Insufficiency of quality of life as the treatment endpoint for balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension.

Background and Objectives: The ability of a quality of life (QoL) to guide balloon pulmonary angioplasty (BPA) among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully investigated. This study explored the relationship between QoL scores and hemodynamics in CTEPH patients after BPA and examined whether QoL could be applied as a treatment endpoint. Materials and Methods: This cohort study included patients with inoperable CTEPH who had undergone at least four sessions of BPA. The patients' demographic and clinical data as well as hemodynamic parameters and scores from the RAND 36-item short-form QoL questionnaire were recorded and compared before and after BPA. Results: After BPA treatments, clinical characteristics, hemodynamic parameters, as well as QoL score improved significantly. A physical component summary (PCS) score of 35 or 46 can be used as the cutoff value for predicting better World Health Organization functional classification (WHO FC). Patients who had a higher PCS would have longer 6-min walk distance (6MWD), lower pulmonary vascular resistance (PVR), and better cardiac output (CO) both before and after BPA. However, 19 patients (55.9%) with a higher PCS score after BPA did not achieve the goal of mean pulmonary arterial pressure (mPAP) ≤30 mmHg. During the follow-up period, a significant reduction of PVR was observed, but the PCS score improved a little. Conclusions: QoL is a useful tool for assessing the exercise endurance of patients with inoperable CTEPH treated with BPA, but is insufficient to serve as a treatment endpoint for BPA.

Gut microbiota and cognitive performance: A bidirectional two-sample Mendelian randomization.

PURPOSE: Previous studies have suggested a potential association between gut microbiota and neurological and psychiatric disorders. However, the causal relationship between gut microbiota and cognitive performance remains uncertain. METHODS: A two-sample Mendelian randomization (MR) study used SNPs linked to gut microbiota (n = 18,340) and cognitive performance (n = 257,841) from recent GWAS data. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were employed. Heterogeneity was assessed via Cochran's Q test for IVW. Results were shown with funnel plots. Outliers were detected through leave-one-out method. MR-PRESSO and MR-Egger intercept tests were conducted to address horizontal pleiotropy influence. LIMITATIONS: Limited to European populations, generic level, and potential confounding factors. RESULTS: IVW analysis revealed detrimental effects on cognitive perfmance associated with the presence of genus Blautia (P = 0.013, 0.966[0.940-0.993]), Catenibacterium (P = 0.035, 0.977[0.956-0.998]), Oxalobacter (P = 0.043, 0.979[0.960-0.999]). Roseburia (P < 0.001, 0.935[0.906-0.965]), in particular, remained strongly negatively associated with cognitive performance after Bonferroni correction. Conversely, families including Bacteroidaceae (P = 0.043, 1.040[1.001-1.081]), Rikenellaceae (P = 0.047, 1.026[1.000-1.053]), along with genera including Paraprevotella (P = 0.044, 1.020[1.001-1.039]), Ruminococcus torques group (P = 0.016, 1.062[1.011-1.115]), Bacteroides (P = 0.043, 1.040[1.001-1.081]), Dialister (P = 0.027, 1.039[1.004-1.074]), Paraprevotella (P = 0.044, 1.020[1.001-1.039]) and Ruminococcaceae UCG003 (P = 0.007, 1.040[1.011-1.070]) had a protective effect on cognitive performance. CONCLUSIONS: Our results suggest that interventions targeting specific gut microbiota may offer a promising avenue for improving cognitive function in diseased populations. The practical application of these findings has the potential to enhance cognitive performance, thereby improving overall quality of life.

Arsenate Anion-π Interactions on Amine-Modified Polydivinylbenzene in Aqueous Systems: Experimental and Theoretical Investigation.

