Spermine oxidase inhibitor, MDL 72527, reduced neovascularization, vascular permeability, and acrolein-conjugated proteins in a mouse model of ischemic retinopathy.

Disruptions in polyamine metabolism have been identified as contributing factors to various central nervous system disorders. Our laboratory has previously highlighted the crucial role of polyamine oxidation in retinal disease models, specifically noting elevated levels of spermine oxidase (SMOX) in inner retinal neurons. Our prior research demonstrated that inhibiting SMOX with MDL 72527 protected against vascular injury and microglial activation induced by hyperoxia in the retina. However, the effects of SMOX inhibition on retinal neovascularization and vascular permeability, along with the underlying molecular mechanisms of vascular protection, remain incompletely understood. In this study, we utilized the oxygen-induced retinopathy (OIR) model to explore the impact of SMOX inhibition on retinal neovascularization, vascular permeability, and the molecular mechanisms underlying MDL 72527-mediated vasoprotection in the OIR retina. Our findings indicate that inhibiting SMOX with MDL 72527 mitigated vaso-obliteration and neovascularization in the OIR retina. Additionally, it reduced OIR-induced vascular permeability and Claudin-5 expression, suppressed acrolein-conjugated protein levels, and downregulated P38/ERK1/2/STAT3 signaling. Furthermore, our results revealed that treatment with BSA-Acrolein conjugates significantly decreased the viability of human retinal endothelial cells (HRECs) and activated P38 signaling. These observations contribute valuable insights into the potential therapeutic benefits of SMOX inhibition by MDL 72527 in ischemic retinopathy.

Age differences in the association of body mass index-defined obesity with abdominal aortic calcification.

Objectives: In cardiovascular disease, previous studies have suggested young age as one of the reasons to explain the obesity paradox. This study attempts to provide a different opinion on this claim through unexpected findings. Methods: We used a cross-sectional analysis of the US nationally representative data, total of 10,175 participants were recruited in 2013-2014 from NHANES. A total of 947 participants were selected to be included in this study through inclusion criteria and exclusion criteria for statistical analysis of the relationship between obesity and abdominal aortic calcification(AAC). Smooth curve fitting and multivariate regression analyses were conducted to examine the associations of obesity with AAC after adjusting for age, gender and associated variates. Results: Depending on the age of the population, the relationship between obesity and AAC showed the different outcome. Obesity was associated with the lower risk of AAC among individuals older than 52 years of age. According to the difference of adjusted covariates, the AAC scores in the obesity group decreased by 0.92, 0.87, and 1.11 for 52 years old or older individuals. In particular, the risk of AAC was lower for patients with obesity with the following characteristics: male, low LDL, low triglyceride, DM, non-cancer patient, smoking, drinking, vigorous work activity, low annual household income, education of 9 - 11th grades and non-Hispanic white. Conclusions: In US, adults aged 52 years or older, obesity was associated with decreased AAC risk. Older age may be one potential reason for the obesity paradox.

Pharmacological Modulation of ß-Catenin Preserves Endothelial Barrier Integrity and Mitigates Retinal Vascular Permeability and Inflammation.

Compromised blood-retinal barrier (BRB) integrity is a significant factor in ocular diseases like uveitis and retinopathies, leading to pathological vascular permeability and retinal edema. Adherens and tight junction (AJ and TJ) dysregulation due to retinal inflammation plays a pivotal role in BRB disruption. We investigated the potential of ICG001, which inhibits ß-catenin-mediated transcription, in stabilizing cell junctions and preventing BRB leakage. In vitro studies using human retinal endothelial cells (HRECs) showed that ICG001 treatment improved ß-Catenin distribution within AJs post lipopolysaccharide (LPS) treatment and enhanced monolayer barrier resistance. The in vivo experiments involved a mouse model of LPS-induced ocular inflammation. LPS treatment resulted in increased albumin leakage from retinal vessels, elevated vascular endothelial growth factor (VEGF) and Plasmalemmal Vesicle-Associated Protein (PLVAP) expression, as well as microglia and macroglia activation. ICG001 treatment (i.p.) effectively mitigated albumin leakage, reduced VEGF and PLVAP expression, and reduced the number of activated microglia/macrophages. Furthermore, ICG001 treatment suppressed the surge in inflammatory cytokine synthesis induced by LPS. These findings highlight the potential of interventions targeting ß-Catenin to enhance cell junction stability and improve compromised barrier integrity in various ocular inflammatory diseases, offering hope for better management and treatment options.

