Engineered Platelet for In Situ Natural Killer Cell Activation to Inhibit Tumor Recurrence.

Natural killer (NK) cells offer profound advantages against tumor recurrence due to their unique immunological behavior. NK cell therapies associated with the antibody-dependent cell-mediated cytotoxicity (ADCC) effect have made remarkable progress while being limited by insufficient antibody binding and the exhausted state of NK cells in the postsurgical immunosuppressive microenvironment. Leveraging the adherence of PLT to tumor cells, we developed an exogenously implanted platelet (PLT)-based NK cell-driven system (PLT-IgG-IL15) to improve the identifiability of residual tumors with IgG antibody labeling for NK cells catching and engaging, which consequently restored the ADCC effect and promoted the recovery of their killing function. Furthermore, interleukin-15 (IL-15) participated in the augmentation of NK cell function. Collectively, PLT-IgG-IL15 served as an NK cell tumor cell engager as well as an NK cell charger, achieving a <40% recurrence rate in mouse tumor models.

All-cause mortality risk with different metabolic abdominal obesity phenotypes: the Rural Chinese Cohort Study.

We aimed to investigate the association of metabolic obesity phenotypes with all-cause mortality risk in a rural Chinese population. This prospective cohort study enrolled 15 704 Chinese adults (38·86 % men) with a median age of 51·00 (interquartile range: 41·00-60·00) at baseline (2007-2008) and followed up during 2013-2014. Obesity was defined by waist circumference (WC: ≥ 90 cm for men and ≥ 80 cm for women) or waist-to-height ratio (WHtR: ≥ 0·5). The hazard ratio (HR) and 95 % CI for the risk of all-cause mortality related to metabolic obesity phenotypes were calculated using the Cox hazards regression model. During a median follow-up of 6·01 years, 864 deaths were identified. When obesity was defined by WC, the prevalence of participants with metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO) and metabolically unhealthy obesity (MUO) at baseline was 12·12 %, 2·80 %, 41·93 % and 43·15 %, respectively. After adjusting for age, sex, alcohol drinking, smoking, physical activity and education, the risk of all-cause mortality was higher with both MUNO (HR = 1·20, 95 % CI 1·14, 1·26) and MUO (HR = 1·20, 95 % CI 1·13, 1·27) v. MHNO, but the risk was not statistically significant with MHO (HR = 0·99, 95 % CI 0·89, 1·10). This result remained consistent when stratified by sex. Defining obesity by WHtR gave similar results. MHO does not suggest a greater risk of all-cause mortality compared to MHNO, but participants with metabolic abnormality, with or without obesity, have a higher risk of all-cause mortality. These results should be cautiously interpreted as the representation of MHO is small.

A Bio-Liposome Activating Natural Killer Cell by Illuminating Tumor Homogenization Antigen Properties.

Natural killer (NK) cell therapies, primarily based on chimeric antigen receptor NK cells (CAR-NK), have been developed and applied clinically for therapeutic treatment of patients with mid-to-late-stage tumors. However, NK cell therapy has limited efficacy due to insufficient antigen expression on the tumor cell surface. Here, a universal "illuminate tumor homogenization antigen properties" (ITHAP) strategy to achieve stable and controlled antigen expression on the surface of tumor cells using nanomedicine, thus significantly enhancing the immune recognizability of tumor cells, is described. The ITHAP strategy is used to generate bio-liposomes (Pt@PL-IgG) composed of intermingled platelet membranes and liposomes with NK-activatable target antigen (IgG antibodies) and cisplatin pre-drug. It is demonstrated that Pt@PL-IgG successfully targets tumor cells using the autonomous drive of platelet membranes and achieves IgG implantation on tumor cells by utilizing membrane fusion properties. Moreover, it is shown that the Pt-DNA complex combined with NK cell-induced pyroptosis causes substantial interferon (IFN) secretion, thus providing a synthase-stimulator of interferon genes (STING)-IFN-mediated positive immune microenvironment to further potentiate NK therapy. These results show that anchoring cancer cells with NK-activatable target antigens is a promising translational strategy for addressing therapeutic challenges in tumor heterogeneity.

