Polyphosphoestered Nanomedicines with Tunable Surface Hydrophilicity for Cancer Drug Delivery.

The surface hydrophilicity of nanoparticles has a major impact on their biological fates. Ascertaining the correlation between nanoparticle surface hydrophilicity and their biological behaviors is particularly instructive for future nanomedicine design and their antitumor efficacy optimization. Herein, we designed a series of polymeric nanoparticles based on polyphosphoesters with well-controlled surface hydrophilicity in the molecular level and systemically evaluated their biological behaviors. The results demonstrated that high surface hydrophilicity preferred lower protein absorption, better stability, longer blood circulation, and higher tumor accumulation but lower cellular uptake. Upon encapsulation of drugs, nanoparticles with high hydrophilicity showed an excellent antitumor therapeutic efficacy in both primary and metastatic tumors as compared to the relatively hydrophobic ones. Further analyses revealed that the superior antitumor outcome was attributed to the balance of tumor accumulation and cellular uptake, demonstrating the particular importance of nanoparticle surface hydrophilicity regulation on the antitumor efficacy. Our work provides a potent guideline for a rational designation on the surface hydrophilicity of nanoparticles for cancer treatment optimization.

Newly detected atrial fibrillation is associated with cortex-involved ischemic stroke.

BACKGROUND: Both cortical and cortical-subcortical (cortex-involved) lesions are typically associated with embolic stroke, of which atrial fibrillation (AF) is the common cause. The aim of this study was to find out the associations between cortex-involved stroke, vascular risk factors, and the subtypes (discovery time and duration) of AF. METHODS: This was an imaging study of the China Atrial Fibrillation Screening in Acute Ischemic Stroke Patients (CRIST) trial. Between October 2013 and June 2015, 1511 acute ischemic stroke or transient ischemic attack (TIA) patients within 7 days after stroke onset at 20 Chinese hospitals were enrolled in this prospective, multicenter cohort, cross-sectional study. The final analysis of this sub-study included 243 patients with AF with required magnetic resonance imaging (MRI) sequences. AF was diagnosed by 6-day Holter monitoring and classified by duration of 24 h. Two stroke specialists blinded to the clinical information reviewed MRI (diffusion-weighted MRI). The third stroke specialists, also blinded to the clinical information, assessed the conflicts. Adjusted large artery atherosclerosis as confounding factor, the associations between cortex-involved lesions, vascular risk factors, and the subtype of AF were evaluated by univariate and multivariate regression analyses. RESULTS: Of 243 acute ischemic stroke patients with AF, 190 were known AF and 53 were newly detected AF. There were 28 patients with AF persistent >24 h and 25 persistent ≤24 h in newly detected AF. Patients with newly detected AF were likely to have a fewer history of stroke or TIA (16.98% vs. 36.31%, P = 0.008) and lower fasting blood glucose (5.91 ±â€Š1.83 mmol/L vs. 6.75 ±â€Š3.83 mmol/L, P = 0.030) than patients with known AF. Among these 243 patients, 102 (41.98%) patients were with cortex-involved lesions. Cortex-involved lesions were significantly related to newly detected AF persistent >24 h (odds ratio [OR]: 4.517, 95% confidence interval [CI]: 1.490-13.696, P = 0.008), proteinuria (OR: 3.431, 95% CI: 1.530-7.692, P = 0.021), and glycosylated hemoglobin (OR: 0.632, 95% CI: 0.464-0.861, P = 0.004). CONCLUSIONS: Compared to previously known AF, newly detected AF persistent >24 h was associated with cortex-involved ischemic stroke. CLINICAL TRIAL REGISTRATION: NCT02156765, https://clinicaltrials.gov/ct2/show/record/NCT02156765.

Inpatient statin use and stroke recurrence in patients with or without diabetes mellitus.

