Jianzhou Chen

Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials.

AcbstractBackgroundInhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been intensively studied to lower low-density lipoprotein cholesterol (LDL-C) levels. The purpose of this meta-analysis was to evaluate the safety and efficacy of anti-PCSK9 antibodies in randomized, controlled trials (RCTs).MethodsPubMed, EMBASE, CENTRAL databases, and recent conferences were searched. Safety outcomes were rates of common adverse events. Efficacy outcomes included percentages of LDL-C lowering and other lipid changes compared with placebo and ezetimibe, respectively.ResultsTwenty-five RCTs encompassing 12,200 patients were included. The rates of common adverse events were firstly reported in our study by pooling together all evidence in RCTs, showing largely no significant difference between anti-PCSK9 antibodies and placebo (or ezetimibe), except that alirocumab was associated with reduced rates of death (relative risk (RR): 0.43, 95 % confidence interval (CI): 0.19 to 0.96, P = 0.04) and an increased rate of injection-site reactions (RR: 1.48, 95 % CI: 1.05 to 2.09, P = 0.02); evolocumab reduced the rate of abnormal liver function (RR: 0.43, 95 % CI: 0.20 to 0.93, P = 0.03), both compared with placebo. No significant difference in safety outcomes was detected between monthly 420 mg and biweekly 140 mg evolocumab treatments. Monthly 420 mg evolocumab treatment significantly reduced LDL-C by −54.6 % (95 % CI: −58.7 to −50.5 %) and by absolute −78.9 mg/dl (95 % CI: −88.9 to −68.9 mg/dl) versus placebo, and by −36.3 % (95 % CI: −38.8 to −33.9 %) versus ezetimibe, and increased high-density lipoprotein cholesterol (HDL-C) by 7.6 % (95 % CI: 5.7 to 9.5 %) versus placebo and 6.4 % (95 % CI: 4.3 to 8.4 %) versus ezetimibe. An equal or even greater change was observed following biweekly 140 mg administration. Significant and favorable changes were also detected in other lipids following evolocumab treatment. Biweekly 50 to 150 mg alirocumab lowered LDL-C by −52.6 % (95 % CI: −58.2 to −47.0 %) versus placebo, by −29.9 % (95 % CI: −32.9 to −26.9 %) versus ezetimibe, and increased HDL-C by 8.0 % (95 % CI: 4.2 to 11.7 %) versus placebo.ConclusionsEvolocumab and alirocumab were safe and well-tolerated from our most-powered analyses. Both antibodies substantially reduced the LDL-C level by over 50 %, increased the HDL-C level, and resulted in favorable changes in other lipids.

Diabetes-Induced Oxidative Stress in Endothelial Progenitor Cells May Be Sustained by a Positive Feedback Loop Involving High Mobility Group Box-1.

Oxidative stress is considered to be a critical factor in diabetes-induced endothelial progenitor cell (EPC) dysfunction, although the underlying mechanisms are not fully understood. In this study, we investigated the role of high mobility group box-1 (HMGB-1) in diabetes-induced oxidative stress. HMGB-1 was upregulated in both serum and bone marrow-derived monocytes from diabetic mice compared with control mice. In vitro, advanced glycation end productions (AGEs) induced, expression of HMGB-1 in EPCs and in cell culture supernatants in a dose-dependent manner. However, inhibition of oxidative stress with N-acetylcysteine (NAC) partially inhibited the induction of HMGB-1 induced by AGEs. Furthermore, p66shc expression in EPCs induced by AGEs was abrogated by incubation with glycyrrhizin (Gly), while increased superoxide dismutase (SOD) activity in cell culture supernatants was observed in the Gly treated group. Thus, HMGB-1 may play an important role in diabetes-induced oxidative stress in EPCs via a positive feedback loop involving the AGE/reactive oxygen species/HMGB-1 pathway.

Fabrication and characterization of NbN/AlN/NbN junction on MgO(001) and AlN/NbN bilayer on MgO(111) substrates

Using direct current (DC) or radio frequency (RF) magnetron sputtering techniques, NbN/AlN/NbN junctions or AlN/NbN bilayers are prepared on single crystal MgO [001] or MgO (111) substrates respectively, both at ambient substrate temperatures. The crystalline structures of such multilayers are characterized layer-by-layer using X-ray diffraction and transmission electron microscopy (TEM). Interestingly, the AlN barrier in NbN/AlN/NbN/ MgO [001] is amorphous while the NbN/AlN/NbN/MgO (111) is single-crystalline with [001] orientation. The electrical properties of these two structures are compared. Also discussed are the DC and high frequency behavior of NbN/AlN/NbN/ MgO [001] junction.

