Sonodynamic therapy suppresses matrix collagen degradation in vulnerable atherosclerotic plaque by modulating caspase 3 - PEDF/HIF-1α - MMP-2/MMP-9 signaling in macrophages.

BACKGROUND: The rupture of vulnerable atherosclerotic plaque is the main cause of acute ischemic vascular events, and is characterized by pathological degradation of matrix collagen in the fibrous cap. In a previous study, we reported that 5-aminolevulinic acid-mediated sonodynamic therapy suppressed collagen degradation in rabbit plaque. However, the underlying molecular mechanism has yet to be fully elucidated. METHODS: We applied sinoporphyrin sodium-mediated sonodynamic therapy (DVDMS-SDT) to balloon-denuded rabbit and apolipoprotein E-deficient (ApoE-/-) mouse models to observe collagen content in plaque. Cultured human THP-1 and mouse peritoneal macrophage-derived foam cells were used for in vitro mechanistic studies. RESULTS: We observed that DVDMS-SDT decreased plaque area and increased the percentages of collagen and smooth muscle cells and reduced the percentage of macrophages in rabbit and ApoE-/- mouse advanced plaques. In vitro, DVDMS-SDT modulated the caspase 3-pigment epithelium-derived factor/hypoxia-inducible factor-1α (PEDF/HIF-1α)-matrix metalloprotease-2/9 (MMP-2/MMP-9) signaling in macrophage foam cells. CONCLUSIONS: Our findings show that DVDMS-SDT effectively inhibits matrix collagen degradation in advanced atherosclerotic plaque by modulating caspase 3-PEDF/HIF-1α-MMP-2/MMP-9 signaling in macrophage foam cells and therefore represents a suitable and promising clinical regimen to stabilize vulnerable plaques.

Perivascular brown adipocytes-derived kynurenic acid relaxes blood vessel via endothelium PI3K-Akt-eNOS pathway.

OBJECTIVE: Several metabolites from the kynurenine pathway of tryptophan metabolism play a critical role in vascular function and vascular wall remodeling. This study aimed to test whether metabolite kynurenic acid (KYNA) from the kynurenine pathway relaxes blood vessels. APPROACH AND RESULTS: We employed histological staining, in vitro cell culture, Western blotting, real-time PCR, and nitric oxide detection to validate kynurenine aminotransferase (KAT) localization in the vasculature as well as KYNA action on endothelial cells. We also detected vascular reactivity by organ chamber and monitored blood pressure by telemetry to investigate the regulation effect of KYNA on vascular tone. The results presented that perivascular adipose tissue (PVAT) from mice thoracic aorta had robust staining of anti-KAT1 and KYNA than PVAT from the abdominal aorta and mesenteric artery, which is consistent with the expression profile of brown adipocyte marker uncoupling protein 1. KYNA, metabolized from kynurenine by KAT, relaxed pre-contracted both aortic ring and mesenteric artery. In addition, KYNA derived from KAT in PVAT participates in the cross-talk between PVAT and vessel by mediating PVAT inhibition on agonist-induced thoracic aorta contraction. Furthermore, intraperitoneal injection of KYNA in mice reduced blood pressure. The vessel relaxation effect of KYNA was through the endothelium-dependent PI3K-Akt-eNOS pathway. Finally, the high-fat diet decreased KAT1 expression in perithoracic aortic fat and led to KYNA reduction in blood. CONCLUSIONS: Our research identified KYNA generated by KAT as a novel perivascular brown adipocyte-derived vascular relaxation factor and suggests that KYNA reduction is a critical event in vascular dysfunction under obese condition.

Optimisation of oral anticoagulants for patients with atrial fibrillation within 12 months after percutaneous coronary intervention: A meta-analysis and systematic review.

