Remote Ischemic Preconditioning Before Drug-Coated Balloon Implantation can Improve the Long-Term Prognosis of Patients with CAD.

Background: Drug-coated balloons (DCBs) have become increasingly vital to percutaneous coronary intervention, offering many advantages. However, a significant challenge is that many patients are intolerant to the myocardial ischemia caused by DCB dilation. Remote ischemic preconditioning (RIPC) is known to enhance heart's tolerance to ischemia and hypoxia. This study investigated whether preoperative RIPC could extend the tolerated DCB inflation time and improve the long-term prognosis of patients with coronary artery disease (CAD). Methods: A total of 653 patients with CAD were recruited and randomized into a RIPC group (n = 323) and a control (n = 330) group. The RIPC group underwent RIPC on the left upper limb twice daily, starting three days before the DCB implantation. The patients were followed up for one year after the operation, and 197 patients returned for coronary angiography (CAG) examination where the quantitative flow ratio (QFR) of the target vessels was measured. The primary endpoint of the study was the incidence of target lesion failure (TLF), which included target lesion revascularization (TLR), target vessel myocardial infarction, and cardiac death. The secondary endpoint was the rate of QFR loss in the target vessels. Results: The findings revealed a significantly lower incidence of TLR in the RIPC group compared to the control group. Additionally, at the one-year follow-up, the rate of QFR loss in target vessels was lower in the RIPC group than in the control group. Conclusions: The preoperative application of RIPC effectively extended the duration patients could tolerate DCB inflation. Furthermore, this approach positively impacted the long-term prognosis of CAD patients undergoing DCB treatment. Clinical Trial Registration Information: NCT04766749.

USF1 transcriptionally activates USP14 to drive atherosclerosis by promoting EndMT through NLRC5/Smad2/3 axis.

BACKGROUND: Endothelial-to-Mesenchymal Transformation (EndMT) plays key roles in endothelial dysfunction during the pathological progression of atherosclerosis; however, its detailed mechanism remains unclear. Herein, we explored the biological function and mechanisms of upstream stimulating factor 1 (USF1) in EndMT during atherosclerosis. METHODS: The in vivo and in vitro atherosclerotic models were established in high fat diet-fed ApoE-/- mice and ox-LDL-exposed human umbilical vein endothelial cells (HUVECs). The plaque formation, collagen and lipid deposition, and morphological changes in the aortic tissues were evaluated by hematoxylin and eosin (HE), Masson, Oil red O and Verhoeff-Van Gieson (EVG) staining, respectively. EndMT was determined by expression levels of EndMT-related proteins. Target molecule expression was detected by RT-qPCR and Western blotting. The release of pro-inflammatory cytokines was measured by ELISA. Migration of HUVECs was detected by transwell and scratch assays. Molecular mechanism was investigated by dual-luciferase reporter assay, ChIP, and Co-IP assays. RESULTS: USF1 was up-regulated in atherosclerosis patients. USF1 knockdown inhibited EndMT by up-regulating CD31 and VE-Cadherin, while down-regulating α-SMA and vimentin, thereby repressing inflammation, and migration in ox-LDL-exposed HUVECs. In addition, USF1 transcriptionally activated ubiquitin-specific protease 14 (USP14), which promoted de-ubiquitination and up-regulation of NLR Family CARD Domain Containing 5 (NLRC5) and subsequent Smad2/3 pathway activation. The inhibitory effect of sh-USF1 or sh-USP14 on EndMT was partly reversed by USP14 or NLRC5 overexpression. Finally, USF1 knockdown delayed atherosclerosis progression via inhibiting EndMT in mice. CONCLUSION: Our findings indicate the contribution of the USF1/USP14/NLRC5 axis to atherosclerosis development via promoting EndMT, which provide effective therapeutic targets.

DNMT3B activates FGFR3-mediated endoplasmic reticulum stress by regulating PTPN2 promoter methylation to promote the development of atherosclerosis.

