Circulating circRNA expression profile and its potential role in late recurrence of paroxysmal atrial fibrillation post catheter ablation.

BACKGROUND: Catheter-based pulmonary vein isolation (PVI) is an effective and well-established intervention for symptomatic paroxysmal atrial fibrillation (PAF). Nevertheless, late recurrences of atrial fibrillation (LRAF) occurring during 3 to 12 months are common, and the underlying mechanisms remain elusive. Circular RNAs (circRNAs) in atrial tissue have been linked to the pathophysiological mechanisms and progression of PAF in a few studies. However, their expression patterns in peripheral blood and regulatory function in LRAF are not clear. METHODS: In the present study, the expression profile of circulating circRNAs in three paired nonvalvular PAF patients with or without LRAF was investigated by high-throughput sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and circRNA/miRNA regulatory network, were performed to predict the functions and potential regulatory roles of differentially expressed (DE) circRNAs. RESULTS: A total of 12,834 circRNAs, comprising 5,491 down-regulated and 7,343 up-regulated circRNAs, were found to be DE in blood smaples from the two groups in peripheral blood between LRAF and non-recurrence control individuals. The most enriched GO categories in terms of molecular function, biological process, and cellular component features were catalytic activity, cellular metabolic process, and intracellular part, respectively. The KEGG enrichment study revealed that the most important metabolic process controlled by DE circRNAs is endocytosis. In the circRNA/microRNAs interaction network, four up-regulated circRNAs (hsa_circ_0002665, hsa_circ_0001953, hsa_circ_0003831, and hsa_circ_0040533) and one down-regulated circRNA (hsa_circ_0041103) were predicted to play potential regulatory roles in the pathogenesis of LRAF. CONCLUSIONS: This investigation discovered the expression pattern of circulating circRNAs that is indicative of PAF late recurrence, which may serve as risk markers or therapeutic targets for LRAF after PVI.

Serum uric acid and outcome in hospitalized elderly patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes.

INTRODUCTION: Elevated serum uric acid (SUA) levels have been associated with poor outcome in patients with heart failure (HF). Uric acid is associated with inflammation and microvascular dysfunction, which may differentially affect left ventricular ejection fraction (EF) phenotypes. We aimed to identify the role of SUA across EF phenotypes in hospitalized elderly patients with chronic HF. METHODS: We analyzed 1355 elderly patients who were diagnosed with chronic HF. All patients had SUA levels measured within the first 24 h following admission. Patients with left ventricle EF were categorized as having HF with reduced EF (HFrEF, EF < 40%), HF with mid-range EF (HFmrEF, 40%≦LVEF ≦ 49%) or HF with preserved EF (HFpEF, LVEF ≥ 50%). Endpoints were cardiovascular death, HF rehospitalization, and their composite. The median follow-up period was 18 months. RESULTS: Compared with the lowest SUA quartile, the highest SUA quartile was significantly associated with the endpoints (adjusted HR: 2.404, 95% CI: 1.178-4.906, P = 0.016; HR: 1.418, 95% CI: 1.021-1.971, P = 0.037; HR: 1.439, 95% CI: 1.049-1.972, P = 0.024, respectively). After model adjustment, a significant association of SUA with cardiovascular death and the composite endpoint persisted among HFrEF and HFmrEF patients in the highest SUA quartile (P < 0.05 for all). CONCLUSIONS: In hospitalized elderly patients with chronic HF, SUA is an independent predictor of adverse outcomes, which can be seen in HFrEF and HFmrEF patients.

Unraveling genomic regions and candidate genes for multiple disease resistance in upland cotton using meta-QTL analysis.

Verticillium wilt (VW), Fusarium wilt (FW) and Root-knot nematode (RKN) are the main diseases affecting cotton production. However, many reported quantitative trait loci (QTLs) for cotton resistance have not been used for agricultural practices because of inconsistencies in the cotton genetic background. The integration of existing cotton genetic resources can facilitate the discovery of important genomic regions and candidate genes involved in disease resistance. Here, an improved and comprehensive meta-QTL analysis was conducted on 487 disease resistant QTLs from 31 studies in the last two decades. A consensus linkage map with genetic overall length of 3006.59 cM containing 8650 markers was constructed. A total of 28 Meta-QTLs (MQTLs) were discovered, among which nine MQTLs were identified as related to resistance to multiple diseases. Candidate genes were predicted based on public transcriptome data and enriched in pathways related to disease resistance. This study used a method based on the integration of Meta-QTL, known genes and transcriptomics to reveal major genomic regions and putative candidate genes for resistance to multiple diseases, providing a new basis for marker-assisted selection of high disease resistance in cotton breeding.