Metabolizable Near-Infrared-II Nanoprobes for Dynamic Imaging of Deep-Seated Tumor-Associated Macrophages in Pancreatic Cancer.

Tumor-associated macrophages (TAMs) play a crucial part in cancer evolution. Dynamic imaging of TAMs is of great significance for treatment outcome evaluation and precision tumor therapy. Currently, most fluorescence nanoprobes tend to accumulate in the liver and are difficult to metabolize, which leads to strong background signals and inadequate imaging quality of TAMs nearby the liver such as pancreatic cancer. Herein, we aim to develop metabolizable dextran-indocyanine green (DN-ICG) nanoprobes in the second near-infrared window (NIR-II, 1 000-1 700 nm) for dynamic imaging of TAMs in pancreatic cancer. Compared to free ICG, the NIR-II fluorescence intensity of DN-ICG nanoprobes increased by 279% with significantly improved stability. We demonstrated that DN-ICG nanoprobes could specifically target TAMs through the interaction of dextran with specific ICAM-3-grabbing nonintegrin related 1 (SIGN-R1), which were highly expressed in TAMs. Subsequently, DN-ICG nanoprobes gradually metabolized in the liver yet remained in pancreatic tumor stroma in mouse models, achieving a high signal-to-background ratio (SBR = 7) in deep tissue (∼0.5 cm) NIR-II imaging of TAMs. Moreover, DN-ICG nanoprobes could detect dynamic changes of TAMs induced by low-dose radiotherapy and zoledronic acid. Therefore, the highly biocompatible and biodegradable DN-ICG nanoprobes harbor great potential for precision therapy in pancreatic cancer.

Increased serum interleukin-6 level as a predictive biomarker for atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is related to a higher risk of thromboembolic events and mortality. Some studies have demonstrated that the inflammatory biomarker interleukin-6 (IL-6) is associated with a higher risk of higher thrombosis in AF patients, but the real effect of IL-6 remains a controversy. METHODS: We conducted a systematic review and meta-analysis to investigate the association between IL-6 and thromboembolic events, as well as bleeding events, acute coronary syndrome (ACS) events and all-cause mortality in AF. RESULTS: A total of five studies involving 22 928 patients met our inclusion criteria for the systematic review. The higher level of IL-6 in AF patients is related to long-term thromboembolic events including stroke (RR 1.44, CI 95% 1.09-1.90, p=0.01). IL-6 meant a higher risk of long-term bleeding risk (RR 1.36, CI 95% 1.06-1.74, p=0.02), ACS risk (RR 1.81, CI 95% 1.43-2.30, p<0.001) and all-cause mortality (RR 2.35, CI 95% 2.09-2.65, p<0.001). CONCLUSION: A higher level of IL-6 may predict a greater number of long-term thromboembolic events and bleeding events, ACS events and mortality in AF patients. Further studies such as the cut-off point of IL-6 need to be conducted in the future.

Combined Hydrophobization of Polyethylenimine with Cholesterol and Perfluorobutyrate Improves siRNA Delivery.

Polyethylenimine (PEI) is a promising delivery vector of nucleic acids, but cytotoxicity and only moderate transfection efficacy with small RNAs limit its applications. Here we hypothesized that hydrophobization of PEI by combined modification with perfluorinated moieties (F) and cholesterol (Ch) will help in addressing both the cytotoxicity and siRNA delivery efficacy. To test the hypothesis, we synthesized a series of copolymers (F-PEI-Ch) by modifying PEI by reaction with heptafluorobutyric anhydride and cholesteryl chloroformate. We investigated and compared the effect of the modifications on siRNA delivery in vitro and in vivo. We found that the F-PEI-Ch copolymers assembled into micellar structures and that the copolymer with the highest Ch content exhibited the best siRNA delivery performance, including lower cytotoxicity, enhanced cell uptake, improved endosomal escape, and the best siRNA silencing efficacy in vitro and in vivo when compared with control PEI, F-PEI, and PEI-Ch. Overall, hydrophobization of PEI with a combination of cholesterol and superhydrophobic perfluorinated moieties represents a promising approach to the design of siRNA delivery vectors with decreased toxicity and enhanced transfection efficacy.

SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/ß-catenin pathway.

BACKGROUND: The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown. METHODS: The relationship between SOX9 expression and T, N, M classification was assessed using the χ2 test and Spearman's analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/ß-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect ß-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines. RESULTS: We found that SOX9 overexpression correlates with the T, N and M stage significantly (p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/ß-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of ß-catenin and increase the phosphorylation of GSK3ß at Ser9. Further, inhibition of ß-catenin suppressed the metastasis-promoting effects of SOX9 overexpression. CONCLUSIONS: This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/ß-catenin pathway.

Association of serum cystatin C levels with acute coronary syndrome in patients of advanced age.

OBJECTIVE: This study was performed to investigate the relationship between the serum cystatin C (Cys C) level and acute coronary syndrome (ACS) in patients of advanced age. METHODS: The study included 184 patients with ACS and 46 healthy control subjects. Statistical analysis was performed using SPSS version 14.0 (SPSS Inc., Chicago, IL, USA). RESULTS: The serum Cys C level was significantly higher in patients with than without ACS (1.24 ± 0.30 vs. 1.42 ± 0.46 mg/L, respectively). Patients with more stenotic coronary arteries were significantly more likely to have higher median serum Cys C and creatinine levels and a lower estimated glomerular filtration rate. The multivariate logistic regression analysis demonstrated that the serum Cys C level was independently associated with the presence of ACS and the quantity of stenotic coronary arteries after adjustment for confounding factors. Additionally, the serum Cys C level was positively correlated with age, the creatinine level, and the N-terminal pro-B-type natriuretic peptide level in all patients but was negatively correlated with the estimated glomerular filtration rate. CONCLUSION: A high serum Cys C level was independently associated with ACS and the quantity of stenotic coronary arteries in patients of advanced age regardless of renal function.

Exosomes derived from miR-146a-modified adipose-derived stem cells attenuate acute myocardial infarction-induced myocardial damage via downregulation of early growth response factor 1.

Multiple studies demonstrated that early growth response factor 1 (EGR1) induces myocardial damage after acute myocardial infarction (AMI). Recent evidence indicates that microRNAs (miRNA) play an important role in exosome-mediated cardioprotection after AMI. Bioinformatics analysis has shown that miR-146a can regulate the expression of EGR1, so the aim of this study was to determine if miR-146a plays a role in exosome-mediated cardioprotection by regulation of EGR1 after AMI. Exosomes were isolated from wild- or miR-146a-modified adipose-derived stem cells (ADSCs), and the therapeutic effect of exosomes was assessed in an AMI model in rats and hypoxic-induced H9c2 model cells. The results showed that miR-146a containing exosomes had more effect than the exosome treatment group on the suppression of AMI-induced apoptosis, inflammatory response, and fibrosis in an AMI rat model. Both in vivo and in vitro experiments found that miR-146a interacted with the 3'-untranslated region of EGR1 and suppressed posttranscriptional EGR1 expression, which was confirmed by the luciferase reporter assay. We also found that suppressed EGR1 expression reversed AMI or hypoxia-induced TLR4/NFκB signal activation, which played an important role in the promotion of myocardial cell apoptosis, inflammatory response, and fibrosis. Taken together, these findings suggested that exosomes derived from miR-146a-modified ADSCs attenuated AMI-induced myocardial damage via downregulation of EGR1.

Pharmacological inhibition of S6K1 facilitates platelet activation by enhancing Akt phosphorylation.

