Mulberry and Hippophae-based solid beverage promotes weight loss in rats by antagonizing white adipose tissue PPARγ and FGFR1 signaling.

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.

LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.

Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2.

BACKGROUND: Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown. METHODS: We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)-specific, endothelial cell-specific, and myeloid cell-specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)- and CaPO4-induced AAA models. RESULTS: Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO4-induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs. CONCLUSIONS: Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

Clinical Impact of Thrombus Aspiration and Interaction With D-Dimer Levels in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Objectives: To evaluate the effect of thrombus aspiration (TA) strategy on the outcomes and its interaction with D-dimer levels in patients with ST-segment elevation myocardial infarction (STEMI) during primary percutaneous coronary intervention (PCI) in "real-world" settings. Materials and Methods: This study included 1,295 patients with STEMI who had undergone primary PCI with or without TA between January 2013 and June 2017. Patients were first divided into a TA+PCI group and a PCI-only group, and the baseline characteristics and long-term mortality between the two groups were analyzed. Furthermore, we studied the effect of TA on the clinical outcomes of patients grouped according to quartiles of respective D-dimer levels. The primary outcome was all-cause mortality, and the secondary outcomes were new-onset heart failure (HF), rehospitalization, re-PCI, and stroke. Results: In the original cohort, there were no significant differences in all-cause mortality between the TA+PCI and PCI-only groups (hazard ratio, 0.789; 95% confidence interval, 0.556-1.120; p = 0.185). After a mean follow-up of 2.5 years, the all-cause mortality rates of patients in the TA + PCI and PCI-only groups were 8.5 and 16.2%, respectively. Additionally, differences between the two groups in terms of the risk of HF, re-PCI, rehospitalization, and stroke were non-significant. However, after dividing into quartiles, as the D-dimer levels increased, the all-cause mortality rate in the PCI group gradually increased (4.3 vs. 6.0 vs. 7.0 vs. 14.7%, p < 0.001), while the death rate in the TA+PCI group did not significantly differ (4.6 vs. 5.0 vs. 4.0 vs. 3.75%, p = 0.85). Besides, in the quartile 3 (Q3) and quartile 4 (Q4) groups, the PCI-only group was associated with a higher risk of all-cause mortality than that of the TA+PCI group (Q3: 4.0 vs. 7.0%, p = 0.029; Q4: 3.75 vs. 14.7%, p < 0.001). Moreover, the multivariate logistic regression analysis demonstrated that TA is inversely associated with the primary outcome in the Q4 group [odds ratio (OR), 0.395; 95% CI, 0.164-0.949; p = 0.038]. Conclusions: The findings of our real-world study express that routine manual TA during PCI in STEMI did not improve clinical outcomes overall. However, patients with STEMI with a higher concentration of D-dimer might benefit from the use of TA during primary PCI. Large-scale studies are recommended to confirm the efficacy of TA.

High molecular weight fibroblast growth factor-2 as a promising prognostic biomarker to predict the occurrence of heart failure in atrial fibrillation patients.

Heart failure (HF) has a significant effect on the prognosis of the patients with atrial fibrillation (AF), and also it is an important risk factor for overall mortality. High molecular weight fibroblast growth factor-2 (Hi-FGF-2) is emerging as a prognostic marker with HF and AF. The aim of this study was to prove that Hi-FGF-2 would predict occurrence of HF in the patients with AF. Subjects diagnosed with paroxysmal AF (Group paAF), persistent AF (Group peAF) and sinus rhythm (Group SR) were enrolled in the study. Serum Hi-FGF-2 concentration was measured by ELISA at baseline. Multivariable logistic models and receiver operating characteristic (ROC) curve analysis were established to predict the prognosis of AF subjects. 260 patients were enrolled in the study: 104 (40.0%) admitted for sinus rhythm (Group SR) and 156 (60.0%) with AF (Group paAF and Group peAF). The Hi-FGF-2 levels were much lower in the Group SR (58.2 ± 27.1 ng/L) than in the Group AF. Furthermore, the Group peAF (84.3 ± 34.1 ng/L) had higher Hi-FGF-2 levels than the Group paAF (72.9 ± 35.8 ng/L). Serum Hi-FGF-2 levels were classified into trisection in the multivariable logistic model (T1 < 57.3 ng/L, 57.3 < T2 < 86.5 ng/L, and T3 > 86.5 ng/L). Hi-FGF-2 showed good predictive ability for new-onset HF in the patients with AF. The occurrence of HF was associated significantly with increased tertile of serum Hi-FGF-2 levels (T2: OR 5.922, 95% CI 1.109-31.626, P = 0.037 and T3: OR 8.262, 95% CI 1.735-39.343, P = 0.008). ROC curve analysis showed that the area under curves for Hi-FGF-2 were 0.720 (P < 0.0001). Hi-FGF-2 has a significant meaning in AF subjects. Further to this, higher circulating Hi-FGF-2 was highly related to persistent AF, and Hi-FGF-2 may be an independent risk factor of occurrence HF in AF subjects.

Potential Roles of Serum Caveolin-3 Levels in Patients with Atrial Fibrillation.