Objectives: Although statin therapy is associated with lower recurrence in patients with acute ischaemic stroke, data-evaluating associations between inpatient statin use and stroke recurrence in diabetic patients after acute stroke onset are limited. Methods: This study was based on population data from the Chinese National Stroke Registry. Patients with acute ischaemic stroke and no history of statin therapy were selected. Individuals treated regularly with any type or dosage of statins during acute hospitalization were defined as having inpatient statin therapy. The subjects were divided into two groups according to statin use status during acute hospitalization. Multivariate logistic regression analysis was used to analyse the associations between statin use and stroke recurrence in patients with or without diabetes. Results: A total of 11,429 patients, 2341 (20.48%) with diabetes, were selected for analysis. Statin therapy during hospitalization was documented in 4982 (43.59%). Logistic analysis showed no significant associations between inpatient statin use and stroke recurrence in diabetic subjects at 3 months (OR = 0.90, 95% CI = 0.69-1.16, P = 0.40) or 1 year (OR = 0.92, 95% CI = 0.74-1.16, P = 0.48), but statin use was significantly associated with lower recurrence in non-diabetic patients at both 3 months (OR = 0.80, 95% CI = 0.69-0.92, P = 0.002) and 1 year (OR = 0.82, 95% CI = 0.72-0.93, P = 0.002) after discharge. Conclusion: Inpatient statin use was associated with lower stroke recurrence in non-diabetic patients after acute ischaemic stroke, but no definite association between inpatient statin use and stroke recurrence in patients with diabetes mellitus was found.

Effect of microRNA-129-5p targeting HMGB1-RAGE signaling pathway on revascularization in a collagenase-induced intracerebral hemorrhage rat model.

BACKGROUND: This study aimed at exploring the effect of microRNA-129-5p (miR-129-5p) targeting high mobility group box-1 (HMGB1)-receptor for advanced glycation end-products (RAGE) signaling pathway on the revascularization in a collagenase-induced intracerebral hemorrhage (ICH) rat model. METHODS: OX26-pGFAP-IL, an immunoliposome expressing miR-129-5p was constructed. The collagenase-induced ICH rat models were successfully established by 96 Sprague Dawley (SD) rats, which were categorized into the sham group, ICH group, miR-129-5p group, negative control (NC) group, ethyl pyruvate (EP, an inhibitor of HMGB1) group and N-benzyl-4-chloro-N-cyclohe-xylbenzamide (FPS-ZM1, a RAGE receptor antagonist) group. The miR-129-5p expression in the brain tissue homogenate was detected using the quantitative real-time polymerase chain reaction (qRT-PCR) and the protein expressions of HMGB1 and RAGE by Western blotting. Immunohistochemistry (IHC) was used for the detection of the vascular endothelial growth factor (VEGF). Microvessel density (MVD) was also detected. RESULTS: Compared to the sham group, the ICH, NC, EP and FPS-ZM1 groups had a decrease in miR-129-5p expressions, and an increase in the protein expressions of HMGB1, RAGE and VEGF and MVD. In comparison to the ICH, NC, EP and FPS-ZM1 groups the miR-129-5p group had an elevation in the miRNA-129-5p expressions. The miR-129-5p and EP groups had decreased HMGB1 protein expression and the miR-129-5p, EP and FPS-ZM1 groups had a reduced RAGE protein expression as compared to the ICH group. In comparison to the ICH group, the miR-129-5p, EP, FPS-ZM1 groups had a decline in the VEGF protein expression and MVD. CONCLUSION: Our study proved that up-regulation of miR-129-5p might suppress the HMGB1-RAGE signaling pathway to restrain the revascularization of rats with ICH.

[Association of Insulin Resistance and ß Cell Function with Lipid Metabolism in Middle-aged and Elderly Hui and Han Populations].

