The application value of 24†h Holter monitoring indices in predicting MACEs outside the hospital within three years after PCI in patients with STEMI.

Background: Evaluating cardiovascular risk in patients experiencing acute ST-elevation myocardial infarction (STEMI) and undergoing percutaneous coronary intervention (PCI) is crucial for early intervention and improving long-term outcomes. 24 h Holter monitoring provides continuous cardiac electrophysiological data, enabling the detection of arrhythmias and autonomic dysfunction that are not captured during routine examinations. This study aimed to examine the relationship between Holter monitoring metrics and the occurrence of out-of-hospital major adverse cardiovascular events (MACEs) following PCI in patients with STEMI, offering insights into cardiovascular risk evaluation. Methods: This prospective cohort study included STEMI patients undergoing PCI. 24 h Holter monitoring data were recorded, including heart rate, heart rate variability (HRV) metrics such as SDNN and SDANN index, heart rate deceleration capacity (DC) at different time scales (DC2, DC4, DC8), and the frequency of premature ventricular contractions (PVCs). Independent correlations between these indices and MACEs, as well as cardiovascular deaths, were investigated using multifactorial logistic regression. Predictive capacities were assessed through receiver operating characteristic (ROC) curves. Results: A total of 172 participants were enrolled in this study. Over the 3-year follow-up period, MACEs were observed in 57 patients, including 20 cases of cardiac death. In logistic regression models adjusted for confounding variables, SDNN [OR: 0.980; 95% CI: (0.967, 0.994); p = 0.005] and SDANN index [OR: 0.982; 95% CI: (0.969, 0.996); p = 0.009] were negatively associated with the incidence of MACEs. Conversely, the slowest heart rate [OR: 1.075; 95% CI: (1.022, 1.131); p = 0.005] and frequent PVCs [OR: 2.685; 95% CI: (1.204, 5.987); p = 0.016] demonstrated a positive association with MACEs. Furthermore, SDNN [OR: 0.957; 95% CI: (0.933, 0.981); p = 0.001], DC [OR: 0. 702; 95% CI: (0.526, 0.938); p = 0.017]) and DC4 [OR: 0.020; 95% CI: (0.001, 0.664); p = 0.029] were negatively associated with cardiac death. The ROC analysis results indicated that SDNN was an effective predictor of both MACEs [AUC: 0.688 (95% CI: 0.601-0.776)] and cardiac death [AUC: 0.752 (95% CI: 0.625-0.879)]. Conclusion: HRV, DC metrics, and frequent PVCs obtained by 24 h Holter monitoring were associated with the risk of MACEs in STEMI patients. These metrics can help clinicians identify at-risk patients early so that timely interventions.

Oxidized Low-Density Lipoprotein Decreases the Survival of Bone Marrow Stem Cells via Inhibition of Bcl-2 Expression.

Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions, including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuates the survival of MSCs through suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 µg/mL) for 24 h with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular lactate dehydrogenase (LDH) in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.

Association of an ADRB3 Variant with Coronary Artery Disease Within the Chinese Han Population: Construction of a Predictive Nomogram Model.

