Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification.

Vascular calcification is a prominent feature of many diseases including atherosclerotic cardiovascular disease (CVD), leading to high morbidity and mortality rates. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism is far from clear. To investigate the role of SelS in inflammation-induced vascular calcification, osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs) induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α were compared between the cells with and without SelS knockdown. LPS or TNF-α induced osteoblastic differentiation and calcification of VSMCs, as showed by the increases of runt-related transcription factor 2 (Runx2) protein levels, Runx2 and type I collagen mRNA levels, alkaline phosphatase activity, and calcium deposition content. These changes were aggravated when SelS was knocked down by small interfering RNA. Moreover, LPS activated both classical and alternative pathways of nuclear factor-κB (NF-κB) signaling in calcifying VSMCs, which were further enhanced under SelS knockdown condition. SelS knockdown also exacerbated LPS-induced increases of proinflammatory cytokines TNF-α and interleukin-6 expression, as well as increases of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and inositol-requiring enzyme 1α expression in calcifying VSMCs. In conclusion, the present study suggested that SelS might inhibit inflammation-induced VSMC calcification probably by suppressing activation of NF-κB signaling pathways and ER stress. Our findings provide new understanding of the role of SelS in vascular calcification, which will be potentially beneficial to the prevention of atherosclerotic CVD.

Selenoprotein S Is Highly Expressed in the Blood Vessels and Prevents Vascular Smooth Muscle Cells From Apoptosis.

Atherosclerosis and related cardiovascular diseases (CVD) represent one of the greatest threats to human health worldwide. The protection of vascular smooth muscle cells (VSMCs) from apoptosis in the plaque has become an important therapeutic target for atherosclerotic plaque stabilization. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism remains unknown. In this paper, SelS expression in the thoracic aorta and its role in the protection of VSMCs from apoptosis have been studied. Western blot analysis showed that SelS was highly expressed in rat thoracic aorta. SelS gene silence by small interference RNA (siRNA) rendered VSMCs more sensitive to hydrogen peroxide- or tunicamycin- induced injury and apoptosis, as determined by MTT assay, Hoechst staining, and annexin V/propidium iodide staining. SelS silence aggravated hydrogen peroxide-induced oxidative stress and phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) in VSMCs. Furthermore, SelS silence enhanced endoplasmic reticulum (ER) stress induced by hydrogen peroxide or tunicamycin, as showed by the increased protein levels of ER chaperone 78 kDa glucose-regulated protein (GRP78), ER stress transducer phosphorylated protein kinase RNA like ER kinase (PERK), and the proapoptotic transcription factor C/EBP homologous protein (CHOP). In conclusion, the present study suggested that SelS highly expressed in the blood vessel might protect VSMCs from apoptosis by inhibiting oxidative stress and ER stress. Our finding provided mechanistic insights for the potential preventive role of SelS in atherosclerotic CVD.

Interleukin-18 Gene Polymorphisms and Rheumatoid Arthritis Susceptibility: An Umbrella Review of Meta-Analyses.

This study systematically analyzes the association between interleukin-18 (IL-18) gene polymorphisms and rheumatoid arthritis (RA) susceptibility. The electronic databases Ovid MEDLINE, Ovid Excerpta Medica Database, and Cochrane Library were searched to identify meta-analyses that included case-control studies reporting IL-18 gene polymorphisms and RA susceptibility. Data were reanalyzed using Review Manager Software 5.1, and Mantel-Haenszel random effects were applied for the five genetic models: allelic, recessive, dominant, homozygote, and heterozygote. The effect size of odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated. A total of seven meta-analyses with poor quality were included. The IL-18 polymorphisms -607 A/C, -137 C/G, -920 T/C, and -105 C/A have been reported. With weak evidence, IL-18 -607 A/C polymorphisms were associated with a reduced risk of RA susceptibility using the allele model (OR = 0.76, 95% CI: 0.61 - 0.93, p=0.01), dominant model (OR = 0.67, 95% CI: 0.50 - 0.90, p=0.008), homozygote model (OR = 0.57, 95% CI: 0.35 - 0.91, p=0.02), and heterozygote model (OR = 0.71, 95% CI: 0.54 - 0.93, p=0.01) in the overall population. IL-18 gene polymorphisms and RA susceptibility are affected by ethnicity: With weak evidence, IL-18 -137 C/G polymorphisms were related to reduce RA susceptibility in the Asian population (allele model: OR = 0.59, 95% CI: 0.40 - 0.88, p=0.01; dominant model: OR = 0.57, 95% CI: 0.37 - 0.89, p=0.01; heterozygote model: OR = 0.60, 95% CI: 0.38 - 0.94, p=0.03). IL-18 -607 A/C gene polymorphisms are a protective factor for RA susceptibility in the overall population, and IL-18 -137 C/G gene polymorphisms are a protective factor for RA susceptibility in the Asian population. Further studies are needed to confirm these results owing to the limitations of the included studies.