Objective: To explore serum caveolin-3 (Cav-3) levels in patients with atrial fibrillation (AF) and to evaluate the role of Cav-3 as a biomarker for AF and incident heart failure (HF). Methods: Three hundred and five patients were enrolled in the study and divided into three groups: sinus rhythm (Group SR), paroxysmal AF (Group paAF), and persistent AF (Group peAF). Serum Cav-3 concentrations were measured by enzyme-linked immunosorbent assay at baseline. Clinical characteristics, and laboratory data were collected during hospitalization, and a follow-up of 12-months was carried out. Results: Serum Cav-3 concentrations were significantly decreased on the Group SR and the highest concentrations of Cav-3 in patients were found on the Group peAF (516.7 ± 274.0 vs. 609.3 ± 287.0 vs. 688.3 ± 264.6 ng/L, P < 0.05). Left atrial diameter (LAD) in the Group peAF was significantly higher than in the Group paAF, and the Group SR had significantly lower LAD than the Group paAF and Group peAF. The risks of new-onset HF in the Group SR, Group paAF, and Group peAF were 8.1, 14.5, and 28.6%, respectively. There was a significant difference between the Group peAF and the other two groups. Serum Cav-3 concentrations were trisected in AF participants (lower tertile: ≤498, middle tertile: >498-703, upper tertile: ≥703). In further tertile studies, subjects in the lower tertile of Cav-3 concentrations were more likely to become paroxysmal AF and had much lower LAD (P < 0.05). And in the middle and upper tertiles, participants with AF tended to suffer from HF compared to the lower group (P < 0.05). Conclusion: We provide evidence that Cav-3 has a significant meaning in AF patients. The levels of Cav-3 may be related to the LAD and new-onset HF.

5-Aminosalicylic Acid Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats by Increasing the Expression of Nur77.

The aim of this study is to investigate the effect of 5-aminosalicylic acid (5-ASA) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats and its molecular mechanism. Sixty male Sprague-Dawley rats (250-300 g) were evenly randomized into six groups: control group; PAH group induced by MCT intraperitoneal injection (50 mg/kg) on day 1; and four PAH groups treated for 30 days from day 2 with 5-ASA at 50 (5-ASA-50 group), 100 (5-ASA-100 group), 150 (5-ASA-150 group), and 200 mg/kg/day (5-ASA-200 group), respectively. Body mass, weight increment, survival rates, pulmonary artery pressure (PAP), right ventricular hypertrophy index (RVHI), and the signal pathway regulated by 5-ASA were assessed. (1) Compared with the control group, the PAH group had lower body mass and weight increment, and relative to the latter, 5-ASA-treated groups had larger body mass and weight increment except for groups 5-ASA-150 and 5-ASA-200 and greater overall survival rates; (2) SPAP, DPAP, MPAP, and RVHI in 5-ASA-treated groups, except for MPAP and RVHI in 5-ASA-200 group, were lower than those in the PAH group; (3) compared with the PAH group, Nur77 expression in the pulmonary arteries of 5-ASA-treated groups was increased; and (4) expression of inflammatory mediators (NF-κB p65) was lower, while that of IκBα was higher in the pulmonary arteries of 5-ASA-treated groups and control group than that in the PAH group (all P < 0.05). 5-ASA attenuates PAH in MCT-injected rats, reducing pulmonary arterial pressures and right ventricular hypertrophy and improving survival rates, via the Nur77-NF-κB/IκBα pathway involved in modulating the pulmonary vascular remodeling.

The Application of Intravascular Ultrasound to Evaluate Pulmonary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension.

BACKGROUND: The aim of this study was to explore the application of intravascular ultrasound (IVUS) to evaluate pulmonary vascular properties and mortality in patients with pulmonary arterial hypertension (PAH). METHODS: Patients (n = 51) with systolic pulmonary artery pressures ≥ 40 mm Hg on echocardiography were prospectively enrolled. All patients underwent right-heart catheterization and IVUS and were divided into three groups: PAH associated with connective tissue diseases (group 1, n = 25), PAH due to other causes (group 2, n = 15), and patients with connective tissue diseases without pulmonary hypertension (group 3, n = 11). PAH groups (groups 1 and 2) were divided into distal (n = 22) and proximal (n = 18) remodeling subtypes on the basis of IVUS results. All patients were followed (19 ± 10 months) to compare the differences among clinical variables, pulmonary vascular properties, and survival rates. RESULTS: A total of 408 segments of pulmonary arteries were studied. The PAH groups demonstrated a greater mean wall thickness than group 3 (P < .01 for all). Pulmonary vascular mechanical properties, including compliance, distensibility, elastic modulus, and stiffness index ß, were found to be worse in the PAH groups than in group 3 (P < .01 for all), but they tended to be better in group 1 than in group 2. An inverse exponential association was found between pulmonary vascular mechanical properties and hemodynamics, with R(2) values ranging from 0.54 to 0.78 (P < .001). In the PAH groups, the mortality in group 1 was similar to that in group 2 (12% vs 13%, P > .05), while the distal remodeling subtype had higher mortality than the proximal remodeling subtype (23% vs 0%, P < .05). CONCLUSIONS: IVUS is useful in PAH assessment by evaluating pulmonary vascular properties and predicting mortality. The classification of the proximal and distal remodeling type of PAH may be proposed to predict mortality and evaluate the prognosis of patients with PAH in clinical practice.

Two-dimensional echocardiography in the assessment of long-term prognosis in patients with pulmonary arterial hypertension.

OBJECTIVE: To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH. METHODS: Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis. RESULTS: Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (rLVDD  = -0.699; rRVDD  = -0.818, both P < 0.001) and at last follow-up (rLVDD  = -0.701; rRVDD  = -0.666, both P<0.001). Furthermore, bi-ventricular (LVDD + RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r =  0.831; r = -0.771, both P < 0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD + RVDD) scores were 0.823 (P < 0.0001), 0.737 (P = 0.0002), and 0.825 (P < 0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH. CONCLUSION: LVDD score, RVDD score and (LVDD + RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.