BACKGROUND: The optimal antithrombotic strategy, especially regarding oral anticoagulants (OACs) for atrial fibrillation (AF) patients with bleeding and thrombosis risk after percutaneous coronary intervention (PCI), remains unknown. This study explored the optimal oral anticoagulants for AF patients after PCI using a meta-analysis. METHODS: Randomised controlled trials were identified from PubMed, Embase, and the Cochrane Library through December 2020. Risk ratios, 95% confidence intervals, and random-effects models were used to compare different antithrombotic strategies through network meta-analysis, and the combination of antithrombotic agents was ranked according to the surface under the cumulative ranking curve and rankograms. Interval plots were drawn to observe pairwise comparisons between the different strategies. RESULTS: Five studies of 11,532 patients were included. Factor IIa inhibitor 110 mg bid plus a P2Y12 inhibitor had the greatest advantage for reducing Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding; Factor Xa inhibitor plus a P2Y12 inhibitor had the greatest advantage for reducing International Society on Thrombosis and Hemostasis major bleeding. For patients at risk of stroke plus all-cause death, factor IIa inhibitor 150 mg bid plus a P2Y12 inhibitor should be prioritised, and for those at risk of myocardial infarction and stent thrombosis, vitamin K antagonists plus a P2Y12 inhibitor were preferred. CONCLUSION: Factor IIa inhibitor 110 mg, factor IIa inhibitor 150 mg, factor Xa inhibitor and vitamin K antagonists should be selected in different situations.

Combined myocardial deformation to predict cardiac resynchronization therapy response in nonischemic cardiomyopathy.

BACKGROUND: 20-30% of patients do not benefit from cardiac resynchronization therapy (CRT) when the established selection criteria were applied. We hypothesized that a combined assessment of mechanical dyssynchrony, myocardial deformation, and diastolic function would identify patients who would benefit most from CRT. METHOD: In 36 CRT patients, clinical evaluation and echocardiography were performed before and after CRT. Patients were classified into three subgroups according to their amount of response: echocardiographic responders, clinical responders, and nonresponders. Radial dyssynchrony and left ventricular (LV) global longitudinal, radial, and circumferential peak strain was assessed by speckle-tracking image. Diastolic function was quantified by conventional echocardiography. RESULT: In addition to left bundle branch block, nonspecific intraventricular conduction disturbance with intraventricular dyssynchrony could also improve LV remodeling. Echocardiographic responders had better global longitudinal strain, global circumferential peak strain, and global radial strain at baseline which significantly increased at 12-month follow-up. An improvement in estimates of LV filling pressure and a decrease in mitral regurgitation and left atrial dimensions were observed only in echocardiographic responders to CRT. Patients with clinical but without echocardiographic response showed a significant improvement in atrioventricular (AV) synchrony and a nonsignificant improvement in other parameters. The nonresponder group did not improve the AV and intraventricular dyssynchrony. CRT could not improve restrictive filling pattern with normal filling time. Overall, those patients with AV and intraventricular dyssynchrony and those with best contractile function and short diastolic filling time of restrictive filling pattern at baseline demonstrated the greatest benefit from CRT. CONCLUSIONS: Mechanical dyssynchrony, contractile function, and filling pattern are important determinants of the benefits in CRT.

Tumor-suppressing roles of miR-214 and miR-218 in breast cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that are key post-transcriptional regulators of gene expression. MicroRNA-214 (miR-214) and microRNA-218 (miR-218) have shown the function of tumor suppressors in various types of human cancers. However, the biological functions of miR-214 and miR-218 in breast cancer have not been elucidated completely. The present study evaluated the expression and biological function of miR-214 and miR-218 in human breast cancer. Our results revealed that the expression of miR-214 and miR-218 were significantly decreased in breast cancer tissues compared with adjacent tissues. The aberrant expression of miR-214 and miR-218 were negatively associated with Ki-67, and the miR-218 expression was positively associated with progesterone receptor (PR) in breast cancer tissues. In vitro, the cell proliferation and migration were decreased, cell apoptosis was induced, and cell cycle was also disturbed in miR-214 or miR-218 overexpressed breast cancer cells. Our results demonstrated that miR-214 and miR-218 function as tumor suppressors in breast cancer, and may become biomarkers and potential therapeutic targets in breast cancer.

Real-time detection of intracellular reactive oxygen species and mitochondrial membrane potential in THP-1 macrophages during ultrasonic irradiation for optimal sonodynamic therapy.