Increased M1 Macrophages Infiltration Is Associated with Thrombogenesis in Rheumatic Mitral Stenosis Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia. In patients with AF, the role of macrophage subsets in thrombogenesis is unclear. In the present study, we analyzed the role of M1 and M2 macrophages and related cytokines in thrombogenesis of AF. Immunohistochemistry, Western blot, and TUNEL assay were used to detect M1/M2 macrophage infiltration, the expression pattern of IL-1β and inflammasome components, and apoptosis of cardiomyocytes in 71 specimens obtained from the left atrial appendage of patients with rheumatic mitral stenosis (MS) with or without thrombosis. We demonstrated that proinflammatory M1 macrophages were predominant in the atrium of MS patients with AF and thrombus. NLRP3 inflammasomes and IL-1β, which are primarily functional in macrophages, were activated in those patients. We also showed that increased cell death was associated with thrombogenesis in MS patients. These data indicate that infiltration of M1 macrophages and over-activation of NLRP3 inflammasomes may play a role in progressive atrial inflammation and thrombogenesis in rheumatic mitral stenosis patients with AF.

Outcomes of off- and on-hours admission in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A retrospective observational cohort study.

AbstractStudies evaluating the outcomes of patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) are scarce, particularly in China. The purpose of present study was therefore to compare the impact of off-hours and on-hours admission on clinical outcomes in STEMI patients from China.We retrospectively analyzed 1594 patients from 4 hospitals. Of these, 903 patients (56.65%) were admitted during off-hours (weekdays from 18:00 to 08:00, weekends and holidays) and 691 (43.35%) were during on-hours (weekdays from 08:00 to 18:00).Patients admitted during off-hours had higher thrombolysis in myocardial infarction risk score (4.67 ± 2.27 vs 4.39 ± 2.10, P = 0.012) and longer door-to-balloon time (72 [50–96] vs 64 [42–92] minutes, P < 0.001) than those admitted during on-hours. Off-hours admission had no association with in-hospital (unadjusted odds ratio 2.069, 95% confidence interval [CI] 0.956–4.480, P = 0.060) and long-term mortality (unadjusted hazards ratio [HR] 1.469, 95%CI 0.993–2.173, P = 0.054), even after adjustment for confounders. However, long-term outcomes, the composite of deaths and other adverse events, differed between groups with an unadjusted HR of 1.327 (95%CI, 1.102–1.599, P = 0.003), which remained significant in regression models. In a subgroup analysis, off-hours admission was associated with higher long-term mortality in the high-risk subgroup (unadjusted HR 1.965, 95%CI 1.103–3.512, P = 0.042), but not in low- and moderate-risk subgroups.This study showed no association between off-hours admission and in-hospital and long-term mortality. Stratified analysis indicated that off-hours admission was significantly associated with long-term mortality in the high-risk subgroup.

Advanced glycation endproducts impair endothelial progenitor cell migration and homing via syndecan 4 shedding

Endothelial progenitor cells (EPCs) are a subtype of bone marrow–derived progenitor cells. Stromal cell‐derived factor 1 (SDF‐1)‐mediated EPC mobilization from bone marrow to areas of ischemia plays an important role in angiogenesis. Previous studies have reported that advanced glycation endproducts (AGEs), which are important mediators of diabetes‐related vascular pathology, may impair EPC migration and homing, but the mechanism is unclear. Syndecan‐4 (synd4) is a ubiquitous heparan sulfate proteoglycan receptor on the cell surface, involved in SDF‐1‐dependent cell migration. The extracellular domain of synd4 (ext‐synd4) is shed in the context of acute inflammation, but the shedding of ext‐synd4 in response to AGEs is undefined. Here we investigated changes in ext‐synd4 on EPCs in response to AGEs, focusing on the influence of impaired synd4 signaling on EPC migration and homing. We found decreased full length and increased residue of synd4 in cells incubated with AGEs, with concomitant increase in the soluble fragment of ext‐synd4 in the cell medium. EPCs from patients with type 2 diabetes expressed less ext‐synd4 as assessed by Western blotting. Flow cytometry analysis showed less ext‐synd4 on circulating CD34+ peripheral blood mononuclear cells, of which EPCs form a subgroup. We then explored the role of synd4 in EPC migration and homing. Impaired migration of synd4‐deficient EPCs was observed by a 2D‐chemotaxis slide. Furthermore, poor homing of synd4−/− EPCs was observed in a mouse model of lower limb ischemia. This study demonstrates that the shedding of synd4 from EPCs plays a key role in AGE‐mediated dysfunction of EPC migration and homing. Stem Cells 2017;35:522–531

Syndecan 4 signaling is required for exercise-induced cardiac hypertrophy.