Anion-π interactions aiding in the adsorption of anions in the solution phase, though challenging to quantify, have attracted a lot of attention in supramolecular chemistry. We present the design of a polymer adsorbent that quantifies the adsorption of arsenate ions experimentally by optimizing anion-π interactions in a purely aqueous system and use density functional theory to compare these results with theoretical data. Arsenate anions are removed from water by amine-functionalized polydivinylbenzene using the comonomer 1-vinyl-1,2,4-triazole, which was cross-linked with divinylbenzene via radical polymerization in a hydrothermal procedure. The amine-functionalized polydivinylbenzene successfully removed arsenate anions from water with a capacity of 46 mg g-1, a 70% increase compared to the nonfunctionalized polydivinylbenzene (27 mg g-1) capacity under the same conditions. Adsorption is best described by the Sips isotherm model with a correlation coefficient R2 factor of 0.99, indicating that adsorption sites are homogeneous, and adsorption occurred by forming a monolayer. Kinetic studies indicated that adsorption is second order in the amine-functionalized polydivinylbenzene. Computational studies using density functional theory showed that the 1-vinyl-1,2,4-triazole comonomer improved the thermodynamic stability of the anionic-π interactions of polydivinylbenzene with arsenate anions. Electrostatic interactions dominate the mechanism of adsorption in polydivinylbenzene compared to the anion-induced interactions that dominate adsorption in amine-functionalized polydivinylbenzene.

Association between intraoperative mean arterial pressure variability and postoperative delirium after hip fracture surgery: a retrospective cohort study.

BACKGROUND: Postoperative delirium (POD) is a common complication in elderly patients after hip fracture surgery. Our study was to investigate whether intraoperative mean arterial pressure variability (MAPV) was associated with POD in elderly patients after hip fracture surgery. METHODS: In this retrospective cohort study, patients aged 65 years and older undergoing hip fracture surgery were included. The correlation between MAPV and POD was investigated using univariate and multivariate logistic regression. Covariate-related confounding effects were eliminated with propensity score matching (PSM) analysis. Then, a subgroup analysis was conducted to further examine the associations between MAPV and POD. RESULTS: Nine hundred sixty-three patients with a median age of 80 years (IQR: 73-84) were enrolled. POD occurred in 115/963 (11.9%) patients within 7 days after surgery. According to multivariate regression analysis, MAPV > 2.17 was associated with an increased risk of POD (OR: 2.379, 95% CI: 1.496-3.771, P < 0.001). All covariates between the two groups were well balanced after PSM adjustment. A significant correlation between MAPV and POD was found in the PSM analysis (OR: 2.851, 95% CI: 1.710-4.746, P < 0.001). CONCLUSIONS: An increased intraoperative MAPV may be a predictor for POD.

The Role of Strain by Cardiac Magnetic Resonance Imaging in Predicting the Prognosis of Patients with Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombotic obstruction of the pulmonary arteries, and right ventricular (RV) dysfunction is a major cause of death. Cardiac magnetic resonance (CMR) is the gold standard for assessing heart wall deformation; therefore, we aimed to determine the prognostic value of CMR strain in patients with CTEPH. Strain derived by CMR was measured at the time of diagnosis in 45 patients with CTEPH, and the relationship between RV strain and prognosis was determined through follow-up. The value of RV strain in the prognostic model was compared with that of pulmonary arterial hypertension (PAH) risk stratification. The RV global peak longitudinal strain (GLS) and global peak circumferential strain (GCS) in CTEPH patients were lower than the normal references of RV strain in the control group. GLS and longitudinal strain in the basal segment were independent risk factors for adverse events (P < .050). Adding CMR parameters to PAH risk stratification improved its predictive power in patients with CTEPH. GLS and GCS scores were impaired in patients with chronic RV overload. RV strain derived by CMR imaging is a promising noninvasive tool for the follow-up of patients with CTEPH.

Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) characterized by immune dysfunction is possibly more vulnerable to herpes simplex virus (HSV) infection. The infection has been intensively considered a common onset and exacerbation of SLE. This study is aimed at elucidating the causal association between SLE and HSV. A bidirectional two-sample Mendelian Randomization (TSMR) analysis was systematically conducted to explore the causal effect of SLE and HSV on each other. The causality was estimated by inverse variance weighted (IVW), MR-Egger and weighted median methods based on the summary-level genome-wide association studies (GWAS) data from a publicly available database. Genetically proxied HSV infection exhibited no causal association with SLE in the forward MR analysis using IVW method (odds ratio [OR] = 0.987; 95% confidence interval [CI]: 0.891-1.093; p = 0.798), nor did HSV-1 IgG (OR = 1.241; 95% CI: 0.874-1.762; p = 0.227) and HSV-2 IgG (OR = 0.934; 95% CI: 0.821-1.062; p = 0.297). Similar null results with HSV infection (OR = 1.021; 95% CI: 0.986-1.057; p = 0.245), HSV-1 IgG (OR = 1.003; 95% CI: 0.982-1.024; p = 0.788) and HSV-2 IgG (OR = 1.034; 95% CI: 0.991-1.080; p = 0.121) were observed in the reverse MR where SLE served as the exposure. Our study demonstrated no causal association between the genetically predicted HSV and SLE.

Analysis of clinical features between active and inactive patients of Takayasu's arteritis with pulmonary arteries involvement.

BACKGROUND: The aim of this study was to investigate the clinical characteristics of patients between active and inactive Takayasu's arteritis with pulmonary artery involvement (PTA) and to identify better markers of disease activity in these patients. METHODS: Sixty-four PTA patients in Beijing Chao-yang hospital (2011 to 2021) were included. According to National Institutes of Health criteria, 29 patients were in active stage and 35 were in inactive stage. Their medical records were collected and analyzed. RESULTS: Compared with inactive group, patients in active group were younger. More patients in active stage presented fever (41.38% vs 5.71%), chest pain (55.17% vs 20%), increased C-reactive protein (2.91 vs 0.46 mg/L), erythrocyte sedimentation rate (35.0 vs 9 mm/h), and platelet count (291 vs 221 × 109/L). Pulmonary artery wall thickening was more common in active group (51.72% vs 11.43%). These parameters were restored after treatment. The incidence of pulmonary hypertension was comparable between groups (34.48% vs 51.43%), but patients in active group had lower pulmonary vascular resistance (PVR) (361.0 vs 891.0 dyn·s·cm-5) and higher cardiac index (2.76 ± 0.72 vs 2.01 ± 0.58 L/min/m2). On multivariate logistic regression analysis, chest pain [odds ratio (OR) 9.37, 95%CI (1.98-44.38), P = 0.005], increased platelet count (>242.5 × 109/L) [OR 9.03, 95%CI (2.10-38.87), P = 0.003] and pulmonary artery wall thickening [OR 7.08, 95%CI (1.44-34.89), P = 0.016] were independently associated with disease activity. CONCLUSION: Chest pain, increased platelet count, and pulmonary artery wall thickening are potential new indicators of disease activity in PTA. Patients in active stage may have lower PVR and better right heart function.

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases.

Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.

A Compendium of Mucosal Molecular Characteristics Provides Novel Perspectives on the Treatment of Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis [UC] is a complex heterogeneous disease. This study aims to reveal the underlying molecular features of UC using genome-scale transcriptomes of patients with UC, and to develop and validate a novel stratification scheme. METHODS: A normalised compendium was created using colon tissue samples (455 patients with UC and 147 healthy controls [HCs]), covering genes from 10 microarray datasets. Upregulated differentially expressed genes [DEGs] were subjected to functional network analysis, wherein samples were grouped using unsupervised clustering. Additionally, the robustness of subclustering was further assessed by two RNA sequencing datasets [100 patients with UC and 16 HCs]. Finally, the Xgboost classifier was applied to the independent datasets to evaluate the efficacy of different biologics in patients with UC. RESULTS: Based on 267 upregulated DEGs of the transcript profiles, UC patients were classified into three subtypes [subtypes A-C] with distinct molecular and cellular signatures. Epithelial activation-related pathways were significantly enriched in subtype A [named epithelial proliferation], whereas subtype C was characterised as the immune activation subtype with prominent immune cells and proinflammatory signatures. Subtype B [named mixed] was modestly activated in all the signalling pathways. Notably, subtype A showed a stronger association with the superior response of biologics such as golimumab, infliximab, vedolizumab, and ustekinumab compared with subtype C. CONCLUSIONS: We conducted a deep stratification of mucosal tissue using the most comprehensive microarray and RNA sequencing data, providing critical insights into pathophysiological features of UC, which could serve as a template for stratified treatment approaches.