Reactive oxygen species (ROS) elevation and mitochondrial membrane potential (MMP) loss have been proven recently to be involved in sonodynamic therapy (SDT)-induced macrophage apoptosis and necrosis. This study aims to develop an experimental system to monitor intracellular ROS and MMP in real-time during ultrasonic irradiation in order to achieve optimal effect in SDT. Cultured THP-1 derived macrophages were incubated with 5-aminolevulinic acid (ALA), and then sonicated at different intensities. Intracellular ROS elevation and MMP loss were detected in real-time by fluorospectrophotometer using fluorescence probe DCFH-DA and jc-1, respectively. Ultrasound at low intensities (less than 0.48W/cm(2)) had no influence on ROS and MMP in macrophages, whereas at an intensity of 0.48W/cm(2), ROS elevation and MMP loss were observed during ultrasonic irradiation. These effects were strongly enhanced in the presence of ALA. Quantitative analysis showed that ROS elevation and MMP loss monotonically increased with the rise of ultrasonic intensity between 0.48 and 1.16W/cm(2). SDT at 0.48 and 0.84W/cm(2) induced mainly apoptosis in THP-1 macrophages while SDT at 1.16W/cm(2) mainly cell necrosis. This study supports the validity and potential utility of real-time ROS and MMP detection as a dosimetric tool for the determination of optimal SDT.

Nup88 mRNA overexpression in colorectal cancers and relationship with p53.

OBJECTIVES: We measured nucleoporin 88 (Nup88) mRNA expression in primary colorectal cancers to investigate its relationship with clinicopathological features and p53. METHODS: The primary cancer tissues, adjacent noncancerous tissues and the proximal and distant margins of normal mucosa were collected from 73 colorectal cancer patients during surgery. Nup88 mRNA expression was measured on these fresh specimens and on colon cell lines HCT-116^{p53 + / + } and HCT-116^{p53 - / - } by RT-PCR while p53 mRNA and ß-actin as controls. Nup88 and p53 protein expression were then immunohistochemistrically examined in other 25 colorectal cancers specimens paraffin embedded and formalin fixed. RESULTS: Nup88 expression was higher in primary cancer tissues than in adjacent noncancerous tissues, and in the proximal and distant margins of normal mucosa. Overexpression of Nup88 mRNA was statistically associated with TNM stage (P=0.044), lymphatic metastasis (P=0.022), and cancer location (P=0.036), while not related to gender, age of patients and histological type, infiltration depth, and differentiation of cancers. The expression of Nup88 mRNA in the HCT-116^{p53 - / - } cell line was not significantly different from expression in the HCT-116^{p53 + / +}cell line. And there was no correlation between Nup88 and p53 protein expression (r=0.632, P=0.368). CONCLUSIONS: Nup88 mRNA was overexpressed in colorectal cancers and the overexpression was associated with cancer development and aggressiveness. Nup88 might be regard as essential contributor to nodal metastagenicity of colorectal cancer.

[Effect of ulinastatin on intestinal mucosal barrier function of rats with obstructive jaundice].

OBJECTIVE: To investigate the effect of ulinastatin on intestinal mucosal barrier function of rats with obstructive jaundice. METHODS: Seventy-two male SD rats were randomly divided into sham operation, obstructive jaundice, and ulinastatin treatment groups (groups A, B, and C, respectively). In groups B and C, the common bile duct was ligated to induce obstructive jaundice. The rats in group C were given intraperitoneal injection of ulinastatin at the daily dose of 40,000 IU/kg after the operation, while those in groups A and group B received equal amount of normal saline. At 3, 5, 7 and 10 days after the operation, the liver function and plasma endotoxin level were evaluated and measured, and bacterial culture of the mesenteric lymph nodes, liver and spleen was performed. The terminal ileum mucosa was observed under light microscope, and the intestinal villi and mucosal thinckness was examined with image analysis system. RESULTS: The indices relative to the liver function and plasma endotoxin level were higher at different time points of observation in group B than in group A (P<0.01), and were lower in group C than in group B (P<0.01). Plasma endotoxin level was similar between groups A and C 3 days after the operation (P>0.05). The rate of bacterial translocation was higher in group B than in group A and C (P<0.01, P<0.05), but comparable between groups A and C (P>0.05). Intestinal mucosal injury was observed in group B 3 days after operation, and aggravated with the passage of time. The injury was milder in group C. The intestinal villus length and mucosal thickness were greater in groups A and C than in group B (P<0.01 or P<0.05), but comparable between the former two groups 3 days after operation (P>0.05). CONCLUSION: In early stage of obstructive jaundice, the intestinal mucosal barrier may sustain injuries which aggravate with time; ulinastatin has significant effect in protecting the mucosal barrier function especially against early pathological changes.