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis (AS). Nevertheless, the regulatory mechanism of ER stress in endothelial cells during AS progression is unclear. Here, the role and regulatory mechanism of DNA (cytosine-5-)- methyltransferase 3 beta (DNMT3B) in ER stress during AS progression were investigated. ApoE-/- mice were fed with high fat diet to construct AS model in vivo. HE and Masson staining were performed to analyze histopathological changes and collagen deposition. HUVECs stimulated by ox-LDL were used as AS cellular model. Cell apoptosis was examined using flow cytometry. DCFH-DA staining was performed to examine ROS level. The levels of pro-inflammatory cytokines were assessed using ELISA. In addition, MSP was employed to detect PTPN2 promoter methylation level. Our results revealed that DNMT3B and FGFR3 were significantly upregulated in AS patient tissues, whereas PTPN2 was downregulated. PTPN2 overexpression attenuate ox-LDL-induced ER stress, inflammation and apoptosis in HUVECs and ameliorated AS symptoms in vivo. PTPN2 could suppress FGFR3 expression in ox-LDL-treated HUVECs, and FGFR3 knockdown inhibited ER stress to attenuate ox-LDL-induced endothelial cell apoptosis. DNMT3B could negatively regulate PTPN2 expression and positively FGFR2 expression in ox-LDL-treated HUVECs; DNMT3B activated FGFR2 expression by increasing PTPN2 promoter methylation level. DNMT3B downregulation repressed ox-LDL-induced ER stress, inflammation and cell apoptosis in endothelial cells, which was reversed by PTPN2 silencing. DNMT3B activated FGFR3-mediated ER stress by increasing PTPN2 promoter methylation level and suppressed its expression, thereby boosting ER stress to facilitate AS progression.

Understanding the microfluidic generation of double emulsion droplets with alginate shell.

The monodisperse double emulsions obtained by microfluidic method can serve as ideal templates for preparing core-shell alginate microcapsules, which have attracted much attention in biological applications, such as drug delivery systems and cell encapsulation, tissue engineering. However, the formation behavior and dynamic analysis of double emulsion with an alginate shell is still unclear due to the complex rheological behavior of alginate solutions. Herein, we employ a dual-coaxial microfluidic device to generate the high-quality double emulsion droplets with alginate shell, focusing on the effects of the fluid properties of alginate solution in the middle phase (viscosity, µm) and the fluid flow rate on the droplet formation mechanism. As the viscosity of the middle fluid (µm) increased, the size of compound droplets (D2) increased and the size of inner droplets (D1) decreased, and the break-up regimes occurred a dripping-to-jetting transition when µm = 160 mPa s. The number of encapsulated inner droplets can be predicted and precisely controlled by regulating the generation frequency of inner (f1) and outer droplets (f2). The breakup dynamics of the alginate thread are also analyzed by using the volume-of-fluid/continuum-surface-force (VOF/CSF) method. The results show that the pressure and velocity in the neck of pinch-off is lower in the jetting than that in the dripping regime. This study will provide useful guidance for the rational design and controllable preparation of core-shell alginate microcapsules.

[Clinical follow-up study of ulnar styloid fractures and classification of distal radial fractures].

OBJECTIVE: To analyze the result of the distal radial fractures with or without ulnar styloid fracture. METHODS: From January 2007 to October 2010, 62 cases with distal radial fractures were treated by ORIF, of which 52 were followed-up entirely with an average of 15 months (6-34 months), including 6 male cases and 46 female cases at an average age of (62.25±8.25) years. All ulnar styloid fractures were not fixed. According to ulnar styloid fractures, all cases were divided into two groups, group A (32 cases with ulnar styloid fractures) and group B (20 cases without). Group A was further divided into type I (tip fracture of ulnar styloid, 12 cases) and type II (base fracture of ulnar styloid, 20 cases). AO classification, volar tilt, radial inclination and radial height were recorded before and after operation. Complications and Garlant-Werley Scores were evaluated 3 months and 1 year after operation. RESULTS: All distal radial fractures were union in 8 weeks to 12 weeks. There were significant differences in radial inclination and radial process height, but not in volar tilt between groups A and B before operation. We found no significant differences in volar tilt, radial inclination, radial process height and Garlant-Werley scores between groups A and B 3 months and 1 year after operation. There were also no significant differences between type I and type II. Fineness was 81%. Complications were found in 6 cases (4 in group A and 2 in group B), in which there were 1 case with a screw cutting-off and traumatic arthritis, 2 cases with sup-nerve injury and 1 case with heterotopic ossification, 1 case of malunion , and 1 case with wrist stiffness and traumatic arthritis. CONCLUSION: ORIF with locking plate in distal radial fracture is safe and effective. There is no significant difference between the outcomes of patients with and without ulnar styloid fractures, also in patients with type I and type II fractures, union or nonunion of fractures, according to the X-ray measurement and Garlant-Werley wrist function scores. However, long-term following-up is still needed.