GhSINA1, a SEVEN in ABSENTIA ubiquitin ligase, negatively regulates fiber development in Upland cotton.

Protein ubiquitination is essential for plant growth and responses to the environment. The SEVEN IN ABSENTIA (SINA) ubiquitin ligases have been extensively studied in plants, but information on their roles in fiber development is limited. Here, we identified GhSINA1 in Upland cotton (Gossypium hirsutum), which has a conserved RING finger domain and SINA domain. Quantitative real-time PCR (qRT-PCR) analysis showed that GhSINA1 was preferentially expressed during fiber initiation and elongation, especially during initiation in the fuzzless-lintless cotton mutant. Subcellular localization experiments indicated that GhSINA1 localized to the nucleus. In vitro ubiquitination analysis revealed that GhSINA1 has E3 ubiquitin ligase activity. Ectopic overexpression of GhSINA1 in Arabidopsis thaliana reduced the number and length of root hairs and trichomes. Yeast two-hybrid (Y2H), firefly luciferase complementation imaging (LCI), and bimolecular fluorescence complementation (BiFC) assays demonstrated that the GhSINA1 proteins could interact with each other to form homodimers and heterodimers. Overall, these results suggest that GhSINA1 may act as a negative regulator in cotton fiber development through homodimerization and heterodimerization.

Incidence, risk factors and prognosis of acute kidney injury in patients treated with immune checkpoint inhibitors: a retrospective study.

Immune checkpoint inhibitors (ICIs) change the prognosis of many cancer patients. With the increasing use of ICIs, immune-related adverse events are occurring, including acute kidney injury (AKI). This study aimed to assess the incidence of AKI during ICI treatment and its risk factors and impact on mortality. Patients treated with ICIs at the First Medical Center of the Chinese PLA General Hospital from January 1, 2014, to December 30, 2019, were consecutively enrolled, and risk factors affecting AKI development in patients treated with ICIs were analyzed using univariate and multivariate logistic regression. Medical record surveys and telephone inquiry were used for follow-up, and Kaplan-Meier survival analysis and Cox regression were used to analyze independent risk factors for death. Among 1615 patients, 114 (7.1%) had AKI. Multivariate logistic regression analysis showed that anemia, Alb < 30 g/L, antibiotic use, diuretic use, NSAID use and proton pump inhibitor use were independent risk factors for AKI development in patients treated with ICIs. Stage 2 or 3 AKI was an independent risk factor for nonrecovery of renal function after AKI onset. Multivariate Cox regression analysis showed that anemia, Alb < 30 g/L, AKI occurrence, and diuretic use were independent risk factors for death in patients treated with ICIs, while high baseline BMI, other tumor types, ACEI/ARB use, and chemotherapy use were protective factors for patient death. AKI occurs in 7.1% of patients treated with ICIs. Anemia, Alb < 30 g/L, and combined medication use are independent risk factors for AKI in patients treated with ICIs. Anemia, Alb < 30 g/L, AKI occurrence, and diuretic use were independent risk factors for death in patients treated with ICIs.

Network of Interactions Between Gut Microbiome, Host Biomarkers, and Urine Metabolome in Carotid Atherosclerosis.