[Risk factors associated with cardiac involvement in patients with dermatomyositis/polymyositis].

OBJECTIVE: To identify risk factors associated with cardiac involvement (CI) in patients with dermatomyositis/polymyositis (DM/PM). METHODS: Medical records of 129 DM/PM patients were reviewed retrospectively. The risk factors associated with CI in those patients were screened through Xt tests or independent tests before a multivariate logistic regression analysis was performed. ROC curves were constructed to determine diagnostic values of the identified risk factors. RESULTS: CI occurred in 59 (45. 74%) of DM/PM patients, with 41 (69. 49%) showing electrocardiographic (ECG) abnormality; 25 (42. 37%) showing ultrasonic cardiogram (UCG) abnormality; 8 (13. 56%) being diagnosed with heart failure, and 2 (3. 39%) being diagnosed with myocardial infarction. Eight (13.56%) of the patients with CI died. CI was more likely to occur in patients with an older age, having interstitial lung disease, antinuclear antibody (ANA) positive, and anti-Jo-1 antibody positive (P<0.05). The logistic regression analysis revealed that interstitial lung disease (beta=1. 554), aspartic aminotransferase/creatine kinases (AST/CK) ratio (beta=1.189), positive ANA (beta= 1. 172) and age (beta=0.042) were risk factors associated with CI (P<0. 05). Notable areas under ROC curve (0. 642) was found for AST/CK in determining CI in DM/PM patients (P<0. 05), albeit with low accuracy. A cut-off of AST/CK ratio at 0. 312 was identified as a reference point for determining CI in patients with DM/PM. CONCLUSION: Cardiac involvement is the most common complication of DM/PM, although the majority are subclinical. ECG and UCG are common tools for diagnosing cardiac involvement. Interstitial lung disease, AST/CK ratio, positive ANA and age are predictors of CI in DM/PM patients.

Study on Adhesion Performance and Aging Strength Degradation Mechanism of SBS Modified Asphalt with Different Anti-Aging Additive.

After aging, the adhesiveness of asphalt deteriorates, leading to a reduction in the durability of asphalt mixtures and affecting the service life of asphalt pavements. To enhance the anti-aging performance of asphalt, this study employed the method of melt blending to prepare three types of modified asphalt: graphene/SBS modified asphalt (G/SBSMA), crumb rubber/SBS modified asphalt (CR/SBSMA), and petroleum resin/SBS modified asphalt (PR/SBSMA). Different dosages of the three types of modified asphalt were tested for changes in conventional performance indicators. The optimal dosages of graphene, crumb rubber, and C9 petroleum resin were determined to be 2%, 15%, and 5%, respectively. Based on the theory of surface free energy, the effects of anti-aging agents on the microscopic properties of SBS modified asphalt before and after aging were analyzed using the three-liquid method. The mechanisms of strength attenuation at the asphalt-aggregate interface under water exposure and aging were revealed. The results showed that with the increase of aging gradient, the asphalt-aggregate biphasic system became more active. The cohesive energy and peel energy of SBS modified asphalt increased continuously, while the adhesive energy decreased continuously, leading to a decrease in the energy ratio parameter. Resin-based anti-aging agents exhibited the most significant improvement in asphalt adhesion performance, while graphene demonstrated a more stable enhancement in asphalt's water stability during the aging stage.

Research on High-Temperature Evaluation Indexes and Performance of Qingchuan Rock-SBS Composite Modified Asphalt.