A multi-arm, parallel, preclinical study investigating the potential benefits of acetazolamide, candesartan, and triciribine in combination with fluconazole for the treatment of cryptococcal meningoencephalitis.

Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.

INKILN is a Novel Long Noncoding RNA Promoting Vascular Smooth Muscle Inflammation via Scaffolding MKL1 and USP10.

BACKGROUND: Activation of vascular smooth muscle cell (VSMC) inflammation is vital to initiate vascular disease. The role of human-specific long noncoding RNAs in VSMC inflammation is poorly understood. METHODS: Bulk RNA sequencing in differentiated human VSMCs revealed a novel human-specific long noncoding RNA called inflammatory MKL1 (megakaryoblastic leukemia 1) interacting long noncoding RNA (INKILN). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation as well as human atherosclerosis and abdominal aortic aneurysm. The transcriptional regulation of INKILN was verified through luciferase reporter and chromatin immunoprecipitation assays. Loss-of-function and gain-of-function studies and multiple RNA-protein and protein-protein interaction assays were used to uncover a mechanistic role of INKILN in the VSMC proinflammatory gene program. Bacterial artificial chromosome transgenic mice were used to study INKILN expression and function in ligation injury-induced neointimal formation. RESULTS: INKILN expression is downregulated in contractile VSMCs and induced in human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB (nuclear factor kappa B) site within its proximal promoter. INKILN activates proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks interleukin-1ß-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1 and the luciferase activity of an NF-κB reporter. Furthermore, INKILN knockdown enhances MKL1 ubiquitination through reduced physical interaction with the deubiquitinating enzyme USP10 (ubiquitin-specific peptidase 10). INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in bacterial artificial chromosome transgenic mice. CONCLUSIONS: These findings elucidate an important pathway of VSMC inflammation involving an INKILN/MKL1/USP10 regulatory axis. Human bacterial artificial chromosome transgenic mice offer a novel and physiologically relevant approach for investigating human-specific long noncoding RNAs under vascular disease conditions.

Triciribine attenuates pathological neovascularization and vascular permeability in a mouse model of proliferative retinopathy.

Proliferative retinopathies are the leading cause of irreversible blindness in all ages, and there is a critical need to identify novel therapies. We investigated the impact of triciribine (TCBN), a tricyclic nucleoside analog and a weak Akt inhibitor, on retinal neurovascular injury, vascular permeability, and inflammation in oxygen-induced retinopathy (OIR). Post-natal day 7 (P7) mouse pups were subjected to OIR, and treated (i.p.) with TCBN or vehicle from P14-P16 and compared with age-matched, normoxic, vehicle or TCBN-treated controls. P17 retinas were processed for flat mounts, immunostaining, Western blotting, and qRT-PCR studies. Fluorescein angiography, electroretinography, and spectral domain optical coherence tomography were performed on days P21, P26, and P30, respectively. TCBN treatment significantly reduced pathological neovascularization, vaso-obliteration, and inflammation marked by reduced TNFα, IL6, MCP-1, Iba1, and F4/80 (macrophage/microglia markers) expression compared to the vehicle-treated OIR mouse retinas. Pathological expression of VEGF (vascular endothelial growth factor), and claudin-5 compromised the blood-retinal barrier integrity in the OIR retinas correlating with increased vascular permeability and neovascular tuft formation, which were blunted by TCBN treatment. Of note, there were no changes in the retinal architecture or retinal cell function in response to TCBN in the normoxia or OIR mice. We conclude that TCBN protects against pathological neovascularization, restores blood-retinal barrier homeostasis, and reduces retinal inflammation without adversely affecting the retinal structure and neuronal function in a mouse model of OIR. Our data suggest that TCBN may provide a novel therapeutic option for proliferative retinopathy.