Objective: Coronary artery disease (CAD) is a the most common type of heart disease, and is associated with the highest mortality rate. The role of the ß3-adrenergic receptor gene (ADRB3) in energy homeostasis and lipolysis suggests that it may be associated with obesity, insulin resistance, diabetes, and hypertension. Herein, we sought to examine the relationship between CAD and variants of the ADRB3 gene in individuals with Han and Uygur ethnicities in China. Methods: All 1022 participants were genotyped for two ADRB3 single nucleotide polymorphisms (SNPs; rs1892818 and rs9693898) using real-time polymerase chain reaction (TaqMan). Uygur (259 CAD patients, 161 control group) and Han (308 CAD patients, 294 control group) were included in two case-control studies. We subsequently developed a predictive model using ADRB3 genetic variation and clinical variables to predict risk of CAD. Results: The rs1892818 CT genotype (8.5% vs 3.9%, p = 0.019) and T allele (4.3% vs 1.9%, p = 0.021) were more frequently detected in the control subjects compared to CAD patients of the Han population but not in the Uygur population. The rs9693898 was not associated with CAD in either ethnic population. Logistic regression analysis further demonstrated that carriers of the rs1892818 CT genotype had a lower risk of CAD than did those with the CC genotype (CT vs CC, p = 0.044, odds ratio [OR] = 0.441, 95% confidence interval [CI]: 0.199-0.976). Using this data, we constructed a predictive nomogram model for CAD with an area under the curve (95% CI) of 0.722 (0.682, 0.761). Conclusions: Our results suggest that rs1892818 is associated with CAD in the Han population and that the CT genotype of rs1892818 may serve as a protective factor for CAD in Han individuals. The proposed nomograms can be used for the prediction of CAD in this population.

Metabolomics analysis reveals the renal protective effect of Panax ginseng C. A. Mey in type 1 diabetic rats.

The dry root and rhizome of Panax ginseng C. A. Mey has garnered much interest owing to its medicinal properties against diabetes and cardiovascular diseases. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS)-based metabolomics approach was used to illustrate the therapeutic mechanisms of ginseng extract on the serum and urinary metabolic profiles in streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. Pharmacological and renal parameters in response to the administration of ginseng were also evaluated. In total, 16 serum endogenous metabolites and 14 urine endogenous metabolites, including pyruvic acid, indoleacetic acid, and phenylacetylglycine, were identified as potential biomarkers for diabetes. Pathway enrichment and network analysis revealed that the biomarkers modulated by ginseng were primarily involved in phenylalanine and pyruvate metabolism, as well as in arginine biosynthesis. Moreover, the levels of several renal injury-related biomarkers in T1DM rats were significantly restored following treatment with ginseng. The administration of the extract helped maintain tissue structure integrity and ameliorated renal injury. The findings suggest that the regulatory effect of ginseng extract on T1DM involves metabolic management of diabetic rats, which subsequently attenuates T1DM-induced early renal dysfunction.

Brugada syndrome associated with out-of-hospital cardiac arrest: A case report.

BACKGROUND: Brugada syndrome (BrS) is an inherited disease characterized by an electrocardiogram (ECG) with a coved-type ST-segment elevation in the right precordial leads (V1-V3), which predisposes to sudden cardiac death (SCD) due to polymorphic ventricular tachycardia or ventricular fibrillation in the absence of structural heart disease. We report the case of a 29-year-old man with out-of-hospital cardiac arrest. BrS is associated with a high incidence of SCD in adults, and increasing the awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving. CASE SUMMARY: A 29-year-old man suffered from out-of-hospital cardiac arrest, and after defibrillation, his ECG demonstrated a coved-type elevated ST segment in V1 and V2. These findings were compatible with type 1 Brugada pattern, and ECG of his brother showed a type 2 Brugada pattern. The diagnosis was BrS, NYHF IV, multiple organ dysfunction syndrome, sepsis, and hypoxic ischemic encephalopathy. The patient had no arrhythmia episodes after discharge throughout a follow-up period of 36 mo. CONCLUSION: Increasing awareness of BrS and prompt recognition of the Brugada ECG pattern can be lifesaving.

Study on the Appropriate Timing of Postoperative Adaptive Radiotherapy for High-Grade Glioma.