Cardiac hypertrophy can be broadly classified as either physiological or pathological. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy and normal heart function. Pathological stimuli including hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Syndecan-4 (synd4) is a transmembrane proteoglycan identified as being involved in cardiac adaptation after injury, but whether it takes part in physiological cardiac hypertrophy is unclear. We observed upregulation of synd4 in exercise-induced hypertrophic myocardium. To evaluate the role of synd4 in the physiological form of cardiac hypertrophy, mice lacking synd4 (synd4−/−) were exercised by swimming for 4 wks. Ultrasonic cardiogram (UCG) and histological analysis revealed that swimming induced the hypertrophic phenotype but was blunted in synd4−/− compared with wild-type (WT) mice. The swimming-induced activation of Akt, a key molecule in physiological hypertrophy was also more decreased than in WT controls. In cultured cardiomyocytes, synd4 overexpression could induce cell enlargement, protein synthesis and distinct physiological molecular alternation. Akt activation also was observed in synd4-overexpressed cardiomyocytes. Furthermore, inhibition of protein kinase C (PKC) prevented the synd4-induced hypertrophic phenotype and Akt phosphorylation. This study identified an essential role of synd4 in mediation of physiological cardiac hypertrophy.

Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus.

PURPOSE Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan cell surface receptor that modulates cell proliferation, migration, mechanotransduction, and endocytosis. The extracellular domain of synd4 sheds heavily in acute inflammation, but the shedding of synd4 in chronic inflammation, such as diabetes mellitus (DM), is still undefined. We investigated the alterations of synd4 endothelial expression in DM and the influence of impaired synd4 signaling on angiogenesis in human umbilical vein endothelial cells (HUVECs), diabetic rats, synd4 null mice, and db/db mice. MATERIAL AND METHODS HUVECs were incubated with advanced glycation end products (AGEs). Western blot analysis was used to determine synd4 protein expression and ELISA was used to detect soluble synd4 fragments. The concentration of synd4 in the aortic endothelia of diabetic rats was detected by immunohistochemical staining. Aortic ring assays were performed to study the process of angiogenesis in the diabetic rats and in synd4 null and db/db mice. Recombinant adenoviruses containing the synd4 gene or null were constructed to enhance synd4 aortic expression in db/db mice. RESULTS Western blot analysis showed decreased expression of the synd4 extracellular domain in HUVECs, and ELISA detected increased soluble fragments of synd4 in the media. Synd4 endothelial expression in the aortas of diabetic rats was decreased. Aortic ring assay indicated impaired angiogenesis in synd4 null and db/db mice, which was partially reversed by synd4 overexpression in db/db mice. CONCLUSION Synd4 shedding from vascular endothelial cells played an important role in the diabetes-related impairment of angiogenesis.

Cardiac repair in a mouse model of acute myocardial infarction with trophoblast stem cells

Various stem cells have been explored for the purpose of cardiac repair. However, any individual stem cell population has not been considered as the ideal source. Recently, trophoblast stem cells (TSCs), a newly described stem cell type, have demonstrated extensive plasticity. The present study evaluated the therapeutic effect of TSCs transplantation for heart regeneration in a mouse model of myocardial infarction (MI) and made a direct comparison with the most commonly used mesenchymal stem cells (MSCs). Transplantation of TSCs and MSCs led to a remarkably improved cardiac function in contrast with the PBS control, but only the TSCs exhibited the potential of differentiation into cardiomyocytes in vivo. In addition, a significantly high proliferation level of both transplanted stem cells and resident cardiomyocytes was observed in the TSCs group. These findings primary revealed the therapeutic potential of TSCs in transplantation therapy for MI.

Oncostatin M was associated with thrombosis in patients with atrial fibrillation.

Abstract The mechanism underlying thrombosis in atrial fibrillation (AF) is not yet clearly understood. Oncostatin M (OSM), as a member of IL-6 family, is involved in atherosclerosis-mediated thrombosis. The present study hypothesizes that OSM and its downstream factors play a role in thrombogenesis in AF. The specimens of left atrial appendages collected from patients with rheumatic mitral stenosis who underwent valve replacement were divided into 3 groups: sinus rhythm, AF(+)/thrombus(−), and AF(+)/thrombus(+) group. The macrophage infiltration in atrial tissue was assessed by immunohistochemistry, and the amount of OSM, tissue factor (TF), and tissue factor pathway inhibitors (TFPIs) was detected by Western blot. The infiltration of the M1 macrophages was significantly increased in the AF with thrombus group compared with the sinus rhythm group (P = .03). Moreover, the expression of OSM and TF was much higher in the AF with thrombus group compared with the sinus rhythm group (P = .02, .009, respectively) while the TFPI was decreased in the AF with thrombus group (P = .04). OSM might be correlated with thrombosis in patients with AF mediated by TF and TFPI.