin activity. Therefore, the relationship between cardiovascular disease and CD38 has been attracting increased attention. In this review, we summarize the structure, regulation, function, targeted drug development, and current research on CD38 in the cardiac context. More importantly, we provide original views about the as yet elusive mechanisms of CD38 action in certain cardiovascular disease models. Based on our review, we predict that CD38 may serve as a novel therapeutic target in cardiovascular disease in the future.

Ligation of patent ductus venosus in a child with pulmonary arterial hypertension and hypersplenism: A case report.

INTRODUCTION: Patent ductus venosus (PDV) is a rare and critical disease, and the majority of patients present with pulmonary arterial hypertension (PAH) or hepatopulmonary syndrome due to congenital portosystemic shunt. We reported that both PAH and hypersplenism were major complications of PDV in this case. This case report can assist the treatment and recovery of the patients with similar symptoms. PATIENT CONCERNS: A 4-year-old male patient presented to our institution with a history of recurrent respiratory infections accompanied by leukocytopenia, thrombocytopenia and presented with tachypnoea. upon mild exertion. DIAGNOSIS: A wide communication, 10 mm in diameter, between the portal vein and inferior vena cava was identified in the subcostal echocardiogram and computed tomography images. Echocardiography showed an estimated systolic pulmonary artery pressure of 106 mm Hg. Right-sided cardiac catheterization indicated a mean pulmonary arterial pressure of 30 mm Hg and a pulmonary vascular resistance of 3 Wood units. Chest X-ray revealed cardiomegaly with a prominent pulmonary segment. INTERVENTIONS: The patient was treated with combination pharmacotherapy of bosentan and tadalafil and PDV ligation. OUTCOMES: A year later, the boy showed normal exercise tolerance and weight gain. Liver and spleen parameters, liver function, blood cells and the general condition of the boy improved. CONCLUSION: Initial combination therapy of bosentan and tadalafil is safe and effective in children with PAH associated with PDV. When PDV banding test shows normal portal pressure, PDV ligation is considered acceptable in children with PAH and hypersplenism associated with PDV.

lncRNA PVT1 identified as an independent biomarker for prognosis surveillance of solid tumors based on transcriptome data and meta-analysis.

PURPOSE: Long noncoding RNA PVT1 is dysregulated in some human tumors and has been found to increase the risk of tumor progression and poor prognosis. This study aimed to reanalyze the effect of PVT1 on tumorous prognosis. MATERIALS AND METHODS: The effect of PVT1 on metastasis and survival were analyzed by univariate logistic regression and Cox proportional hazards model for 32 types of cancer in the Cancer Genome Atlas database (TCGA), and the relationship between PVT1 level and expression of relative genes was assessed by Pearson correlation analysis. RevMan5.3 and STATA14.0 were used to estimate pooled effects of PVT1 on cancer prognosis with data from TCGA and published studies. RESULTS: In TCGA data, high PVT1 expression tended to increase the risk of TNM progression and decreased the overall survival (OS) time in most of cancers. The pooled effect of PVT1 on TNM (pooled-OR=1.46, 95% CI: 1.29-1.65) and OS (pooled HR=1.32, 95% CI: 1.22-1.43), calculated from 37 and 48 cohorts, identified that high PVT1 expression promoted the metastasis and poor prognosis of cancer. Furthermore, the pooled ORs of 2.77 (95% CI: 1.65-4.66), 4.32 (95% CI: 1.99-9.36), 1.35 (95% CI: 1.01-1.80), 1.62 (95% CI: 1.21-2.18) and 1.48 (95% CI: 1.02-2.15) provided evidence that PVT1 played a role in lymph node metastasis, depth of invasion, distant metastasis, differentiation and lymphatic invasion; while the expression of 24 identified target genes was significantly associated with PVT1 level, and high PVT1 expression dependently decreased the OS time under the influence of co-expression genes (OR=1.29, 95% CI: 1.25-1.32) in high-throughput RNA sequencing merging data. In addition, the expression of PVT1 could be upregulated by smoking, with the pooled OR being 1.09 (95% CI 1.01-1.16). CONCLUSION: PVT1 is a dependent biomarker for tumorous prognosis surveillance. However, the reference value of PVT1 needs further study.

LncRNA PVT1 as an effective biomarker for cancer diagnosis and detection based on transcriptome data and meta-analysis.

PURPOSE: Long noncoding RNA (lncRNA) PVT1 was detected all types of cancer from Cancer Genome Atlas (TCGA) project; however, the role of PVT1 in cancer is not clear. This study aimed to reanalyze and determine the effect of PVT1 on cancer diagnosis, especially detection in serum. MATERIALS AND METHODS: Differential expression of PVT1 between cancers and corresponding normal tissues and receiver operating characteristic (ROC) curve were analyzed for all types of cancers in TCGA database. RevMan5.3, Meta-DiSc1.4 and STATA14.0 were used to estimate pooled diagnostic effects of PVT1 in tissue as well as serum. RESULTS: Compared to corresponding normal tissues, PVT1 expression was significantly upregulated in 18 types of cancer and further being an effective diagnosis biomarker in 16 of them. For the 23 diagnosis tests performed in tissue, the pooled AUC and diagnostic odd ratio (DOR) were estimated to be 0.81 (95% CI: 0.76-0.86) and 17.25 (95% CI: 8.43-35.27), when the pooled AUC and DOR were 0.83 (95%CI: 0.75-0.91) and 13.86 (95% CI: 4.70-40.66) for serum tests. Furthermore, the pooled sensitivity and specificity were 0.83 (95% CI: 0.76-0.89) and 0.74 (95% CI:0.70-0.84) for tissue as well as 0.81 (95% CI: 0.76-0.86) and 0.76 (95% CI:0.70-0.81) for serum. CONCLUSIONS: PVT1, especially in serum, might be a usable biomarker for cancer diagnosis / detection.