Platelet activation and thrombus formation is a delicate process involving a series of crosstalk between different pathways. P70 ribosomal S6 kinase1 (S6K1) is a member of serine/threonine kinases and can be phosphorylated by 3-phosphoinositide-dependent protein kinase 1 (PDK1). S6K1 is widely reported to play important roles in cancers and metabolic diseases, but the role of S6K1 and the importance of phosphorylation on Thr229 in platelet activation have not been defined. PF-4708671 is a recently synthesized highly specific inhibitor of S6K1. In this study, we tested PF-4708671 to assess the role of S6K1 in platelet. PF-4708671 facilitated mouse and human platelet aggregation and ATP secretion induced by collagen, thrombin, and adenosine diphosphate through enhanced Akt and Gsk3ß phosphorylation. PF-4708671 also accelerated integrin αIIbß3-mediated clot retraction and spreading. Intravenously given PF-4708671 shortened the occlusion time in arterial thrombosis model. Further results demonstrated that S6K1 was phosphorylated by PDK1 on Thr229 in the resting platelets and dephosphorylated in response to agonist stimulation. PDK1-deficient mice showed higher aggregation when PI3K-Akt-Gsk3ß signaling was blocked by the Gsk3ß-inhibitor SB216763. Thus, S6K1 Thr229 phosphorylation might function as a regulator that prevents platelets from activation. S6K1 inhibition may yield potential pro-thrombotic effects and should be used cautiously when considered as a therapy.

Identification of an obesity index for predicting metabolic syndrome by gender: the rural Chinese cohort study.

BACKGROUND: To compare the accuracy of different obesity indexes, including waist circumference (WC), weight-to-height ratio (WHtR), body mass index (BMI), and lipid accumulation product (LAP), in predicting metabolic syndrome (MetS) and to estimate the optimal cutoffs of these indexes in a rural Chinese adult population. METHODS: This prospective cohort involved 8468 participants who were followed up for 6 years. MetS was defined by the International Diabetes Federation, American Heart Association, and National Heart, Lung, and Blood Institute criteria. The power of the 4 indexes for predicting MetS was estimated by receiver operating characteristic (ROC) curve analysis and optimal cutoffs were determined by the maximum of Youden's index. RESULTS: As compared with WHtR, BMI, and LAP, WC had the largest area under the ROC curve (AUC) for predicting MetS after adjusting for age, smoking, drinking, physical activity, and education level. The AUCs (95% CIs) for WC, WHtR, BMI, and LAP for men and women were 0.862 (0.851-0.873) and 0.806 (0.794-0.817), 0.832 (0.820-0.843) and 0.789 (0.777-0.801), 0.824 (0.812-0.835) and 0.790 (0.778-0.802), and 0.798 (0.785-0.810) and 0.771 (0.759-0.784), respectively. The optimal cutoffs of WC for men and women were 83.30 and 76.80 cm. Those of WHtR, BMI, and LAP were approximately 0.51 and 0.50, 23.90 and 23.00 kg/m2, and 19.23 and 20.48 cm.mmol/L, respectively. CONCLUSIONS: WC as a preferred index over WHtR, BMI, and LAP for predicting MetS in rural Chinese adults of both genders; the optimal cutoffs for men and women were 83.30 and 76.80 cm.

TLR4 Activation Promotes the Progression of Experimental Autoimmune Myocarditis to Dilated Cardiomyopathy by Inducing Mitochondrial Dynamic Imbalance.

Mitochondrial dynamic imbalance associates with several cardiovascular diseases. However, the role of mitochondrial dynamics in TLR4 activation-mediated dilated cardiomyopathy (DCM) progress remains unknown. A model of experimental autoimmune myocarditis (EAM) was established in BALB/c mice on which TLR4 activation by LPS-EB or TLR4 inhibition by LPS-RS was performed to induce chronic inflammation for 5 weeks. TLR4 activation promoted the transition of EAM to DCM as demonstrated by increased cardiomyocyte apoptosis, myocardial fibrosis, ventricular dilatation, and declined heart function. TLR4 inhibition mitigated the above DCM changes. Transmission electron microscope study showed that mitochondria became fragmented, also with damaged crista in ultrastructure in EAM mice. TLR4 activation aggravated the above mitochondrial aberration, and TLR4 inhibition alleviated it. The mitochondrial dynamic imbalance and damage in DCM development were mainly associated with OPA1 downregulation, which may be caused by elevated TNF-α level and ROS stress after TLR4 activation. Furthermore, OMA1/YME1L abnormal degradation was involved in the OPA1 dysfunction, and intervening OMA1/YME1L in H9C2 significantly alleviated mitochondrial fission, ultrastructure damage, and cell apoptosis induced by TNF-α and ROS. These data indicate that TLR4 activation resulted in OPA1 dysfunction, promoting mitochondrial dynamic imbalance and damage, which may involve in the progress of EAM to DCM.