Comprehensive analyses of multi-omics data may provide insights into interactions between different biological layers concerning distinct clinical features. We integrated data on the gut microbiota, blood parameters and urine metabolites of treatment-naive individuals presenting a wide range of metabolic disease phenotypes to delineate clinically meaningful associations. Trans-omics correlation networks revealed that candidate gut microbial biomarkers and urine metabolite feature were covaried with distinct clinical phenotypes. Integration of the gut microbiome, the urine metabolome and the phenome revealed that variations in one of these three systems correlated with changes in the other two. In a specific note about clinical parameters of liver function, we identified Eubacteriumeligens, Faecalibacteriumprausnitzii and Ruminococcuslactaris to be associated with a healthy liver function, whereas Clostridium bolteae, Tyzzerellanexills, Ruminococcusgnavus, Blautiahansenii, and Atopobiumparvulum were associated with blood biomarkers for liver diseases. Variations in these microbiota features paralleled changes in specific urine metabolites. Network modeling yielded two core clusters including one large gut microbe-urine metabolite close-knit cluster and one triangular cluster composed of a gut microbe-blood-urine network, demonstrating close inter-system crosstalk especially between the gut microbiome and the urine metabolome. Distinct clinical phenotypes are manifested in both the gut microbiome and the urine metabolome, and inter-domain connectivity takes the form of high-dimensional networks. Such networks may further our understanding of complex biological systems, and may provide a basis for identifying biomarkers for diseases. Deciphering the complexity of human physiology and disease requires a holistic and trans-omics approach integrating multi-layer data sets, including the gut microbiome and profiles of biological fluids. By studying the gut microbiome on carotid atherosclerosis, we identified microbial features associated with clinical parameters, and we observed that groups of urine metabolites correlated with groups of clinical parameters. Combining the three data sets, we revealed correlations of entities across the three systems, suggesting that physiological changes are reflected in each of the omics. Our findings provided insights into the interactive network between the gut microbiome, blood clinical parameters and the urine metabolome concerning physiological variations, and showed the promise of trans-omics study for biomarker discovery.

Effects of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors on COVID-19.

BACKGROUND: The World Health Organization reported that 28637952 people worldwide had been infected with severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019 (COVID-19), by September 13. AIM: The aim was to investigate whether long-term use of renin-angiotensin-aldosterone system (RAAS) inhibitors for the treatment of hypertension aggravates the performance of COVID-19 patients with hypertension. METHODS: This was a retrospective analysis of lung computed tomography (CT) data and laboratory values of COVID-19 patients with hypertension who were admitted to Huoshenshan Hospital, Wuhan, Hubei Province, between February 18 and March 31, 2020. Patients were divided into two groups. Group A included 19 people who were long-term users of RAAS inhibitors for hypertension; and group B included 28 people who were randomly selected from the database and matched with group A by age, sex, basic diseases, and long-term use of other antihypertensive drugs. All patients underwent a series of CT and laboratory tests. We compared the most severe CT images of the two groups and the laboratory examination results within 2 d of the corresponding CT images. RESULTS: The time until the most severe CT images from the onset of COVID-19 was 30.37 ± 14.25 d group A and 26.50 ± 11.97 d in group B. The difference between the two groups was not significant (t = 1.01, P = 0.32). There were no significant differences in blood laboratory values, C-reactive protein, markers of cardiac injury, liver function, or kidney function between the two groups. There was no significant difference in the appearance of the CT images between the two groups. The semiquantitative scores of each involved lobe were 11.84 ± 5.88 in group A and 10.36 ± 6.04 group B. The difference was not significantly different (t = 0.84, P = 0.41). CONCLUSION: Chest CT is an important imaging tool to monitor the characteristics of COVID-19 and the degree of lung injury. Chronic use of RAAS inhibitors is not related to the severity of COVID-19, and it does not worsen the clinical process.

Genetic structure, gene flow pattern, and association analysis of superior germplasm resources in domesticated upland cotton (Gossypium hirsutum L.).

Gene flow patterns and the genetic structure of domesticated crops like cotton are not well understood. Furthermore, marker-assisted breeding of cotton has lagged far behind that of other major crops because the loci associated with cotton traits such as fiber yield and quality have scarcely been identified. In this study, we used 19 microsatellites to first determine the population genetic structure and patterns of gene flow of superior germplasm resources in upland cotton. We then used association analysis to identify which markers were associated with 15 agronomic traits (including ten yield and five fiber quality traits). The results showed that the upland cotton accessions have low levels of genetic diversity (polymorphism information content = 0.427), although extensive gene flow occurred among different ecological and geographic regions. Bayesian clustering analysis indicated that the cotton resources used in this study did not belong to obvious geographic populations, which may be the consequence of a single source of domestication followed by frequent genetic introgression mediated by human transference. A total of 82 maker-trait associations were examined in association analysis and the related ratios for phenotypic variations ranged from 3.04% to 47.14%. Interestingly, nine SSR markers were detected in more than one environmental condition. In addition, 14 SSR markers were co-associated with two or more different traits. It was noteworthy that NAU4860 and NAU5077 markers detected at least in two environments were simultaneously associated with three fiber quality traits (uniformity index, specific breaking strength and micronaire value). In conclusion, these findings provide new insights into the population structure and genetic exchange pattern of cultivated cotton accessions. The quantitative trait loci of domesticated cotton identified will also be very useful for improvement of yield and fiber quality of cotton in molecular breeding programs.