INKILN is a novel long noncoding RNA promoting vascular smooth muscle inflammation via scaffolding MKL1 and USP10.

Background: Activation of vascular smooth muscle cells (VSMCs) inflammation is vital to initiate vascular disease. However, the role of human-specific long noncoding RNAs (lncRNAs) in VSMC inflammation is poorly understood. Methods: Bulk RNA-seq in differentiated human VSMCs revealed a novel human-specific lncRNA called IN flammatory M K L1 I nteracting L ong N oncoding RNA ( INKILN ). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation and human atherosclerosis and abdominal aortic aneurysm (AAA) samples. The transcriptional regulation of INKILN was determined through luciferase reporter system and chromatin immunoprecipitation assay. Both loss- and gain-of-function approaches and multiple RNA-protein and protein-protein interaction assays were utilized to uncover the role of INKILN in VSMC proinflammatory gene program and underlying mechanisms. Bacterial Artificial Chromosome (BAC) transgenic (Tg) mice were utilized to study INKLIN expression and function in ligation injury-induced neointimal formation. Results: INKILN expression is downregulated in contractile VSMCs and induced by human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-κB site within its proximal promoter. INKILN activates the proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. Mechanistically, INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway. INKILN depletion blocks ILIß-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1, and the luciferase activity of an NF-κB reporter. Further, INKILN knockdown enhances MKL1 ubiquitination, likely through the reduced physical interaction with the deubiquitinating enzyme, USP10. INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in BAC Tg mice. Conclusions: These findings elucidate an important pathway of VSMC inflammation involving an INKILN /MKL1/USP10 regulatory axis. Human BAC Tg mice offer a novel and physiologically relevant approach for investigating human-specific lncRNAs under vascular disease conditions.

Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina.

Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.

MKL1 cooperates with p38MAPK to promote vascular senescence, inflammation, and abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy. Myocardin related transcription factor A (MRTFA, MKL1) is a multifaceted transcription factor, regulating diverse biological processes. However, a detailed understanding of the mechanistic role of MKL1 in AAA has yet to be elucidated. In this study, we showed induced MKL1 expression in thoracic and abdominal aneurysmal tissues, respectively in both mice and humans. MKL1 global knockout mice displayed reduced AAA formation and aortic rupture compared with wild-type mice. Both gene deletion and pharmacological inhibition of MKL1 markedly protected mice from aortic dissection, an early event in Angiotensin II (Ang II)-induced AAA formation. Loss of MKL1 was accompanied by reduced senescence/proinflammation in the vessel wall and cultured vascular smooth muscle cells (VSMCs). Mechanistically, a deficiency in MKL1 abolished AAA-induced p38 mitogen activated protein kinase (p38MAPK) activity. Similar to MKL1, loss of MAPK14 (p38α), the dominant isoform of p38MAPK family in VSMCs suppressed Ang II-induced AAA formation, vascular inflammation, and senescence marker expression. These results reveal a molecular pathway of AAA formation involving MKL1/p38MAPK stimulation and a VSMC senescent/proinflammatory phenotype. These data support targeting MKL1/p38MAPK pathway as a potential effective treatment for AAA.

Association between the non-HDL-cholesterol-to-HDL-cholesterol ratio and the risk of gallbladder polyp formation among men: a retrospective cohort study.