A multifunctional ternary Cu(II)-carboxylate coordination polymeric nanocomplex for cancer thermochemotherapy.

Metal-based photothermal therapy has been widely used in the biomedicine field and includes gold nanoparticles, silver nanoparticles and copper sulfide nanoparticles. Furthermore, the coordination bonding-based metal nanocomplex is a new generation of photothermal agents for cancer therapy due to its high photothermal transduction efficiency, good biocompatibility, biodegradation and bioactivity. In this study, we designed a coordination bonding-based copper (Cu(II))-carboxylate ternary architecture, which consists of a conjugate dopamine-modified nontoxic hyaluronic acid, copper ions and citric acid. When the Cu(II) coordinated with the carboxyl groups, the splitting d orbitals energy gap of Cu(II) and the capability of electron transition were enhanced, which can increase the extinction ability in the near-infrared region for enhancing photothermal therapy. Moreover, the degradation of hyaluronic acid by hyaluronidase highly expressed in the tumor microenvironment led to the release of Cu-citric acid complexes, thus exhibiting an additional chemotherapeutic effect. The nanocomplexes possessed high-performance photothermal conversion, determined to be 21.3%. The solution could be easily heated to above 42 °C, which was sufficient to ablate the cancer cells. An obvious decrease in cell viability was observed in B16F10 cells incubated with the nanocomplexes under laser at the lower concentration of 20 µg/mL Cu(II). Upon near-infrared laser irradiation, the nanocomplexes showed high photothermal therapy and chemotherapeutic efficacy for breast cancer in vivo. This study demonstrated that the Cu(II)-carboxylate coordination nanocomplex is a promising new effective and facilely prepared thermochemotherapy agent for combination therapy against cancer.

Secular trend of the leading causes of death in China from 2003 to 2013.

BACKGROUND: To analyze the epidemiological characteristics and secular trends of the leading causes of death in China. METHODS: Data on the leading causes of death was collected from the Statistical Yearbook of China. Data for 11 years, from 2003 to 2013, was analyzed by regression analysis and chi-square test. RESULTS: The top 3 causes of death from 2009 to 2013 were cancer, cerebrovascular disease, and cardiopathy, with the role of cardiopathy increasing over time (P<0.01). The proportion of deaths related to cardio-cerebrovascular diseases in urban and rural areas increased to 41.9% and 44.8%, respectively, in 2013, and was significantly higher than that for cancer, 25.5% and 22.4% (both P<0.01). Injury and poisoning in urban or rural areas represented the fifth leading cause of death. In 2006, endocrine, nutritional, and metabolic diseases were the sixth main cause of death, with 3.3% in urban areas. The role of genito-urinary, respiratory, and digestive system diseases in urban areas and genito-urinary system diseases in rural areas decreased during this period (all P<0.05). CONCLUSION: Cancer, cerebrovascular disease, and cardiopathy accounted for more than 67% of all deaths from 2007 to 2013 in China, and significantly increased in proportion from 2003 to 2013.

Role of Rab5 in the formation of macrophage-derived foam cell.

BACKGROUND: Foam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell. METHODS: Immunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL). RESULTS: Rab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. CONCLUSIONS: Rab5 plays an important role in modulating the intracellular cholesterol of macrophages and consequently mediating the formation of foam cells.

Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus.

BACKGROUND: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. METHODS: We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y12 receptor expression in megakaryocytes. RESULTS: Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P<0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y12 receptor expression in diabetes mellitus. CONCLUSIONS: Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.