Assessing inflammation in Chinese subjects with subtypes of heart failure: an observational study of the Chinese PLA Hospital Heart Failure Registry.

BACKGROUND: Inflammation is an important element of the pathophysiological process of heart failure (HF) and is correlated with subtypes of HF. The association between multiple biomarkers of inflammation and HF subtypes in Chinese subjects remains unclear. This study aimed to compare the differences in inflammation biomarkers among Chinese patients with different subtypes of HF who have been identified to date. METHODS: We included 413 consecutive patients with HF, including 262 with preserved ejection fraction (HFpEF), 55 with middle-ranged ejection fraction (HFmrEF) and 96 with reduced ejection fraction (HFrEF). Ten inflammation biomarkers were analyzed and compared according to the HF subtypes. One hundred contemporary non-HF subjects were also recruited as the control group. Moreover, the correlations between the inflammatory biomarkers and left ventricular ejection fraction of the HF subtypes were assessed. RESULTS: The mean age of the HF patients was 65.0 ± 12.0 years, 65.8% were male. Distinct subtypes of HF demonstrated different inflammation biomarker panels. IL-6, PTX-3, ANGPTL-4 and TNF-α were correlated with HFrEF; IL-1ß and PTX-3 were correlated with HFmrEF; and IL-1ß and IL-6 were correlated with HFpEF. The multivariable logistic regression showed that IL-1ß [relative ratio (RR) = 1.08, 95% CI: 1.02-1.15, P = 0.010], IL-6 (RR = 1.03, 95% CI: 1.01-1.06, P = 0.016), PTX-3 (RR = 1.31, 95% CI: 1.11-1.55, P = 0.001), and ANGPTL-4 (RR = 1.05, 95% CI: 1.02-1.07, P < 0.001) were independently associated with HF, while IL-6 (RR = 1.03, 95% CI: 1.01-1.04, P = 0.019), PTX-3 (RR = 1.23, 95% CI: 1.06-1.43, P = 0.007), and ANGPTL-4 (RR = 1.03, 95% CI: 1.01-1.06, P = 0.005) were independently associated with the HF subtype. CONCLUSIONS: Diverse inflammation biomarkers have multifaceted presentations according to the subtype of HF, which may illustrate the diverse mechanisms of inflammation in Chinese HF patients. IL-6, PTX-3, and ANGPTL-4 were independent inflammation factors associated with HFrEF and HF.

Repeated measurement of growth-differentiation factor-15 in Chinese Han patients with post-myocardial infarction chronic heart failure.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a promising prognostic biomarker in patients with chronic heart failure (CHF). Comparatively little is known about the value of repeated measurement of GDF-15 with CHF in Chinese Han population. This study sought to identify the clinical value of repeated measurement of GDF-15 in Chinese Han patients with post-myocardial infarction CHF. METHODS: In total, 232 consecutive Chinese Han patients with post-myocardial infarction CHF were enrolled prospectively from January 2014 to June 2016.The plasma concentration of GDF-15 was determined on admission and over 12 months. Patients were followed up for all-cause death and a composite outcome of major adverse cardiac events (MACE) included all-cause death, myocardial infarction and first heart failure (HF) re-hospitalization. Association with other clinical variables and adverse outcomes of repeated measurement of GDF-15 was explored. RESULTS: The median baseline GDF-15 level was 2025 ng/L. Baseline GDF-15 was moderately associated with baseline N-terminal pro-B type natriuretic peptide (NT-proBNP) (coefficient 0.561, P < 0.001). During a median follow-up of 20 months, there were 53 deaths and 100MACE. GDF-15 remained an independent predictor of all-cause death (adjusted hazard ratio 1.826 per 1 Ln U, 95% CI: 1.037-8.360; P = 0.037) and MACE (adjusted hazard ratio 2.243 per 1 Ln U, 95% CI: 1.181-1.775; P < 0.001) adjusted for established risk factors. Repeated measurement of GDF-15 was performed in 173 survivals over 12months. Increase of GDF-15 over 12 months was associated with dilatation of left ventricle and acted as an independent predictor of subsequent all-cause death (adjusted HR = 3.164, 95% CI: 1.245-0.041; P = 0.015). In the joint model, GDF-15 was also shown to be a risk factor for all-cause death (HR = 2.749, 95% CI: 1.667-3.831; P < 0.001) and MACE (HR = 2.434, 95% CI: 1.425-3.443; P < 0.001). CONCLUSIONS: Repeated measurements of GDF-15 have promising prognostic value of the risk of all-cause death in Chinese Han patients with CHF post-myocardial infarction. GDF-15 may influence the post-myocardial infarction CHF through the path physiological pathway of myocardial remodeling.