PURPOSE: To investigate the appropriate timing of adaptive radiotherapy (ART) for high-grade glioma. METHODS: Ten patients with high-grade gliomas were selected and underwent CT/MRI (CT1/MRI1, CT2/MRI2, CT3/MRI3, and CT4/MRI4) scans before RT and during 10-, 20- and 30-fraction RT, and the corresponding RT plans (plan1, plan2, plan3 and plan4) were made. The dose of the initial plan (plan1) was projected to CT2 and CT3 using the image registration technique to obtain the projection plans (plan1-2 and plan1-3) and by superimposing the doses to obtain the ART plans (plan10+20 and plan20+10), respectively. The dosimetric differences in the target volume and organs at risk (OARs) were compared between the projection and adaptive plans. The tumor control probability (TCP) for the planning target volume (PTV) and normal tissue complication probability (NTCP) for the OARs were compared between the two adaptive plans. RESULTS: Compared with the projection plan, the D2 to the PTV of ART decreased, the conformity index (CI) to the PTV increased, and the D2/Dmean to the brainstem, optic chiasm and pituitary, as well as the V20, V30, V40 and V50 to the normal brain decreased. The D2 to the pituitary and optic chiasm as well as the V20, V30, V40 and V50 to the normal brain in plan10+20 were lower than those in plan20+10, while the CI to the PTV was higher than that in plan20+10. The TCP of the PTV in plan10+20 was higher than that in plan20+10. CONCLUSION: ART can improve the precision of target volume irradiation and reduce the irradiation dose to the OARs in high-grade glioma. The time point after 10 fractions of RT is appropriate for ART.

Genetic Variation of Migration Inhibitory Factor Gene rs2070766 Is Associated With Acute Coronary Syndromes in Chinese Population.

Genetic variation of macrophage migration inhibitory factor (MIF) gene has been linked to coronary artery disease. We investigated an association between the polymorphism of MIF gene rs2070766 and acute coronary syndromes (ACS) and the predictive value of MIF gene variation in clinical outcomes. This study involved in 963 ACS patients and 932 control subjects from a Chinese population. All participants were genotyped for the single nucleotide polymorphism (SNP) of MIF gene rs2070766 using SNPscan™. A nomogram model using MIF genetic variation and clinical variables was established to predict risk of ACS. Major adverse cardiovascular events (MACE) were monitored during a follow-up period. The frequency of rs2070766 GG genotype was higher in ACS patients than in control subjects (6.2 vs 3.8%, p = 0.034). Multivariate logistic regression analysis revealed that individuals with mutant GG genotype had a 1.7-fold higher risk of ACS compared with individuals with CC or CG genotypes. Using MIF rs2070766 genotypes and clinical factors, we developed a nomogram model to predict risk of ACS. The nomogram model had a good discrimination with an area under the curve of 0.781 (95% CI: 0.759-0.804), concordance index of 0.784 (95% CI: 0.762-0.806) and well-fitted calibration. During the follow-up period of 25 months, Kaplan-Meier curves demonstrated that ACS patients carrying GG phenotype developed more MACE compared to CC or CG carriers (p < 0.05). GG genotype of MIF gene rs2070766 was associated with a higher risk of ACS in a Chinese population. The GG genotype carriers in ACS patients had worse clinical outcomes compared with those carrying CC or CG genotype. Together with rs2070766 genetic variant of MIF gene, we established a novel nomogram model that can provide individualized prediction for ACS.

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction.

Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.

Circulating MIF Levels Predict Clinical Outcomes in Patients With ST-Elevation Myocardial Infarction After Percutaneous Coronary Intervention.