BACKGROUND: Dyslipidaemia and male sex are associated with gallbladder polyp (GBP) formation. However, the potential relation between the non-high-density lipoprotein-cholesterol-to-high-density lipoprotein-cholesterol (non-HDL-c/HDL-c) ratio and GBPs in men is unclear. METHODS: A total of 1866 eligible subjects were selected for this retrospective cohort study from Wuhan Union Hospital between April 1, 2013, and November 30, 2014. Clinical and laboratory data of subjects were collected. Patients with GBPs or cholecystectomy at baseline, with missing data for baseline lipid profiles, following abdominal ultrasonography or taking lipid-lowering drugs were excluded. The patients were divided into five groups based on their non-HDL-c/HDL-c ratios, and descriptive analyses of the baseline data were performed. A Cox proportional hazards model was applied to estimate the relationship between the non-HDL-c/HDL-c ratio and GBPs. RESULTS: After a median follow-up of 1 year, 7.34% (n = 137) of the subjects developed GBPs. Compared with subjects without GBPs, those who developed GBPs after follow-up had significantly higher triglyceride (TG) levels and non-HDL-c/HDL-c ratios. The prevalence of GBPs showed a linearity increment with age, peaked in the 30-39 years group, 40-49 years group and 50-59 years group, and then declined slightly. The results of univariate analysis showed that the non-HDL-c/HDL-c ratio (hazard ratio (HR) = 1.29, 95% confidence interval (CI), 1.05-1.60, P = 0.0159) was positively correlated with GBPs. In the fully adjusted Cox regression model, the HRs were 2.24 for quintile 2 (95% CI: 1.13-4.44, P = 0.0203), 1.50 for quintile 3 (95% CI: 0.73-3.10, P = 0.269), 2.52 for quintile 4 (95% CI: 1.26-5.01, P = 0.0087) and 2.13 for quintile 5 (95% CI: 1.04-4.37, P = 0.0397). No interaction was found among the subgroups. CONCLUSIONS: A higher non-HDL-c/HDL-c ratio is independently related to a higher risk of GBP formation in Chinese men. Further research is needed to investigate whether this association exists in different regions and races.

Maternal exposure to ambient fine particulate matter and risk of premature rupture of membranes in Wuhan, Central China: a cohort study.

BACKGROUND: The associations between maternal exposure to ambient PM2.5 during pregnancy and the risk of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) are controversial. And no relevant study has been conducted in Asia. This study aimed to determine the association between maternal exposure to ambient PM2.5 during pregnancy and the risk of (P)PROM. METHODS: A cohort study including all singleton births in a hospital located in Central China from January 2015 through December 2017 was conducted. Multivariable logistic regression models, stratified analysis, generalized additive model, and two-piece-wise linear regression were conducted to evaluate how exposure to ambient PM2.5 during pregnancy is associated with the risks of PROM and PPROM. RESULTS: A total of 4364 participants were included in the final analysis, where 11.71 and 2.34% of births were complicated by PROM and PPROM, respectively. The level of PM2.5 exhibited a degree of seasonal variation, and its median concentrations were 63.7, 59.3, 55.8, and 61.8 µg/m3 for the first trimester, second trimester, third trimester, and the whole duration of pregnancy, respectively. After adjustment for potential confounders, PROM was positively associated with PM2.5 exposure (per 10 µg/m3) [Odds Ratio (OR) = 1.14, 95% Confidence Interval (CI), 1.02-1.26 for the first trimester; OR = 1.09, 95% CI, 1.00-1.18 for the second trimester; OR = 1.13, 95% CI, 1.03-1.24 for the third trimester; OR = 1.35, 95% CI, 1.12-1.63 for the whole pregnancy]. PPROM had positive relationship with PM2.5 exposure (per 10 µg/m3) (OR = 1.17, 95% CI, 0.94-1.45 for first trimester; OR = 1.11, 95% CI, 0.92-1.33 for second trimester; OR = 1.19, 95% CI, 0.99-1.44 for third trimester; OR = 1.53, 95% CI, 1.03-2.27 for the whole pregnancy) Positive trends between the acute exposure window (mean concentration of PM2.5 in the last week and day of pregnancy) and risks of PROM and PPROM were also observed. CONCLUSIONS: Exposure to ambient PM2.5 during pregnancy was associated with the risk of PROM and PPROM.

Growth arrest-specific gene 6 transfer promotes mesenchymal stem cell survival and cardiac repair under hypoxia and ischemia via enhanced autocrine signaling and paracrine action.

