Endothelial colony-forming cell-derived exosomal miR-21-5p regulates autophagic flux to promote vascular endothelial repair by inhibiting SIPL1A2 in atherosclerosis.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) represents an efficient therapeutic method for atherosclerosis but conveys a risk of causing restenosis. Endothelial colony-forming cell-derived exosomes (ECFC-exosomes) are important mediators during vascular repair. This study aimed to investigate the therapeutic effects of ECFC-exosomes in a rat model of atherosclerosis and to explore the molecular mechanisms underlying the ECFC-exosome-mediated effects on ox-LDL-induced endothelial injury. METHODS: The effect of ECFC-exosome-mediated autophagy on ox-LDL-induced human microvascular endothelial cell (HMEC) injury was examined by cell counting kit-8 assay, scratch wound assay, tube formation assay, western blot and the Ad-mCherry-GFP-LC3B system. RNA-sequencing assays, bioinformatic analysis and dual-luciferase reporter assays were performed to confirm the interaction between the miR-21-5p abundance of ECFC-exosomes and SIPA1L2 in HMECs. The role and underlying mechanism of ECFC-exosomes in endothelial repair were explored using a high-fat diet combined with balloon injury to establish an atherosclerotic rat model of vascular injury. Evans blue staining, haematoxylin and eosin staining and western blotting were used to evaluate vascular injury. RESULTS: ECFC-exosomes were incorporated into HMECs and promoted HMEC proliferation, migration and tube formation by repairing autophagic flux and enhancing autophagic activity. Subsequently, we demonstrated that miR-21-5p, which is abundant in ECFC-exosomes, binds to the 3' untranslated region of SIPA1L2 to inhibit its expression, and knockout of miR-21-5p in ECFC-exosomes reversed ECFC-exosome-decreased SIPA1L2 expression in ox-LDL-induced HMEC injury. Knockdown of SIPA1L2 repaired autophagic flux and enhanced autophagic activity to promote cell proliferation in ox-LDL-treated HMECs. ECFC-exosome treatment attenuated vascular endothelial injury, regulated lipid balance and activated autophagy in an atherogenic rat model of vascular injury, whereas these effects were eliminated with ECFC-exosomes with knockdown of miR-21-5p. CONCLUSIONS: Our study demonstrated that ECFC-exosomes protect against atherosclerosis- or PTCA-induced vascular injury by rescuing autophagic flux and inhibiting SIAP1L2 expression through delivery of miR-21-5p. Video Abstract.

Effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: A pilot test.

OBJECTIVE: To investigate the effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 66 STEMI patients with sinus rhythm and the resting heart rate ≥80 bpm after successful emergency PCI were included. The patients in the test group were treated with ivabradine combined with metoprolol at 12 hr after PCI, while the control group was given only metoprolol orally. Their resting heart rate was controlled to <70 bpm at discharge and followed for 180 days. Heart rate and blood pressure were measured regularly. Echocardiogram was performed. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity troponin T, high sensitivity troponin I, and high sensitivity C-reactive protein were measured. The major adverse cardiovascular events during hospitalization and follow-up period were recorded. RESULTS: Compared with the control group, the heart rate of the test group decreased significantly (p < .05). Compared with the control group, the left ventricular end-diastolic volume and left ventricular end-systolic volume were significantly decreased while left ventricular ejection fraction was significantly increased in the test group at 90 days after operation. NT-proBNP of the test group was significantly lower than that of the control group at 7 days after operation (p < .05). CONCLUSION: For STEMI patients, early use of ivabradine combined with standard therapy such as ß-blocker after successful reperfusion can achieve effective heart rate control, with great safety and tolerance. But the effect of ivabradine on left ventricular remodeling is uncertain.

Dual-Sensitive Carbohydrate-Based Nanosystem for Targeted Drug Delivery to Potentiate the Therapeutic Efficacy of Ulcerative Colitis.