BACKGROUND: The purpose of the study was to assess the value of admission macrophage migration inhibitory factor (MIF) levels in predicting clinical outcomes in ST-elevation myocardial infarction (STEMI) patients. METHODS: For this study we recruited 498 STEMI patients after they received percutaneous coronary intervention (PCI), 40 with stable angina pectoris and 137 healthy participants. Plasma MIF levels were measured at admission and after PCI. The primary end points were in-hospital mortality and major adverse cardio-and/or cerebrovascular events (MACCE) during hospitalization and 3.2-year follow-up period. RESULTS: Admission MIF levels were elevated in 88.4% of STEMI patients over the upper reference limit of healthy controls and it was 3- to 7-fold higher than that in stable angina pectoris and control groups (122 ± 61 vs 39 ± 19 vs 17 ± 8 ng/mL; P < 0.001). Admission MIF levels were significantly higher in patients who died after myocardial infarction vs survivors. For predicting in-hospital mortality using the optimal cutoff value (127.8 ng/mL) of MIF, the area under the receiver operating characteristic curve for MIF was 0.820, similar area under the receiver operating characteristic curve values for predicting short-term outcomes were observed for high-sensitivity troponin T, CK-MB, N-terminal probrain natriuretic peptide, and Global Registry of Acute Coronary Events (GRACE) score. Although peak high-sensitivity troponin T and N-terminal probrain natriuretic peptide also predicted MACCE during the follow-up period, only higher admission MIF levels predicted in-hospital mortality and MACCE during the 3.2-year follow-up. Multivariate regression analysis showed the independent predictive value of a higher admission MIF level (≥ 127.8 ng/mL) on in-hospital mortality (odds ratio, 9.1; 95% confidence interval, 1.7-47.2) and 3.2-year MACCE (hazard ratio, 2.8; 95% confidence interval, 1.5-5.6). CONCLUSIONS: A higher admission MIF level is an independent predictor for in-hospital mortality and long-term MACCE in STEMI patients who underwent PCI.

[Regulatory Effect of MiR-543 on Proliferation and Apoptosis of Human Leukemia Cell Line K562 and Its Mechanism].

OBJECTIVE: To investigate the regulatory effect of miR-543 on proliferation and apoptosis of human leukemia cell line K562 and its mechanism. METHODS: 46 CML patients treated in our hospital from 2018.2-2018.9 was selected and enrolled in CML group, and 30 healthy persons were selected and enrolled in control group at the same time. After Lipofectamine 2000 liposome was used to transfer the miR-543 mimic and negative control (Scramble mimic) to K562 cells, CCK8 assay was used to detect the effect of miR-543 on proliferation of K562 cells; Luciferase reporter assay was used to report the targeting relationship of miR-543 to Wnt gene. Flow cytometry was used to detect the effect of miR-543 on apoptosis of K562 cells; Western blot method was used to detect the Wnt, ß-catenin, BCL-2, c-MYC and BAX expression level. RESULTS: The level of miRNA-543 in CML patients was significantly lower than that in healthy controls (P＜0.05). The expression level of miR-543 in mimic group was significantly higher than that in blank control group (P＜0.05). The Wnt gene expression level in mimic group was significantly lower than that in blank control group (P＜0.05). The expression of luciferase of Wnt wild plasmid was decreased by miR-543 mimic (P＜0.05), and the luciferase activity of Wnt mutant plasmid was not inhibited by miR-543 mimic after mutation of binding site (P＜0.05). There was no significant difference in the proliferation ability of K562 cells between the blank control group and the negative control (Scramble mimic) group (P＞0.05). The proliferation level of K562 cells in mimic group was significantly lower than that in blank control group and negative control (Scramble mimic) group (P＜0.05). Apoptotic level of K562 cells in miR-543 mimic group was significantly higher than that in blank control group and negative control (Scramble mimic) group (P＜0.05). Western blot assay showed that Wnt, ß-catenin, BCL-2 and c-MYC protein levels in miR-543 mimic group were significantly lower than those in blank control group and negative control (Scramble mimic) group (P＜0.05); BAX protein level in miR-543 mimic group was higher than that in blank control group and negative control (Scramble mimic) group (P＜0.05). CONCLUSION: miR-543 can target Wnt protein to inhibit the activity of Wnt signaling pathway, thereby inhibiting the proliferation of leukemia cells and increasing the level of apoptosis.

Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome­mediated IL­1ß secretion via c­Jun N­terminal kinase activation and cell apoptosis during diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and c­Jun N­terminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. Sprague­Dawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes. HK2 cells and rat glomerular mesangial cells (RGMCs) were examined to detect the expression of JNK and NLRP3 inflammasome­associated proteins following treatment with a Syk inhibitor or Syk­small interfering (si)RNA in a high glucose condition. In the present study, it was revealed that the protein and mRNA expression levels of NLRP3 inflammasome­associated molecules and the downstream mature interleukin (IL)­1ß were upregulated in vivo and in vitro. The Syk inhibitor and Syk­siRNA suppressed high glucose­induced JNK activation, and subsequently downregulated the activation of the NLRP3 inflammasome and mature IL­1ß in HK2 cells and RGMCs. Furthermore, high glucose­induced apoptosis of HK2 cells was reduced by the Syk inhibitor BAY61­3606. Therefore, the present results determined that high glucose­induced activation of the NLRP3 inflammasome is mediated by Syk/JNK activation, which subsequently increased the protein expression level of IL­1ß and mature IL­1ß. The present study identified that the Syk/JNK/NLRP3 signaling pathway may serve a vital role in the pathogenesis of DN.

Down regulation of G protein-coupled receptor 137 expression inhibits proliferation and promotes apoptosis in leukemia cells.

BACKGROUND: G protein-coupled receptors (GPR) are involved in a wide range of physiological processes, some of which, however, can be hijacked by tumor cells. Over-expression of G protein-coupled receptors 137 (GPR137) are associated with the growth of tumor cells, but under-expression of GPR137 has shown to inhibit cell proliferation in several different types of cancers. Currently, the role of GPR137 in leukemia is still unclear. In this study, the effect of under-expression of GPR137 on inhibiting the proliferation of leukemia cells is explored, to identify a novel target for leukemia treatment. MATERIALS AND METHODS: In this study, lentivirus-mediated RNA interference (RNAi) was employed to investigate the role of GPR137 in two leukemia cell lines K562 and HL60. The gene expression of GPR137 was analyzed by RT-PCR and its protein expression was determined by Western blot. Flow cytometry and Annexin V/7-AAD Apoptosis Detection Kit was used respectively in cell cycle and apoptosis analysis. The protein expression of CyclinD1, CDK4, BCL-2 and caspase-3 were also determined. RESULTS: There was high level of constitutive expression of GPR137 in leukemia cancer cell lines K562 and HL60. Lentivirus-mediated RNAi could significantly down-regulate gene and protein expression of GPR137 in both cell lines. Down regulation of GPR137 was associated with the reduction in proliferation rate and colony forming capacity. In addition, down regulation of GPR137 arrested cells in the G0/G1 phase of cell cycle and induced apoptosis in both leukemia cell lines K562 and HL60. CONCLUSIONS: The expression of GPR137 is associated with the proliferation of leukemia cell lines. Down regulation of GPR137 could inhibit proliferation and promote apoptosis in leukemia cells, which makes it a promising bio-marker and therapeutic target to treat patients with leukemia.

Lixisenatide Improves Glycemic Control in Asian Type 2 Diabetic Patients Inadequately Controlled With Oral Antidiabetic Drugs: An Individual Patient Data Meta-Analysis.

INTRODUCTION: Lixisenatide is a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus (T2DM). Its efficacy and safety have been assessed in a series of phase 3 studies included in the GetGoal program. In these studies, lixisenatide was found to be superior to placebo in glycemic control. The aim of this meta-analysis was to assess the safety and efficacy of lixisenatide as an adjunct therapy in Asian patients with T2DM in adequately controlled with oral antidiabetic drugs (OADs). METHODS: We performed a meta-analysis from five lixisenatide phase 3 studies. In each of these multiethnic studies, patients with T2DM inadequately controlled (glycated hemoglobin, HbA1c ≥7%) with established OADs were randomized to lixisenatide or placebo for 24 weeks, with a balanced distribution of Asian patients in these two arms (503 and 338 patients in the intent-to-treat population, respectively). RESULTS: Lixisenatide was superior to placebo in reducing HbA1c (weighted, total mean difference -0.57%; P = 0.002). More patients treated with lixisenatide versus placebo achieved HbA1c targets of ≤7% (49.1% vs. 28.4%, P = 0.003). Lixisenatide was superior to placebo in lowering 2-h postprandial glucose (PPG) (weighted, total mean difference -5.50 mmol/l, P = 0.0005). More patients treated with lixisenatide versus placebo achieved 2-h PPG targets of ≤7.8 mmol/l (39.2% vs. 2.2%, P < 0.0001). More patients treated with lixisenatide versus placebo achieved both an HbA1c target of ≤7% and a 2-h PPG target of ≤10 mmol/l (34.8% vs. 2.69%, P < 0.00001). The body weight of the lixisenatide group tended to decrease. Lixisenatide was generally well tolerated. CONCLUSION: Lixisenatide as an adjunct therapy can significantly improve the glycemic control of Asian patients with type 2 DM who do not meet targets for glycemic control with an established OAD regimen. FUNDING: Sanofi (China) Investment Co., Ltd., Shanghai, China.