The phenomenon of structural destabilization damage to asphalt pavement is becoming increasingly serious as a result of high temperatures and heavy traffic. Considering the advantages of Qingchuan rock asphalt (QRA) in its durability, high-temperature rutting resistance, and good compatibility with asphalt, it was proposed to compound rock asphalt with SBS to ameliorate the high-temperature performance of asphalt. In this study, DSR and BBR were used to determine the rheological properties of Qingchuan rock-modified asphalt (QRMA) and Qingchuan rock-SBS-modified asphalt (QRA-SBSMA), and the optimum blending amount of rock asphalt was determined based on the PG classification results. Secondly, four different structures of '30 mm AC-10 upper layer (70-A, QRMA, SBSMA, QRA-SBSMA) + 50 mm AC-16 lower layer (70-A)' double-layer composite specimens were prepared. Multiple high-temperature performance evaluation indexes (G*/sinδ, Ds, rutting depth, micro-strain, Fn, modulus) were used to assess the improvement effect of QRA. Finally, using a 1/3 scale accelerated loading testing machine, we simulated high-temperature, water, and high-temperature coupled environments to assess the impact of high temperature and water on the performance of QRMA and QRA-SBSMA, respectively. The findings demonstrated that QRA can increase the PG classification of 70-A and SBSMA as well as its resistance to high-temperature deformation. Multi-index comprehensive evaluation methods were used to consummate the asphalt high-temperature evaluation system. The QRA-SBSMA had the smallest rutting depth and creep rate and the largest dynamic modulus, characterizing its ability to optimally resist high-temperature rutting and deformation.

Evaluation on Improvement Effect of Different Anti-Stripping Agents on Pavement Performance of Granite-Asphalt Mixture.

There are abundant granite reserves in China, but the adhesion between granite and asphalt is poor, and there are problems such as insufficient water stability, which seriously restrict the application and promotion of granite in asphalt pavement. In order to improve the adhesion between granite and asphalt, as well as the water stability of asphalt mixture, amines and polymers were selected as anti-stripping agents. First, silane coupling agent modified asphalt (SCAMA), rock asphalt modified asphalt (RMA), SBS modified asphalt (SBS), and double rock composite modified asphalt (SCA&RMA) were produced; the modification effect of different anti-stripping modified asphalts was evaluated. Then, the adhesion of different types of asphalts and granite aggregates before and after aging was evaluated by time-delayed water immersion method. Finally, AC-10 and AC-16 granite-asphalt mixtures were designed, through indoor performance test and 1/3 scale accelerated loading test, evaluating the improvement effect of granite-asphalt mixture on pavement performance. The results show that the asphalt modified by amine or organic polymers anti-stripping agent could significantly improve the adhesion between granite and asphalt. The Hamburg wheel-tracking test failed to fully reflect the whole process of high-temperature rutting failure. When evaluating the high-temperature performance and water stability of asphalt mixtures, it is recommended that the evaluation method should cover the whole failure stage of asphalt mixtures; considering the coupling effect of water and high temperature, the order of water stability of granite-asphalt mixture is proposed as follows: SCA&RMA > RMA > SBS > SCAMA > 70-A, and SCA&RMA has the best modification effect.

Predictive significance of joint plasma fibrinogen and urinary alpha-1 microglobulin-creatinine ratio in patients with diabetic kidney disease.

BACKGROUND: Although many biomarkers have high diagnostic and predictive power for diabetic kidney disease (DKD), less studies were performed for the predictive assessment in DKD and its progression with combined blood and urinary biomarkers. This study aims to explore the predictive significance of joint plasma fibrinogen (FIB) concentration and urinary alpha-1 microglobulin-creatinine (α1-MG/CR) ratio in DKD. METHODS: A total of 234 patients with type 2 diabetes were enrolled, and their clinical and laboratory data were retrospectively assessed. A ROC curve analysis was performed to evaluate the power of plasma FIB and urinary α1-MG/CR ratio for identifying DKD and advanced DKD, respectively. The predictive power for DKD and advanced DKD was analyzed by regression analysis. RESULTS: Plasma FIB and urinary α1-MG/CR levels were higher in patients with DKD than with pure T2D (p<0.001). The multivariate-adjusted odds ratios (ORs) were 5.047 (95%CI: 2.276-10.720) and 2.192 (95%CI: 1.539-3.122) (p<0.001) for FIB and α1-MG/CR as continuous variables for DKD prediction, respectively. The optimal cut-off values were 3.21 g/L and 2.11mg/mmol for identifying DKD, and 5.58 g/L and 11.07 mg/mmol for advanced DKD from ROC curves. At these cut-off values, the sensitivity and specificity of joint FIB and α1-MG/CR were 0.95 and 0.92 for identifying DKD, and 0.62 and 0.67 for identifying advanced DKD, respectively. The area under curve was 0.972 (95%CI: 0.948-0.995) (p<0.001) and 0.611, 95%CI: 0.488-0.734) (p>0.05). The multivariate-adjusted ORs for joint FIB and α1-MG/CR at the cut-off values were 214.500 (95%CI: 58.054-792.536) and 3.252 (95%CI: 1.040-10.175) (p<0.05), respectively. CONCLUSION: The present study suggests that joint plasma FIB concentration and urinary α1-MG/CR ratio can be used as a powerful predictor for general DKD, but it is less predictive for advanced DKD.