Comparative Chloroplast Genomics of Gossypium Species: Insights Into Repeat Sequence Variations and Phylogeny.

Cotton is one of the most economically important fiber crop plants worldwide. The genus Gossypium contains a single allotetraploid group (AD) and eight diploid genome groups (A-G and K). However, the evolution of repeat sequences in the chloroplast genomes and the phylogenetic relationships of Gossypium species are unclear. Thus, we determined the variations in the repeat sequences and the evolutionary relationships of 40 cotton chloroplast genomes, which represented the most diverse in the genus, including five newly sequenced diploid species, i.e., G. nandewarense (C1-n), G. armourianum (D2-1), G. lobatum (D7), G. trilobum (D8), and G. schwendimanii (D11), and an important semi-wild race of upland cotton, G. hirsutum race latifolium (AD1). The genome structure, gene order, and GC content of cotton species were similar to those of other higher plant plastid genomes. In total, 2860 long sequence repeats (>10 bp in length) were identified, where the F-genome species had the largest number of repeats (G. longicalyx F1: 108) and E-genome species had the lowest (G. stocksii E1: 53). Large-scale repeat sequences possibly enrich the genetic information and maintain genome stability in cotton species. We also identified 10 divergence hotspot regions, i.e., rpl33-rps18, psbZ-trnG (GCC), rps4-trnT (UGU), trnL (UAG)-rpl32, trnE (UUC)-trnT (GGU), atpE, ndhI, rps2, ycf1, and ndhF, which could be useful molecular genetic markers for future population genetics and phylogenetic studies. Site-specific selection analysis showed that some of the coding sites of 10 chloroplast genes (atpB, atpE, rps2, rps3, petB, petD, ccsA, cemA, ycf1, and rbcL) were under protein sequence evolution. Phylogenetic analysis based on the whole plastomes suggested that the Gossypium species grouped into six previously identified genetic clades. Interestingly, all 13 D-genome species clustered into a strong monophyletic clade. Unexpectedly, the cotton species with C, G, and K-genomes were admixed and nested in a large clade, which could have been due to their recent radiation, incomplete lineage sorting, and introgression hybridization among different cotton lineages. In conclusion, the results of this study provide new insights into the evolution of repeat sequences in chloroplast genomes and interspecific relationships in the genus Gossypium.

Neutrophil-to-lymphocyte ratio compared to N-terminal pro-brain natriuretic peptide as a prognostic marker of adverse events in elderly patients with chronic heart failure.