Poor cell viability after transplantation has restricted the therapeutic capacity of mesenchymal stem cells (MSCs) for cardiac dysfunction after myocardial infarction (MI). Growth arrest-specific gene 6 (Gas6) encodes a secreted γ-carboxyglutamic acid (Gla)-containing protein that functions in cell growth, adhesion, chemotaxis, mitogenesis and cell survival. In this study, we genetically modified MSCs with Gas6 and evaluated cell survival, cardiac function, and infarct size in a rat model of MI via intramyocardial delivery. Functional studies demonstrated that Gas6 transfer significantly reduced MSC apoptosis, increased survival of MSCs in vitro and in vivo, and that Gas6-engineered MSCs (MSCGas6)-treated animals had smaller infarct size and showed remarkably functional recovery as compared with control MSCs (MSCNull)-treated animals. Mechanistically, Gas6 could enhance phosphatidylinositol 3-kinase (PI3K)/Akt signaling and improve hypoxia-inducible factor-1 alpha (HIF-1α)-driven secretion of four major growth factors (VEGF, bFGF, SDF and IGF-1) in MSCs under hypoxia in an Axl-dependent autocrine manner. The paracrine action of MSCGas6 was further validated by coculture neonatal rat cardiomyocytes with conditioned medium from hypoxia-treated MSCGas6, as well as by pretreatment cardiomyocytes with the specific receptor inhibitors of VEGF, bFGF, SDF and IGF-1. Collectively, our data suggest that Gas6 may advance the efficacy of MSC therapy for post-infarcted heart failure via enhanced Gas6/Axl autocrine prosurvival signaling and paracrine cytoprotective action.

Non-HDL-cholesterol to HDL-cholesterol ratio is a better predictor of new-onset non-alcoholic fatty liver disease than non-HDL-cholesterol: a cohort study.

BACKGROUND: The nonHDLc/HDLc ratio (in which nonHDLc is defined as total cholesterol minus HDLc) is positively associated with multiple dyslipidemia-related disorders. This study aimed to determine whether the nonHDLc/HDLc ratio is an independent predictor of new-onset NAFLD (non-alcoholic fatty liver disease) in Chinese population. METHODS: A perspective cohort study consisting of 3374 Chinese adults without liver diseases or metabolic disturbances was performed. Anthropometric parameters and data of metabolic and plasma lipid profile were collected. Univariate and multivariate Cox proportional analyses were carried out to evaluate the association of the nonHDLc/HDLc ratio with incident NAFLD. ROC curve analysis was preformed to compare the predictive value between the nonHDLc/HDLc and the nonHDLc for NAFLD. RESULTS: Two thousand seven hundred seventeen participants were included in the final analysis. During a median follow-up period of 1.6 years, 264 participants (9.71%) developed NAFLD. After adjustment for potential confounders, a high nonHDLc/HDLc ratio (highest tertile) was associated with elevated risk of NAFLD (HR = 2.66; 95% CI, 1.13-6.24; P = 0.025 in female and HR = 2.11; 95% CI, 1.15-3.90; P = 0.016 in male). A nonlinear relationship was observed when the nonHDLc/HDLc ratio was ≤3.5. AUC values for nonHDLc/HDLc ratios (0.717 in female and 0.682 in male) were significantly higher than nonHDLc (0.675 in female and 0.653 in male) (P = 0.049 in female and P = 0.037 in male). In addition, the optimal cut-off value of nonHDLc/HDLc ratio for detection of NAFLD was 2.4 in female and 2.3 in male. CONCLUSIONS: The nonHDLc/HDLc ratio is an independent predictor of NAFLD and a stronger predictor than nonHDLc in Chinese population, which might be expected to better guide early identification of individuals at risk of NAFLD.

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability.

BACKGROUND/AIMS: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. METHODS: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. RESULTS: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4+ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. CONCLUSION: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

Metabolic Syndrome and Its Components Predict the Risk of Type 2 Diabetes Mellitus in the Mainland Chinese: A 3-Year Cohort Study.