EPC infusion ameliorates acute graft-versus-host disease-related endothelial injury after allogeneic bone marrow transplantation.

Introduction: Graft-versus-host disease (GVHD) damages vascular endothelium. Endothelial progenitor cell (EPC) can differentiate to endothelial cell and promote angiogenesis, but its role in endothelial damage in GVHD is unclear. Methods: In this study, we intend to assess whether EPC infusion promotes the repair of endothelial injury in GVHD mouse model. Male BALB/c mice were randomly divided into 5 groups: control group, total body irradiation group (TBI group), allogeneic bone marrow transplantation group (Allo-BMT group), acute graft versus host disease group (GVHD group), EPC infusion group (GVHD+EPC group) followed by analysis of mice survival, acute GVHD (aGVHD) score, T cell infiltration by immunofluorescence, as well as continuity of vascular endothelium in liver. Results: Compared with Allo-BMT group, the clinical and pathological score of aGVHD mice were higher. On day 21 after transplantation, a large number of mononuclear cell infiltrations were seen in the target tissues of aGVHD mice and mice died within 30 days. In addition, aGVHD group also presented increased subendothelial infiltration of CD3+ T cells in the liver, decreased VE-cadherin expression and elevated major histocompatibility complex (MHC) II molecule expression in the endothelium. Moreover, expression of MHC-II molecule increased in endothelial cell after irradiation injury and LPS stimulation, indicating abnormally activated endothelial cell with antigen-presenting function. Interestingly, infusion of EPC reduced the clinical and pathological score of aGVHD, decreased infiltration of mononuclear cells, improved survival as well as upregulated VE-cadherin and downregulated MHC-II molecule. Discussion: EPC infusion can mobilize to affected endothelium to decrease the infiltration of T cells and pathological endothelial activation contributing to ameliorating the damage of endothelium. EPC infusion combined with bone marrow transplantation might be a perspective strategy for the prevention and treatment of aGVHD.

MicroRNA-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through modulating TRAF6.

Evidence indicates that macrophages play an important role in the immune system. Therefore, research involving inflammatory and oxidative stress responses in macrophages is of great significance. Many factors contribute to inflammation and oxidative stress, including Salmonella. We investigated the effect of the miR-139-5p/TRAF6 axis on the inflammatory and oxidative stress responses of Salmonella -infected macrophages. Our findings revealed that miR-139-5p decreased IL-1ß and TNF-α levels to inhibit Salmonella-induced inflammatory responses in the RAW264.7 macrophage cell line. Furthermore, miR-139-5p inhibited Salmonella-induced oxidative stress by strengthening SOD, CAT and GSH-PX activity, as well as lowering the malondialdehyde level in the RAW264.7 macrophages cell line. Subsequently, it was verified that TRAF6 was a downstream target of miR-139-5p in RAW264.7 cells. Rescue assays indicated that the over-expression of miR-139-5p inhibits the effects of TRAF6 on inflammatory and oxidative stress responses including Salmonella infection in RAW264.7 cells. To our knowledge, this study is the first to verify that miR-139-5p inhibits inflammatory and oxidative stress responses of Salmonella-infected macrophages through regulating TRAF6. This discovery may offer new insights on inflammatory and oxidative stress responses in macrophages.

hnRNPDL extensively regulates transcription and alternative splicing.

RNA binding proteins (RBPs) are key players of genome regulation. Here we report the transcriptome study of HnRNP D-Like protein, which belongs to the hnRNP family. We used RNA-seq to analyze the global transcript level and alternative splicing on hnRNPDL shRNA-treated cells and control. Sh-hnRNPDL extensively increased in the expression of genes involved in female pregnancy, cell apoptosis, cell proliferation and cell migration. HnRNPDL regulated alternative splicing of hundreds of genes enriched in transcription regulation and signaling pathways including NOD-like receptor signaling, Notch signaling, and TNF signaling. This study provides the first transcriptome-wide analysis of hnRNPDL regulation of gene expression, which adds to the understanding of critical hnRNPDL functions.