BACKGROUND: The neutrophil-to-lymphocyte (N/L) ratio has been associated with poor prognosis in patients with heart failure, but it has not been compared with N-terminal pro-brain natriuretic peptide (NT-proBNP) in elderly patients with chronic heart failure (CHF). We sought to make this comparison. METHODS: A total of 1355 elderly patients with CHF were analyzed. A multivariate logistic regression model was used to analyze the variables associated with atrial fibrillation (AF). Cox regression analysis was used to assess the multivariable relationship between the N/L ratio, NT-proBNP level, and subsequent major cardiovascular events (MCE). RESULTS: In the multiple logistic regression analysis, the N/L ratio was demonstrated as a risk factor for AF in elderly patients with CHF [odds ratio (OR): 1.079, 95% confidence interval (CI): 1.027-1.134, P = 0.003]. The median follow-up period was 18 months. In a multivariable model using tertiles of both variables, the highest tertile of the N/L ratio was significantly associated with MCE [hazard ratio (HR): 1.407, 95% CI: 1.098-1.802, P = 0.007] compared with the lowest tertile. Similarly, the highest NT-proBNP tertile was also significantly associated with MCE (HR: 1.461, 95% CI: 1.104-1.934, P = 0.008). CONCLUSIONS: In elderly patients with CHF, the N/L ratio is one of the important risk factors for AF and it is an inexpensive and readily available marker with similar independent prognostic power to NT-proBNP. The risk of MCE increases 1.407-fold when the N/L ratio is elevated to the highest tertile.

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.

Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene-modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-ß1, and the oxidative stress factor (hydroxyproline) were evaluated after MnSOD-MSC transplant. Apoptotic rates were evaluated by terminal deoxynucleotidyl transferase-mediated nick-end labeling immunohistochemical method. Colonization and differentiation of MnSOD-MSCs in the irradiated lung were analyzed by immunofluorescence staining. Consequently, systemic administration of MnSOD-MSCs significantly attenuated lung inflammation, ameliorated lung damage, and protected the lung cells from apoptosis. MnSOD-MSCs could differentiate into epithelial-like cells in vivo. MnSOD-MSCs were effective in modulating RILI in mice and had great potential for accelerating from bench to bedside.

Prediction model of in-hospital mortality in elderly patients with acute heart failure based on retrospective study.

OBJECTIVES: The aim of this study was to develop a clinical risk model that is predictive of in-hospital mortality in elderly patients hospitalized with acute heart failure (AHF). METHODS: 2486 patients who were 60 years and older from intensive care units of Cardiology Department in the hospital were analyzed. Independent risk factors for in-hospital mortality were obtained by binary logistic regression and then used to establish the risk prediction score system (RPSS). The area under the curve (AUC) of receiver operator characteristic and C-statistic test were adopted to assess the performance of RPSS and to compare with previous get with the guidelines-heart failure (GWTG-HF). RESULTS: By binary logistic regression analysis, heart rate (OR: 1.043, 95% CI: 1.030-1.057, P < 0.001), left ventricular ejection fraction (OR: 0.918, 95% CI: 0.833-0.966, P < 0.001), pH value (OR: 0.001, 95% CI: 0.000-0.002, P < 0.001), renal dysfunction (OR: 0.120, 95% CI: 0.066-0.220, P < 0.001) and NT-pro BNP (OR: 3.463, 95% CI: 1.870-6.413, P < 0.001) were independent risk factors of in-hospital mortality for elderly AHF patients. Additionally, RPSS, which was composed of all the above-mentioned parameters, provided a better risk prediction than GWTG-THF (AUC: 0.873 vs. 0.818, P = 0.016). CONCLUSIONS: Our risk prediction model, RPSS, provided a good prediction for in-hospital mortality in elderly patients with AHF.

Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats.

The phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2α dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echocardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia.

Genome-wide analysis of tunicamycin-induced endoplasmic reticulum stress response and the protective effect of endoplasmic reticulum inhibitors in neonatal rat cardiomyocytes.

Tunicamycin (TM) is an inducer of endoplasmic reticulum (ER) stress. However, which genes related to ER stress was induced in cardiomyocytes on a genome-wide scale remains poorly understood. Salubrinal and its derivatives are ER stress inhibitors. However, the cellular protection mechanisms remain unresolved. Neonatal rat cardiomyocytes were cultured from ventricles of one-day-old Wistar rats. Cells were exposed to salubrinal, its derivatives (PP1-12, PP1-24) or vehicle followed by TM treatment at different times. Total RNA was isolated from cells for RNA-sequencing analysis. The expressions of 189, 182, 556, 860, and 1314 genes were changed in cells exposed to TM for 1, 3, 6, 12, and 24 h. Five well-known UPR genes (Hspa5, Hsp90b1, Calr, Ddit3, and Atf4) were significantly increased in a time-dependent manner. Six not well-known genes (Hyou1, Herpud1, Manf, Creld2, Sdf2l1, and Slc3a2) were highlighted to be involved in ER stress. Compared with TM-only treated cells, the expressions of 36 genes upregulated by TM and 74 genes downregulated by TM were reversed by salubrinal. In comparison, 121 genes upregulated by TM and 92 genes downregulated by TM were reversed by PP1-12. Most genes altered by salubrinal are in the category of transcription (1 h) and cell cycle (24 h). Most genes altered by PP1-12 are in the category of response to ER stress (3 h) and cell cycle (24 h). Our findings help elucidate the mechanism for TM treatment and may be useful for future drug screens involved in ER stress.