Long-term Outcomes and Predictors of Chronic Thromboembolic Pulmonary Hypertension After Pulmonary Endarterectomy.

BACKGROUND: Pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients which can significantly improve symptoms and pulmonary hemodynamics. Therefore, this retrospective study evaluated the long-term outcomes after pulmonary endarterectomy (PEA) and analyze the predictors of long-term outcomes for chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: From 2002-2020, 76 CTEPH patients successfully discharged after PEA in Beijing Chaoyang Hospital were followed-up by scheduled clinical visits or telephone interviews. The follow-up time lasted for 18 years and median time was 7.29 years. RESULTS: The survival rate at 1,3,5,10,15 years postoperatively was 100.00%, 97.10%, 95.40%, 89.80% and 82.90%, respectively. Multivariate logistics regression analysis showed that postoperative mPAP (hazard ratio: 1.144; 95%confidence interval: 1.018-1.285; P = 0.023) was associated with a higher risk of late death, right atrium right and left diameters (hazard ratio: 1.113; 95%confidence interval, 1.006-1.231; P = 0.038) were associated with a higher risk of major adverse events. CONCLUSION: Pulmonary endarterectomy is an effective way to treat CTEPH. Long-term outcome is excellent for patients who undergoing pulmonary endarterectomy who survived from peri-operation time. Postoperative mPAP is a significant prognostic factor for long-term death and right atrium right and left diameters is a significant prognostic factor for major adverse events. That shows patients with high postoperative mPAP and right atrium right and left diameter should be followed up closely.

Single-cell RNA-sequencing and microarray analyses to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension.

Objective: The present study aimed to explore the pathological mechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) using a gene chip array and single-cell RNA-sequencing (scRNA-seq). Materials and methods: The mRNA expression profile GSE130391 was downloaded from the Gene Expression Omnibus database. The peripheral blood samples of five CTEPH patients and five healthy controls were used to prepare the Affymetrix microRNA (miRNA) chip and the Agilent circular RNA (circRNA) chip. The pulmonary endarterectomized tissues from five CTEPH patients were analyzed by scRNA-seq. Cells were clustered and annotated, followed by the identification of highly expressed genes. The gene chip data were used to identify disease-related mRNAs and differentially expressed miRNAs and circRNAs. The protein-protein interaction (PPI) network and the circRNA-miRNA-mRNA network were constructed for each cell type. Results: A total of 11 cell types were identified. Intersection analysis of highly expressed genes in each cell type and differentially expressed mRNAs were performed to obtain disease-related genes in each cell type. TP53, ICAM1, APP, ITGB2, MYC, and ZYX showed the highest degree of connectivity in the PPI network of different types of cells. In addition, the circRNA-miRNA-mRNA network for each cell type was constructed. Conclusion: For the first time, the key mRNAs, miRNAs, and circRNAs, as well as their possible regulatory relationships, during the progression of CTEPH were analyzed using both gene chip and scRNA-seq data. These findings may contribute to a better understanding of the pathological mechanisms of CTEPH.