Purpose: Conventional oral formulations for inflammatory bowel disease (IBD) treatment are less than satisfactory, due to the poor controllability of drug release and lack of specificity to the inflammation sites in the gastrointestinal (GI) tract. To overcome these limitations, we developed a multiple carbohydrate-based nanosystem with pH/ROS dual responsibility and charge-mediated targeting ability for IBD-specific drug delivery. Methods: In view of the overproduction of ROS and overexpression of cationic proteins in the inflammatory colon, the designed nanosystem was composed of oxidation-sensitive cyclodextrin (OX-CD), chitosan (CS) and pectin (AHP). OX-CD was utilized to load dexamethasone (DM) by the solvent evaporation method. CS and AHP with opposite charges were sequentially coated onto OX-CD to generate the nanosystems by the electrostatic self-assembly method. The physicochemical properties, stability, dual-sensitive drug release behavior, cytotoxicity, cellular uptake and anti-inflammatory activity were investigated in vitro. In vivo bio-distribution and therapeutic efficacy of the nanosystem were further evaluated in the ulcerative colitis (UC) mice. Results: The obtained AHP/CS/OX-CD-DM nanosystem (ACOC-DM) could maintain stability under the GI pH environments, and release drug in the inflammatory colon with pH/ROS sensitivity. Dual polysaccharide-coated ACOC-DM exhibited higher cellular uptake and anti-inflammatory efficacy in macrophages than single polysaccharide-coated CS/OX-CD-DM nanosystem (COC-DM). Orally administrated ACOC-DM could enhance inflammation targeting ability and therapeutic efficacy of DM in the UC mice. Conclusion: This carbohydrate-based nanosystem with pH/ROS dual sensitivity and inflammation targeting capacity may serve as a safe and versatile nanoplatform for IBD therapy.

Functional, physicochemical, and structural properties of the hydrolysates derived from the abalone (Haliotis discus subsp hannai Ino) foot muscle proteins.

This study was conducted to investigate functional, physicochemical, and structural properties of abalone foot muscle proteins (AFPs) and their hydrolysates (HAFPs) obtained using animal protease (HA), papain (HPP), and Protamex® (HP) at different time points. The HA-hydrolysate obtained after 0.5 h of treatment demonstrated the highest solubility at pH 7.0 (84.19%); the HPP-hydrolysate at 4 h exhibited the highest degree of hydrolysis (11.4%); the HPP-hydrolysate at 0.5 h had the highest oil holding capacity (2.62 g/g) and emulsion stability index (39.73 min), and the HP-hydrolysate at 4 h had the highest emulsifying activity index (93.23 m2/g) and foaming stability (91.45%); Regarding the physicochemical properties, the HPP-hydrolysates revealed the largest particle size, higher absolute zeta potential, and superior interfacial activity. Structural characterization demonstrated the enzymolysis-based changes in the composition and the secondary structure of the AFPs. These results provide practical support for the theoretical basis of the use of AFPs as a source of nutritive proteins in the food industry.

miR-149 rs2292832 C allele enhances the cytotoxic effect of temozolomide against glioma cells.

Glioma is a common cancer that affects people worldwide with high morbidity and mortality. Human miR-149 rs2292832 C/T polymorphism and miR-149-5p expressions have been documented to play important roles in various type of cancers. This study aims to assess the impact of miR-149 rs2292832 C/T polymorphism and miR-149-5p expressions in cytotoxic effect of temozolomide against glioma cells. A total of 137 cases of glioma patients and 21 healthy cases were enrolled in this study for clinical research. We found that miR-149-5p was significantly downregulated in glioma cell lines and in blood leukocyte of glioma patients. Furthermore, miR-149 rs2292832 C/T polymorphism was significantly associated with glioma prognosis and temozolomide resistance. Subsequently, the glioma cell lines stable transfected with common miR-149 expression construct (miR-149-T) and the variant miR-149 expression construct (miR-149-C) were used to determine the regulatory effect of miR-149 rs2292832 C on glioma cells progression. Data revealed that miR-149 rs2292832 C allele could enhance the miR-149-5p expressions, and therefore, prevent the proliferation of glioma cells and increase the cytotoxicity of temozolomide against glioma cells. These functions of miR-149-C were demonstrated to be triggered by CDK6/SOX2 pathway inhibition. The above results demonstrated that miR-149 rs2292832 C/T polymorphism was a potential prognostic biomarker for glioma development by regulating miR-149/CDK6 axis.

Selenium nanoparticles reduce glucose metabolism and promote apoptosis of glioma cells through reactive oxygen species-dependent manner.