High-content screening identifies inhibitors of the nuclear translocation of ATF6.

Activating transcription factor 6 (ATF6) is a transmembrane protein that consists of a cytoplasmic domain and an endoplasmic reticulum (ER) luminal domain. As unfolded protein levels arise in the ER, the ER cytoplasmic domain of ATF6 moves to the nucleus, where it activates the transcription of a range of genes, including those involved in apoptosis. As ATF6 only becomes functional once it has moved to the nucleus, compounds that inhibit its re-localization are of therapeutic interest. The aim of the present study was to rapidly and accurately identify such compounds using a novel image­based, high­content screening (HCS) technique. The results from the HCS analysis were then confirmed by luciferase reporter assays, western blot analysis and the measurement of cell viability. We found that HCS identified compounds which inhibited ATF6 nuclear translocation with high specificity, as confirmed by the luciferase reporter assay and western blot analysis. Moreover, we demonstrated that 3 of the 80 identified compounds impaired ATF6-mediated induced cell death. The data from this study support the theory that HCS is a novel, high throughput method which can be used for accurate and rapid compound screening.

Salubrinal protects cardiomyocytes against apoptosis in a rat myocardial infarction model via suppressing the dephosphorylation of eukaryotic translation initiation factor 2α.

The aim of the present study was to examine the role of eIF2α in cardiomyocyte apoptosis and evaluate the cardioprotective role of salubrinal in a rat myocardial infarction (MI) model. Rat left anterior descending coronary arteries were ligated and the classical proteins involved in the endoplasmic reticulum stress (ERS)-induced apoptotic pathway were analyzed using quantitative polymerase chain reaction and western blot analysis. Salubrinal was administered to the rats and cardiomyocyte apoptosis and infarct size were evaluated by a specific staining method. Compared with the sham surgery group, the rate of cardiomyocyte apoptosis in the MI group was increased with the development of the disease. It was also demonstrated that the mRNA and protein levels of GRP78, caspase-12, CHOP and the protein expression of p-eIF2α were increased in the MI group. Furthermore, the results showed that treatment with salubrinal can decrease cardiomyocyte apoptosis and infarct size by increasing eIF2α phosphorylation and decreasing the expression of caspase-12 and CHOP. The present study suggests that salubrinal protects against ER stress-induced rat cadiomyocyte apoptosis via suppressing the dephosphorylation of eIF2α in the ERS-associated pathway.

Usefulness of S100A12 as a prognostic biomarker for adverse events in patients with heart failure.

OBJECTIVES: S100A12 has been proposed as a novel pivotal factor in inflammation produced by granulocytes. The purpose of this study was to investigate the relationship between S100A12 and chronic heart failure (CHF). DESIGN AND METHODS: One hundred and seventy-seven patients with CHF and 66 subjects without CHF were included in this study. Plasma levels of S100A12 and high-sensitivity C-reactive protein (hs-CRP) were measured in all participants. After a follow-up period of 18months for CHF patients, major cardiovascular events (MCE), including cardiac death and rehospitalization for heart failure, were recorded. RESULTS: Plasma levels of S100A12 were significantly higher in CHF patients than in control subjects (P<0.001) and positively correlated with hs-CRP (r=0.316, P<0.001). S100A12 levels were also higher in MCE patients than in MCE-free patients. The occurrence of MCE increased with advancing plasma S100A12 levels by stratification according to quartiles (Q4 vs Q1, P=0.015). Cox proportional hazards regression analysis revealed that S100A12 was an independent risk factor for MCE in CHF patients (P=0.009). CONCLUSIONS: S100A12 is a potential biomarker of CHF that may provide important information regarding the prediction of MCE in patients with CHF.