INTRODUCTION: It has well established that metabolic syndrome (MetS) can predict the risk of type 2 diabetes mellitus (T2DM) in some population groups. However, limited evidence is available regarding the predictive effect of MetS for incident T2DM in mainland Chinese population. METHODS: A 3-year cohort study was performed for 9735 Chinese without diabetes at baseline. MetS and its components were assessed by multivariable analysis using Cox regression. Prediction models were developed. Discrimination was assessed with area under the receiver operating characteristic curves (AUCs), and performance was assessed by a calibration curve. RESULTS: The 3-year cumulative incidence of T2DM was 11.29%. Baseline MetS was associated with an increased risk of T2DM after adjusting for age (HR = 2.68, 95% CI, 2.27-3.17 in males; HR = 2.59, 95% CI, 1.83-3.65 in females). Baseline MetS exhibited relatively high specificity (88% in males, 94% in females) and high negative predictive value (90% in males, 94% in females) but low sensitivity (36% in males, 23% in females) and low positive predictive value (31% in males and females) for predicting the 3-year risk of T2DM. AUCs, including age and components of MetS, for the prediction model were 0.779 (95% CI: 0.759-0.799) in males and 0.860 (95% CI: 0.836-0.883) in females. Calibration curves revealed good agreement between prediction and observation results in males; however, the model could overestimate the risk when the predicted probability is >40% in females. CONCLUSIONS: MetS predicts the risk of T2DM. The quantitative MetS-based prediction model for T2DM risk may improve preventive strategies for T2DM and present considerable public health benefits for the people in mainland China.

The clinical value of inflammatory biomarkers in coronary artery disease: PTX3 as a new inflammatory marker.

OBJECTIVE: Previous experiments have demonstrated that several inflammatory biomarkers, including pentraxin 3 (PTX3), matrix metalloprotein 9 (MMP9), interleukin-6 (IL-6), and the neutrophil to lymphocyte ratio (NLR), are differentially elevated in coronary artery disease (CAD). This study aims to compare the associations between plasma levels of these biomarkers and CAD, identifying the best biomarker that has the most powerful association with CAD. METHODS: Blood samples were collected from 64 patients admitted to the Department of Cardiology, 31 of whom had CAD and 33 of whom were CAD-free. Plasma levels of PTX3, MMP9, and IL-6 were measured via ELISA. The coronary Gensini score was used to evaluate the severity of coronary artery lesions. RESULTS: PTX3 levels and NLR levels between the CAD group and the CAD-free group were statistically significant (P<0.05). Stepwise multiple linear regression analysis showed that PTX3 levels and NLR levels were independently associated with CAD (r=1.3, P<0.05; r=1.8, P<0.05). Only PTX3 was associated with the severity of coronary artery stenosis. A PTX3 threshold of 4.38ng/mL maximized true-positive and false-negative results. PTX3 displayed a greater area under the receiver operating characteristic curve (AUC) than NLR, MMP9, and IL-6 (0.733 versus 0.612 versus 0.725 versus 0.518). CONCLUSIONS: Compared to NLR, MMP9, and IL-6, PTX3 displayed greater AUC and association with CAD. PTX3 may become a potentially powerful inflammatory biomarker for CAD.

Coexistence of congenital left ventricular aneurysm and prominent left ventricular trabeculation in a patient with LDB3 mutation: a case report.

BACKGROUND: The coexistence of congenital left ventricular aneurysm and abnormal cardiac trabeculation with gene mutation has not been reported previously. Here, we report a case of coexisting congenital left ventricular aneurysm and prominent left ventricular trabeculation in a patient with LIM domain binding 3 gene mutation. CASE PRESENTATION: A 30-year-old Asian man showed paroxysmal sinus tachycardia and Q waves in an electrocardiogram health check. There were no specific findings in physical examinations and serological tests. A coronary-computed tomography angiography check showed normal coronary artery and no coronary stenosis. Both left ventricle contrast echocardiography and cardiac magnetic resonance showed rare patterns of a combination of an apical aneurysm-like out-pouching structure with a wide connection to the left ventricle and prominent left ventricular trabecular meshwork. High-throughput sequencing examinations showed a novel mutation in the LDB3 gene (c.C793>T; p.Arg265Cys). CONCLUSIONS: Our finding indicates that the phenotypic expression of two heart conditions, congenital left ventricular aneurysm and prominent left ventricular trabeculation, although rare, can occur simultaneously with LDB3 gene mutation. Congenital left ventricular aneurysm and prominent left ventricular trabeculation may share the same genetic background.

