Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection.

New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

Comparative proteomic analysis of Aurelia coerulea for its locomotion system molecular structure-function inference.

BACKGROUND: Rhythmic contraction and autonomous movement play a key role in the predation, production and displacement of jellyfish. METHODS: Four independent body parts of the jellyfish Aurelia coerulea, including Bell, Tentacle, Oral arm and Gastric pouch were extracted and have been carried out a compared proteomics by liquid chromatography-mass spectrometry/mass-spectrometry (LC-MS/MS). ResultsA total of 13,429 peptides and 1916 proteins with molecular weights in the range of 10.6-980.9 kDa were identified, where 1916, 1562, 1474 and 1441 proteins were matched in the Gastric pouch, Tentacle, Oral arm and Bell, respectively. Gene Ontology (GO) analysis showed that translation, cytoplasma and ATP binding occupy the top differential terms of the three subdomains Biological process, Cellular Component and Molecular Function. A total of 326 pathways were successfully mapped that are mainly associated with intracellular synthesis, metabolism as well as intracellular functions. Moreover, a total of 27 contractile machinery associated proteins including 22 myosin, 3 actin and 2 tropomyosin were identified. CONCLUSIONS: Our results provide a composition profile in the four independent body parts of the jellyfish A. coerulea, of which the identified muscular proteins will greatly help in the understanding of the structural and functional relationship, as well as their operating mechanisms in the jellyfish locomotion system. SIGNIFICANCE: Omics studies have gained a new overall insight into the function of gene and protein networks during the development of motor systems in both bilateral and radial symmetrical animals. A compared proteomics using the label-free method of nano-LC-MS/MS has been performed through the four independent body parts of the moon jellyfish A. coerulea, including Bell, Tentacle, Oral arm and Gastric pouch. In addition to conventional bioinformatics analyses such as GO and KEGG, we have scanned the locomotion-related components, aligned their sequences, simulated three dimensional structures as well as did the molecular phylogenetic analyses. Our investigation provides a composition profile in the four independent body parts of the jellyfish A. coerulea, of which the identified muscular proteins will greatly help in the understanding of the structural and functional relationship, as well as their operating mechanisms in the jellyfish locomotion system.

Impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities of glucose and uric acid metabolisms.

Treatment of hypertension with thiazide diuretics may trigger hypokalemia, hyperglycemia, and hyperuricemia. Some studies suggest simultaneous potassium supplementation in hypertensive patients using thiazide diuretics. However, few clinical studies have reported the impact of long-term potassium supplementation on thiazide diuretic-induced abnormalities in blood glucose and uric acid (UA) metabolisms. One hundred hypertensive patients meeting the inclusion criteria were equally randomized to two groups: IND group receiving indapamide (1.25-2.5 mg daily) alone, and IND/KCI group receiving IND (1.25-2.5 mg daily) plus potassium chloride (40 mmol daily), both for 24 weeks. At the end of 24-week follow-up, serum K+ level in IND group decreased from 4.27 ± 0.28 to 3.98 ± 0.46 mmol/L (P < 0.001), and fasting plasma glucose (FPG) and UA increased from 5.11 ± 0.52 to 5.31 ± 0.57 mmol/L (P < 0.05), and from 0.404 ± 0.078 to 0.433 ± 0.072 mmol/L (P < 0.05), respectively. Serum K+ level in IND/KCl group decreased from 4.27 ± 0.36 to 3.89 ± 0.28 mmol/L (P < 0.001), and FPB and UA increased from 5.10 ± 0.41 to 5.35 ± 0.55 mmol/L (P < 0.01), and from 0.391 ± 0.073 to 0.457 ± 0.128 mmol/L (P < 0.001), respectively. The difference value between the serum K+ level and FPG before and after treatment was not statistically significant between the two groups. However, the difference value in UA in IND/KCl group was significantly higher than that in IND group (0.066 (95% confidence interval (CI): 0.041-0.090) mmol/L vs. 0.029 (95% CI: 0.006-0.058) mmol/L, P < 0.05). The results showed that long-term routine potassium supplementation could not prevent or attenuate thiazide diuretic-induced abnormalities of glucose metabolism in hypertensive patients; rather, it may aggravate the UA metabolic abnormality.

Immediate- and medium-term effects of simultaneous percutaneous corrections of secundum type atrial septal defect combined with pulmonary valve stenosis in local anesthesia and without transesophageal echocardiography guidance.

BACKGROUND: The feasibility and efficacy of simultaneous percutaneous treatment of secundum type atrial septal defect (ASD) combined with pulmonary valve stenosis (PS) have not been proved. OBJECTIVE: To evaluate the safety and efficacy on the clinical benefit of simultaneous percutaneous correction of these two pathologies under local anesthesia and without transesophageal echocardiography guidance. METHODS: Transpulmonary gradient, functional status, pulmonary regurgitation (PR), and tricuspid regurgitation (TR) were studied in 35 patients undergoing percutaneous balloon pulmonary valvuloplasty and ASD closure from March 2004 to July 2012. All patients were followed up until January 2013, an average of 39 months. RESULTS: According to color Doppler transthoracic echocardiography (TTE) before the intervention, the ASD defect size and transpulmonary gradient were 17±8.4 mm and 88±37.8 mmHg, respectively. Post-interventionally, the peak-to-peak transpulmonary gradient decreased from 77±37.6 mmHg to 20±16.2 mmHg (p<0.001) and the ASD occluder size was 23±10.5 mm. In all those patients, there was no residual shunt detected, and moderate and severe TR decreased from 45.7% (16/35) and 20% (7/35) to 8.6% (3/35) and 5.7% (2/35) before and after intervention detected by TTE, respectively. Eight patients had mild PR after procedure and two of them recovered at 6 months and no patient encountered severe adverse events at the latest follow-up. CONCLUSION: Simultaneous percutaneous corrections of ASD combined with PS are feasible, safe, and effective with satisfactory results.

Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis.

AIM: MicroRNAs (miRNAs) play key roles in inflammatory responses of macrophages. However, the function of miRNAs in macrophage-derived foam cell formation is unclear. Here, we investigated the role of miRNAs in macrophage-derived foam cell formation and atherosclerotic development. METHODS AND RESULTS: Using quantitative reverse transcription-PCR (qRT-PCR), we found that the level of miR-155 expression was increased significantly in both plasma and macrophages from atherosclerosis (ApoE(-/-)) mice. We identified that oxidized low density lipoprotein (oxLDL) induced the expression and release of miR-155 in macrophages, and that miR-155 was required to mediate oxLDL-induced lipid uptake and reactive oxygen species (ROS) production of macrophages. Furthermore, ectopic overexpression and knockdown experiments identified that HMG box-transcription protein1 (HBP1) is a novel target of miR-155. Knockdown of HBP1 enhanced lipid uptake and ROS production in oxLDL-stimulated macrophages, and overexpression of HBP1 repressed these effects. Furthermore, bioinformatics analysis identified three YY1 binding sites in the promoter region of pri-miR-155 and verified YY1 binding directly to its promoter region. Detailed analysis showed that the YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress oxLDL-induced foam cell formation. Importantly, inhibition of miR-155 by a systemically delivered antagomiR-155 decreased clearly lipid-loading in macrophages and reduced atherosclerotic plaques in ApoE(-/-) mice. Moreover, we observed that the level of miR-155 expression was up-regulated in CD14(+) monocytes from patients with coronary heart disease. CONCLUSION: Our findings reveal a new regulatory pathway of YY1/HDACs/miR-155/HBP1 in macrophage-derived foam cell formation during early atherogenesis and suggest that miR-155 is a potential therapeutic target for atherosclerosis.

Vinyl chloride monomer (VCM) induces high occurrence of neural tube defects in embryonic mouse brain during neurulation.

The aim of this study was to explore the direct embryonic teratogenicity of vinyl chloride monomer (VCM), especially the toxic effects on the early development of the nervous system and its underlying mechanisms. Pregnant mice at embryonic day 6.5 (E6.5) were injected with different doses of VCM (200, 400 and 600 mg/kg) and embryos were harvested at E10.5. Our results showed that doses higher than 400 mg/kg of VCM increased the incidence of malformed embryos, especially the neural tube defects (NTDs). In addition, high-dose of VCM decreased mitotic figure counts in the neuroepithelium and enhanced the percentage of cells in G0/G1 phase, while they were reduced in S phase. The more VCM was injected into mice, the fewer positive PCNA cells were seen and the more positive TUNEL cells were observed in the neuroepithelium. Moreover, significant increases in the levels of caspase-3 protein were observed in NTD embryos. Our results demonstrate that during early pregnancy, exposure to doses higher than 400 mg/kg of VCM increases the incidence of malformations and particularly the rate of NTDs. High-dose of VCM inhibits the proliferation of neural cells and induces cell apoptosis, leading to an imbalance in the ratio of proliferation and apoptosis. Meanwhile, the apoptosis of neuroepithelial cells might be accelerated by the activation of the caspase-3 pathway, and it might be a reason for NTDs.

Effect of metformin on weight gain during antihypertensive treatment with a beta-blocker in Chinese patients.

BACKGROUND: Overweight and obesity are associated with cardiovascular disease (CVD). This study was designed to investigate whether combined use of nitrendipine and atenolol has any effect on body weight (BW) and whether metformin can prevent antihypertensive medication-induced weight gain and has any effect on blood glucose (BG). METHODS: Included in the present study were 94 hypertensive patients with a body mass index (BMI) > or =25 kg/m(2), of whom 45 patients were treated with nitrendipine plus atenolol (N/A group), and the remaining 49 patients were treated with nitrendipine, atenolol, and metformin (N/A/M group). The mean follow-up duration was 14 months. BW and glucose tolerance were measured. RESULTS: In N/A group, BW and fasting BG significantly increased from 73.5 +/- 9.6 kg to 74.2 +/- 9.7 kg (P < 0.05) and from 94.2 +/- 10.5 mg/dl to 97.9 +/- 11.3 mg/dl (P < 0.01), respectively, whereas postprandial BG did not change significantly. In N/A/M group, BW slightly decreased from 72.7 +/- 10.1 kg to 72.3 +/- 10.2 kg (P = 0.30), and fasting BG did not change significantly (93.5 +/- 10.4 mg/dl vs. 92.7 +/- 10.2 mg/dl, P = 0.59), whereas 2-h postprandial BG significantly decreased from 133.7 +/- 30.5 mg/dl to 124.0 +/- 29.6 mg/dl (P < 0.05). Furthermore, a significant difference was observed in difference value of BW before and after treatment between the two groups (0.7 (95% confidence interval, 0.1-1.3) kg in N/A group vs. -0.4 (95% confidence interval, -1.3 to 0.4) kg in N/A/M group, P < 0.05). CONCLUSIONS: Combination therapy of nitrendipine and atenolol may significantly increase BW and fasting BG in overweight or obese patients with hypertension. Metformin may prevent BW gain and improve BG levels in hypertensive patients who received combination therapy of nitrendipine and atenolol.