The source of circulating selenoprotein S and its association with type 2 diabetes mellitus and atherosclerosis: a preliminary study.

BACKGROUND: Selenoprotein S (SelS) is a transmembrane protein that is expressed in the liver, skeletal muscle, adipose tissue, pancreatic islets, kidney, and blood vessels. In addition to its transmembrane localization, SelS is also secreted from hepatoma HepG2 cells (but not L6 skeletal muscle cells, 3T3-L1 adipocytes, Min6 pancreatic ß cells and human embryonic kidney 293 cells) and has been detected in the serum of some human subjects, with a detection rate of 31.1 %. These findings prove that serum SelS is secreted by hepatocytes. However, whether vascularly expressed SelS can be secreted has not been reported. Transmembrane SelS has been suggested to play different roles in the pathogenesis and progression of diabetes mellitus (DM) and atherosclerosis (AS), but the association of secreted SelS with DM and macroangiopathy remains unclear. RESEARCH DESIGN AND METHODS: Supernatants were collected from human umbilical vein endothelial cells (HUVECs), human aortic vascular smooth muscle cells (HA/VSMCs) and human hepatoma HepG2 cells that were untransfected or transfected with the indicated plasmid and concentrated for western blotting. Serum samples were collected from 158 human subjects with or without type 2 DM (T2DM) and/or AS. Serum SelS levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Secreted SelS was only detected in the supernatants of hepatoma HepG2 cells. The SelS detection rate among the 158 human serum samples was 100 %, and the average SelS level was 64.81 ng/dl. The serum SelS level in the isolated DM subjects was lower than the level in the healthy control subjects (52.66 ± 20.53 vs 70.40 ± 21.38 ng/dl). The serum SelS levels in the DM complicated with SAS subjects (67.73 ± 21.41 ng/dl) and AS subjects (71.69 ± 27.00 ng/dl) were significantly increased compared with the serum SelS level in the isolated DM subjects. There was a positive interaction effect between T2DM and AS on the serum SelS level (P = 0.002). Spearman correlation analysis showed that the serum SelS level was negatively correlated with fasting plasma glucose. CONCLUSIONS: Vascular endothelial and vascular smooth muscle cells could not secrete SelS. Serum SelS was primarily secreted by hepatocytes. SelS was universally detected in human serum samples, and the serum SelS level was associated with T2DM and its macrovascular complications. Thus, regulating liver and serum SelS levels might become a new strategy for the prevention and treatment of DM and its macrovascular complications.

Associations among glycemic excursions, glycated hemoglobin and high-sensitivity C-reactive protein in patients with poorly controlled type 2 diabetes mellitus.