The emerging role of interleukin-37 in cardiovascular diseases.

INTRODUCTION: Interleukin (IL)-37 is a newly identified member of the IL-1 family, and shows a growing role in a variety of diseases. This review aims at summarizing and discussing the role of IL-37 in cardiovascular diseases. METHODS: Data for this review were identified by searches of MEDLINE, Embase, and PubMed using appropriate search terms. RESULTS: IL-37 is a newly identified cytokine belonging to the IL-1 family and is expressed in inflammatory immune cells and several parenchymal cells. It has potent anti-inflammatory and immunosuppressive properties, with two mechanisms underlying this function. IL-37 is produced as a precursor and then cleaved into mature form in the cytoplasm by caspase-1, translocating to nucleus and suppressing the transcription of several pro-inflammatory genes by binding SMAD-3. Besides, IL-37 can be secreted extracellularly, and binds to IL-18Ra chain and recruits Toll/IL-1R (TIR)-8 for transducing anti-inflammatory signaling. IL-37 is upregulated in an inducible manner and negatively regulates signaling mediated by TLR agonists and pro-inflammatory cytokines. The cytokine has been shown to inhibit both innate and adaptive immunological responses, exert antitumor effects, and act as a prognostic marker in a variety of autoimmune diseases. CONCLUSIONS: Recent studies have suggested that IL-37 plays a role in cardiovascular diseases. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its cardio-protective effects, and suggest guidelines for future research.

Palmitate impairs angiogenesis via suppression of cathepsin activity.

Angiogenesis requires the interaction of multiple variable factors to promote endothelial cell adhesion, migration and survival. Palmitate, a free fatty acid, exhibits an anti­angiogenic effect via interference with endothelial cell function, whereas cysteine proteases are important in protein turnover and are termed positive modulators of neovascularization. However, the association between these two factors regarding the regulation of human endothelial cell function remains to be elucidated. By using cell counting kit­8, the Transwell method and an annexin V­fluorescein isothiocyanate/propidium iodide apoptosis detection kit, the present study reported that high levels of palmitate result in a significant decrease in endothelial cell proliferation and invasion, and induced cell apoptosis; cathepsin L and S inhibitors may suppress palmitate­induced apoptosis. Conversely, the results of the cathepsin L and S activity assay and reverse-transcription-quantitative polymerase chain reaction indicated that palmitate inhibited cathepsin­induced endothelial cell invasion, partially via suppressing the expression and activity of cathepsin L and S. The findings of the present study suggested that the potent anti­angiogenic properties of palmitate may be mediated by cysteine proteases.

Essential thrombocythemia presenting as acute coronary syndrome: case reports and literature review.

For the patients with essential thrombocythemia (ET), systemic thrombosis presents as one of the most dangerous complications. It's been widely accepted that acute coronary syndrome (ACS) is a kind of thrombotic diseases. However, there are very few case reports about ET first presenting as ACS. For some patients diagnosed as ACS, but without markedly elevated platelet, underlying ET was missed. And there are some controversies in the principles and target of treatment in those patients. We reported three cases of ACS, in which the patients who did not have common risk factors for coronary artery diseases and presented only mild atherosclerotic stenosis during coronary angiography, one of which had recurrent coronary artery thrombosis. Noticing their elevated blood platelet level and characteristics in angiography, diagnosis of ET was made according to bone marrow morphology and genetic tests. Although they had only mild thrombocytosis, we applied intensive treatment with dual anti-platelet therapy combined with cytoreduction in addition to early coronary intervention, having satisfying outcomes. During the diagnosis and treatment of ACS, if patients present thrombocytosis, but lack common coronary disease risk factors and thrombotic coronary artery occlusion, cardiologists should search for possible ET as an underlying cause of thrombotic coronary event. All those patients were high-risk according to ET risk stratification. Treatment of cytoreduction in combination with anti-thrombosis therapy and revascularization are beneficial. Treatment aims at the target of complete response with platelet count below 400 × 109/L.