Gliomas are the most common, malignant, and lethal tumors in adults. Furthermore, gliomas are highly resistant to current chemotherapeutic drugs. Thus, new effective anticancer drugs for glioma are urgently needed. Selenium nanoparticles have been reported to have potent anti-tumor activity, although the specific mechanism is not fully understood. This study aimed to test the anti-tumor effect of selenium nanoparticles and its mechanism. We used selenium nanoparticles to treat commercial glioma cell lines, and patient-derived glioma cells, and then used the MTT assay to determine selenium nanoparticles effect against these. Apoptotic cell death was determined by annexin V-Fluos staining kit. Glucose uptake, lactate, and adenosine triphosphate production, together with hexokinase 2 and pyruvate kinase activities were measured to determine the glucose metabolism level. Reactive oxygen species production was tested using 2',7'-dichlorodihydrofluorescein diacetate. Our results showed that selenium nanoparticles had a potent cytotoxic effect in glioma cells, regardless of whether they were drug-resistant or not, whereas it showed less toxic effect in normal healthy cells. Further tests showed that selenium nanoparticles treatment leads to apoptotic cell death enhancement and glucose metabolism reduction, and this process was in a reactive oxygen species pathway-dependent manner. These results may provide a novel direction for glioma therapy in the future.

Association of CALCA genetic polymorphism with essential hypertension.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is the predominant neurotransmitter in capsaicin-sensitive sensory nerves. Participation of CGRP in hypertension is one of the most extensively studied topics in the field. There is growing evidence to the effect that CGRP is associated with essential hypertension (EH). The aims of this study were to pinpoint whether single nucleotide polymorphisms (SNPs) in the genes coding for CALCA were associated with EH susceptibility in a Hunan Han population. METHODS: A total of 293 subjects with EH and 208 controls were enrolled in the study. Genomic DNA was extracted from peripheral blood leucocytes by a phenol-chloroform method. The CALCA T-692C was genotyped using a restriction fragment length polymorphism method. RESULTS: A statistically significant difference in CALCA T-692C genotypic distribution was observed between cases and controls (P=0.001). Moreover, the frequencies of the C allele were 14.85% in the EH group and 7.45% in the control group, prevalence of C alleles in EH subjects and controls was significantly incomparable (P<0.001). Furthermore, the results of Logistic regression analysis showed that the carriers of C allele (TC+CC genotypes) were associated with increased EH risk (OR=2.093, 95% CI: 1.317-3.326, P<0.01). CONCLUSIONS: CALCA genetic polymorphism is associated with EH susceptibility. Carriers of at least one C allele at the polymorphic site CALCA T-692C showed increased risk for EH.

Experimental study on hemorheological and pathological changes following severe myocardial contusion.

OBJECTIVE: To investigate the mechanism of severe myocardial contusion in rabbits. METHODS: A total of 32 New Zealand rabbits were randomly divided into 2 groups, the severe myocardial contusion group (the experimental group, n=16) and the sham-impact control group (the control group, n=16). Hemorheological parameters, interleukin-8 (IL-8) in serum, the water contents of myocardium and polymorphonuclear neutrophil (PMN) infiltration in contused myocardium were observed at 24 hours after the experiment. RESULTS: As compared with the control group, the hemorheological parameters in the experimental group including the whole blood viscosity (etab), erythrocyte aggregation index (EAI), hematocrit (HCT), serum fibrinogen (Fib), Casson viscosity (Gammay) and erythrocyte sedimentation rate (ESR), significantly increased. The IL-8, PMN infiltration and the water contents of the contused myocardium also significantly increased. CONCLUSIONS: It suggests that the hemorheological disorder, increase of IL-8 in serum, and PMN infiltration in contused myocardium may contribute to the development of cardiac edema and secondary myocardial damage following severe myocardial contusion in rabbits.

[Outcomes of percutaneous coronary intervention for intermediate coronary artery disease guided by intravascular ultrasound or fractional flow reserve].

OBJECTIVE: To evaluate the long-term clinical outcomes of fractional flow reserve (FFR)-guided versus intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) for intermediate coronary lesions. METHODS: A total of 226 patients with 293 intermediate coronary artery lesions (stenosis of 40%-70%) confirmed by coronary angiography were randomized into 3 groups to undergo PCI for a minimal lumen cross sectional area (MLA)<4 mm(2) (IVUS group, 98 lesions) or for a FFR<0.80 (FFR group, 101 lesions), or to receive standard medical treatment (medication group, 94 lesions). The primary outcome was major adverse cardiac events including death, myocardial infarction, and ischemia-driven target vessel revascularization at 1 year after the index procedure. RESULTS: The baseline percent diameter stenosis and lesion length were similar between the 3 groups, but more patients in IVUS group than in FFR group received PCI (P<0.001). No significant difference was found in the incidence of major adverse cardiac events between the 3 groups (P=0.182). CONCLUSION: Both FFR- and IVUS-guided PCI strategy for intermediate coronary artery disease are associated with favorable outcomes, but IVUS-guided PCI based on the single index of MLA can increase the rate of revascularization therapy.