RRP9 promotes gemcitabine resistance in pancreatic cancer via activating AKT signaling pathway.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy regarding digestive system, which is the fourth leading factor of cancer-related mortalities in the globe. Prognosis is poor due to diagnosis at advanced disease stage, low rates of surgical resection, and resistance to traditional radiotherapy and chemotherapy. In order to develop novel therapeutic strategies, further elucidation of the molecular mechanisms underlying PC chemoresistance is required. Ribosomal RNA biogenesis has been implicated in tumorigenesis. Small nucleolar RNAs (snoRNAs) is responsible for post-transcriptional modifications of ribosomal RNAs during biogenesis, which have been identified as potential markers of various cancers. Here, we investigate the U3 snoRNA-associated protein RRP9/U3-55 K along with its role in the development of PC and gemcitabine resistance. METHODS: qRT-PCR, western blot and immunohistochemical staining assays were employed to detect RRP9 expression in human PC tissue samples and cell lines. RRP9-overexpression and siRNA-RRP9 plasmids were constructed to test the effects of RRP9 overexpression and knockdown on cell viability investigated by MTT assay, colony formation, and apoptosis measured by FACS and western blot assays. Immunoprecipitation and immunofluorescence staining were utilized to demonstrate a relationship between RRP9 and IGF2BP1. A subcutaneous xenograft tumor model was elucidated in BALB/c nude mice to examine the RRP9 role in PC in vivo. RESULTS: Significantly elevated RRP9 expression was observed in PC tissues than normal tissues, which was negatively correlated with patient prognosis. We found that RRP9 promoted gemcitabine resistance in PC in vivo and in vitro. Mechanistically, RRP9 activated AKT signaling pathway through interacting with DNA binding region of IGF2BP1 in PC cells, thereby promoting PC progression, and inducing gemcitabine resistance through a reduction in DNA damage and inhibition of apoptosis. Treatment with a combination of the AKT inhibitor MK-2206 and gemcitabine significantly inhibited tumor proliferation induced by overexpression of RRP9 in vitro and in vivo. CONCLUSIONS: Our data reveal that RRP9 has a critical function to induce gemcitabine chemoresistance in PC through the IGF2BP1/AKT signaling pathway activation, which might be a candidate to sensitize PC cells to gemcitabine. Video abstract.

Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling.

Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease: a meta-analysis and systematic review.

Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aß1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

Diagnostic value of miRNA expression and right ventricular echocardiographic functional parameters for chronic thromboembolic pulmonary hypertension with right ventricular dysfunction and injury.

BACKGROUND: We aimed to establish the relationships between the expression of microRNAs (miRNAs) and echocardiographic right ventricular (RV) function parameters, and to explore the effectiveness and clinical value of miRNA expression in predicting RV injury and dysfunction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: In this retrospective study, clinical data were collected from eight CTEPH patients and eight healthy individuals. RV parameters on echocardiography were analyzed, and the expression levels of specific miRNAs were measured by quantitative real-time PCR. Correlation analysis was performed on structural and functional RV parameters and five candidate miRNAs (miR-20a-5p, miR-17-5p, miR-93-5p, miR-3202 and miR-665). The diagnostic value of RV functional parameters and miRNAs expression was assessed by receiver operating characteristic (ROC) curve analysis and C statistic. RESULTS: Among the tested miRNAs, miR-20a-5p expression showed the best correlation with echocardiographic RV functional parameters (P < 0.05), although the expression levels of miR-93-5p, miR-17-5p and miR-3202 showed positive associations with some RV parameters. ROC curve analysis demonstrated the ability of miR-20a-5p expression to predict RV dysfunction, with a maximum area under the curve of 0.952 (P = 0.003) when the predicted RV longitudinal strain was less than -20%. The C index for RV dysfunction prediction by the combination of miRNAs (miR-20a-5p, miR-93-5p and miR-17-5p) was 1.0, which was significantly larger than the values for miR-93-5p and miR-17-5p individually (P = 0.0337 and 0.0453, respectively). CONCLUSION: Among the tested miRNAs, miR -20a-5p, miR -93-5p and miR -17-5p have potential value in the diagnosis of CTEPH based on the correlation between the abnormal expression of these miRNAs and echocardiographic parameters in CTEPH patients. miR-20a-5p showed the strongest correlation with echocardiographic RV functional parameters. Moreover, expression of a combination of miRNAs seemed to show excellent predictive power for RV dysfunction.

A comparative analysis of the osteogenic capacity of osteoblasts from newborn and two-week-old rats.