The aim of the present study was to explore the associations among glycemic excursions, glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP) in patients with poorly controlled type 2 diabetes mellitus (T2DM) using a continuous glucose monitoring system (CGMS). Sixty-three patients with T2DM whose HbA1c levels were >7% wore a CGMS device for 72 h. According to their HbA1c levels, patients were divided into three groups as follows: Group A (HbA1c ≤9.32%), group B (9.32%< HbA1c ≤11.76%) and group C (HbA1c >11.76%). Patients were also divided into two groups according to the mean amplitude of glycemic excursions (MAGE) as follows: Low glycemic excursion group (MAGE, <3.9 mmol/l) and high glycemic excursion group (MAGE, ≥3.9 mmol/l). Clinical data and the hs-CRP levels in different groups were compared. No significant difference was observed in the MAGE among groups A, B and C (P>0.05). The level of hs-CRP was significantly higher in group C compared with that in groups A and B, and in group B compared with that in group A (P<0.05). Multivariate stepwise regression analysis indicated that HbA1c correlated with hs-CRP (P<0.05). MAGE and HbA1c were independent indices for the assessment of glycemic control. In addition, HbA1c had a considerable effect on the serum hs-CRP level.

Corin is down-regulated and exerts cardioprotective action via activating pro-atrial natriuretic peptide pathway in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM. METHODS: Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague-Dawley rats (180-220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson's trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay. RESULTS: The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats. CONCLUSIONS: Our results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.

[Value of mean platelet volume and Gensini score on predicting short-term outcome in acute ST segment elevation myocardial infarction patient post emergency percutaneous coronary intervention].

OBJECTIVE: To explore the value of mean platelet volume (MPV) and Gensini score on predicting short-term prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) post emergency percutaneous coronary intervention (PCI). METHODS: From September 2011 to June 2013, 102 consecutive hospitalized STEMI patients undergoing emergency PCI were included. All patients routine blood test was made immediately after admission, and Gensini score was calculated according to the results of coronary angiography. Incidence of major adverse cardiac events (MACE) during hospitalization and 6 months after PCI was observed. RESULTS: MPV, Gensini score and percent of coronary artery three vessel lesions were significantly higher in MACE patients than in patients without MACE(P < 0.05 or 0.01). Area under the curve (AUC) of MPV plus Gensini score for predicting in hospital MACE and at 6 months post PCI was 0.836 (95%CI:0.706-0.966, P = 0.003) and 0.718 (95%CI:0.571-0.866, P = 0.006) , respectively. Kaplan-Meier survival analysis showed that incidence of without MACE at 6 months post PCI was significantly lower in patients with high MPV (>10.65 fl) than in patients with low MPV ( ≤ 10.65 fl) at admission (log-rank = 4.272, P = 0.039), and in patients with high Gensini score (>89) than in low Gensini score ( ≤ 89) (log-rank = 7.355, P = 0.007) at admission. CONCLUSIONS: High MPV and Gensini score are associated with lower MACE during hospitalization and at 6 months after PCI in acute STEMI patient. These two parameters could thus be used to predict short-term MACE in STEMI patients post PCI.

Berberine protects endothelial progenitor cell from damage of TNF-α via the PI3K/AKT/eNOS signaling pathway.

Endothelial progenitor cells (EPCs) dysfunction is closely correlated with the coronary artery injury induced by Kawasaki disease (KD). The level of tumor necrosis factor-α (TNF-α) elevated significantly in acute phase of KD which can damage the functions of EPCs. The aim of this study was to investigate whether berberine (BBR) can protect EPCs from the inhibition caused by TNF-α via the PI3K (Phosphatidyl Inositol 3-kinase) /AKT (Serine/threonine protein kinase B) /eNOS (endothelial Nitric Oxide synthase) signaling pathway. The cell proliferative ability of EPCs was determined by MTT (methyl thiazolyl tetrazolium) assays. Nitric oxide (NO) level was determined in supernatants. The mRNA level of eNOS, PI3K and AKT were measured by Real Time-Polymerase Chain Reaction (RT-PCR), and the protein levels of eNOS, phospho-eNOS (p-eNOS), Akt, phospho-Akt (p-Akt) and PI3K were analyzed using Western-blot. The results demonstrated that TNF-α inhibits the proliferative ability of EPCs. However, BBR improves the proliferative activity of EPCs inhibited by TNF-α. Blockade of PI3K by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Ly294002) and blockade of eNOS by l-NAME (NG-Nitroarginine Methyl Ester) attenuates the effect of BBR. BBR can increase the level of PI3K/Akt/eNOS mRNA and the protein level of PI3K, p-Akt, eNOS and p-eNOS, which can be blocked by PI3K inhibitor (LY294002) and eNOS inhibitor (l-NAME). Therefore, we concluded that impaired EPCs proliferation could be reversed by BBR via the PI3K/AKT/eNOS signaling pathway.