The efficacy advantage of evolocumab (AMG 145) dosed at 140mg every 2weeks versus 420mg every 4weeks in patients with hypercholesterolemia: Evidence from a meta-analysis.

BACKGROUND: Evolocumab (AMG 145), a PCSK9 inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels. Doses of 140mg administered every 2weeks (Q2W) and 420mg administered every 4weeks (Q4W) are widely used, and both dosing schedules were effective in clinical trials. However, some researchers have speculated that 140mg Q2W administration has equal or even greater efficacy. This meta-analysis was performed to assess the differences in efficacy and safety between the two doses. METHODS: We searched the PubMed, EMBASE, and Web of Science databases to identify relevant clinical trials published before January 2016. A total of 2403 patients from 8 randomized controlled trials were identified and included in the analysis. RESULTS: Evolocumab administered at 140mg Q2W resulted in a greater percent change from baseline in LDL-C concentration (-7.27; 95% confidence interval (CI), -10.36 to -4.18) and had greater efficacy in achieving the treatment goal of LDL-C ≤1.8mmol/L with an relative risk (RR) of 1.09 (95% CI, 1.00 to 1.18) compared with 420mg Q4W in patients who were concomitantly treated with statins. These findings were not significantly different between the 140mg Q2W and 420mg Q4W groups when evolocumab was administered as monotherapy. There was no difference in the rate of occurrence of the main treatment-related adverse events between the two doses. CONCLUSIONS: Evolocumab administered at 140mg Q2W was more effective than the 420mg Q4W dosage at lowering lipid concentrations, especially in patients who concomitantly received stable statin therapy.

TSLPR deficiency attenuates atherosclerotic lesion development associated with the inhibition of TH17 cells and the promotion of regulator T cells in ApoE-deficient mice.

AIMS: We generated thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice to directly explore the role of thymic stromal lymphopoietin (TSLP) in atherogenesis. METHODS AND RESULTS: Both thymic stromal lymphopoietin (TSLP) and its receptor are expressed in atherosclerotic aortas of apolipoprotein E knockout (ApoE KO) mice. Serum thymic stromal lymphopoietin (TSLP) is markedly increased in apolipoprotein E knockout (ApoE KO) mice fed with a high fat diet (HFD). Arterial lesion formation was significantly decreased in thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice compared with apolipoprotein E knockout (ApoE KO) mice. Bone marrow chimera studies indicated reduced lesions in apolipoprotein E knockout (ApoE KO) mice which received the bone marrow of thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice as well as in TSLPR KO mice which received bone marrow of ApoE-TSLPR DKO mice. Compared with apolipoprotein E knockout (ApoE KO) mice, IFN-γ secretion by activated T cells was increased but IL-4 expression was reduced in thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice. Consisted with these results, the mRNA of IFN-γ was increased but IL-4 was reduced in root. These findings suggest that a reduction in atherosclerotic lesions in thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice may not be due to a Th1/Th2 imbalance. On the other hand, the number of Th17 cells, the secretion of IL-17A by activated CD4(+) T cells and the mRNA expression of IL-17A in root were decreased in thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice. Notably, the number of regulatory T cell expression of IL-10 was increased in thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice. CONCLUSIONS: Collectively, our data suggest that activating thymic stromal lymphopoietin (TSLP) promotes atherosclerosis by inducing Th17/Treg imbalance through thymic stromal lymphopoietin/thymic stromal lymphopoietin R-receptor (TSLP/TSLPR) signal way in apolipoprotein E-deficient mice fed with HFD model.