AIM: To compare the proliferation and osteogenic differentiation of osteoblasts between newborn rats (1d group) and two-week-old rats (14d group) and to clarify the mechanism underlying these effects. METHOD: The endogenous expression of osteogenic marker genes was detected by qPCR, including ALP, OCN, Col1a1, and Runx2. The osteoblasts proliferation was evaluated by EdU assay and Western Blotting [PCNA and Cyclin D1]. ALP activities in osteoblasts were detected using a PNPP kit, ALP staining and qPCR. Mineralized nodule formation and intracellular calcium levels were assessed by Alizarin Red staining and calcium colorimetric assay respectively while OCN, Col1a1 and Runx2 levels in osteoblasts were analyzed by immunostaining. Osteogenesis-associated pathways including Wnt/ß-Catenin, Akt/PPAR and Smad were analyzed via Western Blotting. RESULT: Endogenous ALP, OCN, Col1a1, and Runx2 expression levels were significantly higher in osteoblasts from 14d group than those from 1d group. After treatment with osteogenic induction medium, osteoblast proliferation, ALP activity, mineralized nodule formation, and intracellular calcium levels were markedly increased in osteoblasts from 1d group, with similar results also being observed for the expression of OCN, Col1a1, and Runx2. Wnt3a, ß-catenin, p-Akt, p-Smad1/5/8, and p-Smad5 protein levels were also higher in osteoblasts from 1d group relative to those from 14d group, while the expression of PPARγ was lower. CONCLUSION: The superior osteogenic differentiation capacity in osteoblasts was associated with the higher activation levels of Wnt/ß-Catenin, Akt/PPAR and Smad signaling pathways, and the enhanced proliferative activity in osteoblasts from 1d group.

MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3.

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.

Targeting the forkhead box protein P1 pathway as a novel therapeutic approach for cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide and encompasses diverse diseases of the vasculature, myocardium, cardiac electrical circuit, and cardiac development. Forkhead box protein P1 (Foxp1) is a large multi-domain transcriptional regulator belonging to the Fox family with winged helix DNA-binding protein, which plays critical roles in cardiovascular homeostasis and disorders. The broad distribution of Foxp1 and alternative splicing isoforms implicate its distinct functions in diverse cardiac and vascular cells and tissue types. Foxp1 is essential for diverse biological processes and has been shown to regulate cellular proliferation, apoptosis, oxidative stress, fibrosis, angiogenesis, cardiovascular remodeling, and dysfunction. Notably, both loss-of-function and gain-of-function approaches have defined critical roles of Foxp1 in CVD. Genetic deletion of Foxp1 results in pathological cardiac remodeling, exacerbation of atherosclerotic lesion formation, prolonged occlusive thrombus formation, severe cardiac defects, and embryo death. In contrast, activation of Foxp1 performs a wide range of physiological effects, including cell growth, hypertrophy, differentiation, angiogenesis, and cardiac development. More importantly, Foxp1 exerts anti-inflammatory and anti-atherosclerotic effects in controlling coronary thrombus formation and myocardial infarction (MI). Thus, targeting for Foxp1 signaling has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of CVD, and an increased understanding of cardiovascular actions of the Foxp1 signaling will help to develop effective interventions. In this review, we focus on the diverse actions and underlying mechanisms of Foxp1 highlighting its roles in CVD, including heart failure, MI, atherosclerosis, congenital heart defects, and atrial fibrillation.

Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level.

BACKGROUND: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. METHODS: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. RESULTS: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. CONCLUSIONS: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

Low temperature exerts protective effects by inhibiting mitochondria-mediated apoptosis pathway following pressure injury to rat muscle.

OBJECTIVE: We aimed to determine the effect of different low-temperature range interventions at different time-points in a rat model of pressure injury (PI) produced by Ischemia/Reperfusion (I/R) injury. METHODS: Sprague-Dawley rats were randomly assigned to blank control, injury control, and temperature intervention groups. Rats in the injury control and temperature intervention groups (involving exposure to different temperature range at different time-points) were subjected to three cycles of I/R injury with 2-h ischemia and 0.5-h reperfusion to induce PI. RESULTS: The muscle tissues exhibited degenerative changes after compression. Low temperature intervention of 16-18°C in the ischemia period resulted in the lowest degree of tissue damage and significantly decreased levels of Bcl-2-associated X protein (Bax), caspase-9, and caspase-3. Moreover, it resulted in the highest expression level of B-cell lymphoma 2 (Bcl-2) and lowest expression levels of Bax, caspase-9, and caspase-3 in muscle tissues among all intervention groups. CONCLUSION: Low-temperature intervention at 16-18°C during the ischemia period showed optimal effects on the expressions of apoptotic factors during the development of PI with I/R-induced tissue damage.