The role of hepatitis B core-related antigen in predicting hepatitis B virus recurrence after liver transplantation.

BACKGROUND: Hepatitis B core-related antigen (HBcrAg) is a viral marker for the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, the relationship between HBcrAg and HBV recurrence after liver transplantation (LT) is unclear. AIM: To investigate the correlation of serum HBcrAg level with HBV recurrence post-LT to evaluate the prognostic role of the pre-LT HBcrAg level. METHODS: This retrospective cohort study enrolled 357 CHB patients who received LT for a median of 36.6 months. Univariate and multivariate analyses and time-dependent receiver operating characteristic (ROC) curves for markers associated with HBV recurrence were analysed. RESULTS: 48 patients (13.4%) had HBV recurrence after LT. HBcrAg, detectable HBV DNA, HCC and HCC recurrence were associated with HBV recurrence. In a multivariate analysis, HBcrAg level was independently associated with HBV recurrence, and the relationship between HBcrAg level and incident HBV recurrence was significant and graded (HR: 3.17 per unit; 95% CI: 1.97-5.11; P for trend < .001). Additionally, HBcrAg level was superior to HBV DNA level in predicting HBV recurrence by time-dependent ROC analysis. Patients with an HBcrAg ≥ 5.0 log U/mL had a significantly higher 5-year cumulative recurrence rate than those with an HBcrAg < 5.0 log U/mL (37.6% vs 6%, P < .001); the adjusted hazard ratio was 5.27 (95% CI 2.47-11.25, P < .001). CONCLUSION: An elevated serum HBcrAg level was independently associated with the risk of HBV recurrence in patients with CHB after LT.

Clinical Significance of Hemostatic Parameters in the Prediction for Type 2 Diabetes Mellitus and Diabetic Nephropathy.

It would be important to predict type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). This study was aimed at evaluating the predicting significance of hemostatic parameters for T2DM and DN. Plasma coagulation and hematologic parameters before treatment were measured in 297 T2DM patients. The risk factors and their predicting power were evaluated. T2DM patients without complications exhibited significantly different activated partial thromboplastin time (aPTT), platelet (PLT), and D-dimer (D-D) levels compared with controls (P < 0.01). Fibrinogen (FIB), PLT, and D-D increased in DN patients compared with those without complications (P < 0.001). Both aPTT and PLT were the independent risk factors for T2DM (OR: 1.320 and 1.211, P < 0.01, resp.), and FIB and PLT were the independent risk factors for DN (OR: 1.611 and 1.194, P < 0.01, resp.). The area under ROC curve (AUC) of aPTT and PLT was 0.592 and 0.647, respectively, with low sensitivity in predicting T2DM. AUC of FIB was 0.874 with high sensitivity (85%) and specificity (76%) for DN, and that of PLT was 0.564, with sensitivity (60%) and specificity (89%) based on the cutoff values of 3.15 g/L and 245 × 109/L, respectively. This study suggests that hemostatic parameters have a low predicting value for T2DM, whereas fibrinogen is a powerful predictor for DN.

Fatty Acid Oxidation in Zebrafish Adipose Tissue Is Promoted by 1α,25(OH)2D3.

1α,25(OH)2D3 (vitamin D3) is crucial for mineral homeostasis in mammals, but the precise effects of 1α,25(OH)2D3 in adipose tissue remain to be clarified in vivo. The initial 25-hydroxylation is catalyzed by liver microsomal cytochrome P450 2R1 (CYP2R1), which is conserved in vertebrates. To probe the physiological function(s) of 1α,25(OH)2D3 in teleosts, we generated two independent cyp2r1-deficient zebrafish lines. These mutants exhibit retarded growth and increased obesity, especially in the visceral adipose tissue (VAT). These defects could be rescued with 25(OH)D3 treatments. ChIP-PCR analyses demonstrated that pgc1a is the target of the vitamin D receptor in the liver and VAT of zebrafish. Significantly decreased protein levels of Pgc1a, impaired mitochondrial biogenesis, and free fatty acid oxidation are also observed in the cyp2r1 mutant VAT. Our results demonstrate that regulation of 1α,25(OH)2D3 during lipid metabolism occurs through the regulation of Pgc1a for mitochondrial biogenesis and oxidative metabolism within zebrafish VAT.