OBJECTIVE: To explore the association of insulin resistance and ß cell function with lipid metabolism in middle-aged and elderly Hui and Han populations. METHODS: A total of 1000 subjects age over 40 years were recruited from five urban communities in Yinchuan and Wuzhong cities of Ningxia. The composition ratio between Hui and Han nationality was 1:2. A questionnaire-based survey was performed. Physical examinations were carried out to measure the height, body mass, waistline, and hipline. The levels of triglyceride (TG), total cholesterol (TC), blood uric acid (BUA), fasting blood glucose and insulin were measured. The boby mass index (BMI), waist-hip ratio (WHR), and secretion related index including insulin resistance index (IR), insulin sensitivity index (IAI), and beta cell function index (HBCI) were calculated. RESULTS: The BMI, WHR, IAI, HBCI, and the prevalence rate of diabetes in Hui nationality were significantly higher than those in Han nationality (P<0.01). The levels of BUA, fasting blood glucose, TC, and IR in Han nationality were significantly lower than those in Hui nationality (P<0.01). In Hui populations, TG, BMI, WHR, and BUA were positively correlated with IR (r=0.234, r=0.193, r=0.143, and r=0.129, respectively; P<0.01) and were negatively correlated with IAI (r=-0.234, r=-0.193, r=-0.143, r=-0.129, respectively; P<0.01), whereas TC was negatively correlated with HBCI (r=-0.169, P<0.01). In Han populations, TC, TG, BMI, WHR, and BUA were positively correlated with IR (r=0.140, r=0.257, r=0.288, r=0.163, r=0.104, P<0.01) and negatively correlated with IAI (r=-0.140, r=-0.257, r=-0.288, r=-0.163, and r=-0.104, P<0.01), whereas BMI was negatively correlated with HBCI (r=-0.111, P<0.01). After the influential factors such as gender, nationality, and age were adjusted, the TC, TG, BMI, WHR, BUA levels were positively correlated with IR (r=0.109, r=0.256, r=0.253, r=0.139, and r=0.142, P<0.01) and negatively correlated with IAI (r=-0.109, r=-0.256, r=-0.253, r=-0.139, and r=-0.142, P<0.01). TC and BMI were negatively correlated with HBCI (r=-0.113, r=-0.086, P<0.01). TG and BMI were independently associated with IR and IAI (r=0.218, r=0.182, r=-0.218, r=-0.182), while TC and BMI were independently associated with HBCI (r=-0.113, r=-0.086). CONCLUSIONS: The distributions of TC, TG, BMI, WHR, BUA, IR, IAI, and HBCI differ between Han and Hui populations. The development of insulin resistance is closely related with the increased levels of TC, TG, BMI, WHR, and BUA. However, the HBCI increases with the increased level of TC and BMI. TG and BMI may be related with insulin resistance. Also, TC and BMI may affect the secretion function of ß cells.

Synthetic retinoid Am80 up-regulates apelin expression by promoting interaction of RARα with KLF5 and Sp1 in vascular smooth muscle cells.

Previous studies have demonstrated that both retinoids and apelin possess potent cardiovascular properties and that retinoids can mediate the expression of many genes in the cardiovascular system. However, it is not clear whether and how retinoids regulate apelin expression in rat VSMCs (vascular smooth muscle cells). In the present study, we investigated the molecular mechanism of apelin expression regulation by the synthetic retinoid Am80 in VSMCs. The results showed that Am80 markedly up-regulated apelin mRNA and protein levels in VSMCs. Furthermore, KLF5 (Krüppel-like factor 5) and Sp1 (stimulating protein-1) co-operatively mediated Am80-induced apelin expression through their direct binding to the TCE (transforming growth factor-ß control element) on the apelin promoter. Interestingly, upon Am80 stimulation, the RARα (retinoic acid receptor α) was recruited to the apelin promoter by interacting with KLF5 and Sp1 prebound to the TCE site of the apelin promoter to form a transcriptional activation complex, subsequently leading to the up-regulation of apelin expression in VSMCs. An in vivo study indicated that Am80 increased apelin expression in balloon-injured arteries of rats, consistent with the results from the cultured VSMCs. Thus the results of the present study describe a novel mechanism of apelin regulation by Am80 and further expand the network of RARα in the retinoid pathway.

One-year clinical prediction in Chinese ischemic stroke patients using the CHADS2 and CHA2DS2-VASc scores: the China National Stroke Registry.

AIMS: We investigated whether CHADS2 or CHA2DS2-VASc scores could be used to predict 1-year prognosis in stroke recurrence, mortality, and mortality of ischemic stroke or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (NVAF). METHODS: Patients were selected from a national prospective registry in China. The clinical prediction of the scores was examined using the C statistic. Univariate and multivariate logistic regressions were performed to analyze the relevant risk factors. RESULTS: Thousand two hundred and ninety-seven of 22,216 patients were enrolled in the study. For stroke recurrence rate, the C statistic value was 0.53 (odds ratio [OR] 1.15, 95% confidence interval [CI]: 1.01 to 1.32) for CHADS2 and 0.55 (OR 1.14, 95% CI: 1.05 to 1.24) for CHA2DS2-VASc; adding baseline National Institutes of Health Stroke Scale (NIHSS) score to these two scores, the value of C statistic was 0.58 (OR 1.25 95% CI: 1.14 to 1.37) and 0.58 (OR 1.19, 95% CI: 1.11 to 1.27), respectively. CONCLUSIONS: Both CHADS2 and CHA2DS2-VASc scores have limitations in predicting the 1-year prognosis of stroke/TIA patients with NVAF in China. The predictive value of these two scores improved by adding the baseline NIHSS score.