Effects of selenoprotein S on oxidative injury in human endothelial cells.

BACKGROUND: Selenoprotein S (SelS) is an important endoplasmic reticulum and plasma membrane-located selenoprotein implicated in inflammatory responses and insulin resistance. However, the effects of SelS on endothelial cells (ECs) have not been reported. In the present study, the role of SelS in oxidative stress and the underlying mechanism were investigated in human ECs. METHODS: A SelS over-expression plasmid (pc-SelS) and a SelS-siRNA plasmid were transfected into human umbilical vein endothelial cells (American Type Culture Collection, USA). The cells were divided into four groups: control, SelS over-expression (transfected with pc-SelS), vector control, and SelS knockdown (transfected with siRNA-SelS). After treating the cells with H2O2, the effects of oxidative stress and the expression of caveolin-1 (Cav-1) and protein kinase Cα (PKCα) were investigated. RESULTS: Following treatment with H2O2, over-expression of SelS significantly increased cell viability and superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) production and Cav-1 gene and protein expression. However, no effects on PKCα were observed. In contrast, knockdown of SelS significantly decreased cell viability, SOD activity, and PKCα gene and protein expression, and increased MDA production and Cav-1 gene and protein expression. CONCLUSIONS: SelS protects ECs from oxidative stress by inhibiting the expression of Cav-1 and PKCα.

[Relationship of amyloid-ß with vascular endothelial cell damage induced by diabetic serum].

OBJECTIVE: To explore the relationship of the impairment of human umbilical vein endothelial cell (HUVEC) with amyloid-ß. METHODS: HUVECs were cultured in the serum of patients with type 2 diabetes mellitus (DM) or serum of healthy control (HC), while fetal bovine serum (FBS) was used as a negative control. The proliferative activity of HUVEC were assessed by thiazolyl blue tetrazolium bromide (MTT) after 72 h. The supernatant concentrations of superoxide dismutase (SOD), maleic dialdehyde (MDA), nitric oxide (NO), amyloid-ß40 (Aß40) and Aß42 were measured after 0.5, 3 and 72 h respectively. RESULTS: Glycosylated hemoglobin values, fasting plasma glucose and fasting plasma Aß40 concentrations of diabetic patients were higher than those of healthy counterparts (P < 0.01). Proliferative activity of HUVECs in group DM were significantly lower than that of group HC. Both group and the time of intervention had crossover effects on the levels of MDA, SOD, NO and Aß40 ((163 ± 64), (207 ± 69), (286 ± 75) ng/L in group DM; (146 ± 76), (154 ± 75), (161 ± 72) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05) and Aß42 ((48 ± 46), (54 ± 43), (79 ± 44) ng/L in group DM; (41 ± 12), (44 ± 16), (48 ± 12) ng/L in group HC after 0.5, 3 and 72 h, P < 0.05). With the elongating time of intervention, the levels of SOD and NO decreased significantly in group DM and reached the lowest after 72 h while increased significantly in groups HC and FBS and peaked after 72 h. The concentrations of MDA, Aß40 and Aß42 increased significantly in all three groups while the fastest and marked increments were found in group DM (P < 0.01). Pearson correlation analysis showed that SOD was negatively correlated with Aß40 (r = -0.482, P = 0.02) and Aß42 (r = -0.422, P = 0.02) while MDA positively with Aß40 (r = 0.418, P < 0.05) and Aß42 (r = 0.833, P < 0.05) after 72 h. CONCLUSION: Oxidative stress of vascular endothelial cells may be correlated with Aß40 and Aß42 in diabetes.