2020) MiR155-5p in adventitial fibroblastsderived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing ABSTRACT Proliferation of vascular smooth muscle cells (VSMCs) plays crucial roles in vascular remodelling and stiffening in hypertension. Vascular adventitial fibroblasts are a key regulator of vascular wall function and structure. This study is designed to investigate the roles of adventitial fibroblasts-derived extracellular vesicles (EVs) in VSMC proliferation and vascular remodelling in normotensive Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR), an animal model of human essential hypertension. EVs were isolated from aortic adventitial fibroblasts of WKY (WKY-EVs) and SHR (SHR-EVs). Compared with WKY-EVs, miR155-5p content was reduced, while angiotensin-converting enzyme (ACE) content was increased in SHR-EVs. WKY-EVs inhibited VSMC proliferation of SHR, which was prevented by miR155-5p inhibitor. SHR-EVs promoted VSMC proliferation of both strains, which was enhanced by miR155-5p inhibitor, but abolished by captopril or losartan. Dual luciferase reporter assay showed that ACE was a target gene of miR155-5p. MiR155-5p mimic or overexpression inhibited VSMC proliferation and ACE upregulation of SHR. WKY-EVs reduced ACE mRNA and protein expressions while SHR-EVs only increased ACE protein level in VSMCs of both strains. However, the SHR-EVs-derived from the ACE knockdown-treated adventitial fibroblasts lost the roles in promoting VSMC proliferation and ACE upregulation. Systemic miR155-5p overexpression reduced vascular ACE, angiotensin II and proliferating cell nuclear antigen levels, and attenuated hypertension and vascular remodelling in SHR. Repetitive intravenous injection of SHR-EVs increased blood pressure and vascular ACE contents, and promoted vascular remodelling in both strains, while WKY-EVs reduced vascular ACE contents and attenuated hypertension and vascular remodelling in SHR. We concluded that WKY-EVs-mediated miR155-5p transfer attenuates VSMC proliferation and vascular remodelling in SHR via suppressing ACE expression, while SHR-EVs-mediated ACE transfer promotes VSMC proliferation and vascular remodelling. ARTICLE HISTORY
Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients.
Objective: To assess the effectiveness of tele-monitored cardiac rehabilitation in patients who have undergone ablation for atrial fibrillation. Design: Single-centre, prospective, assessment-blinded, randomised controlled trial. Setting: Domiciliary rehabilitation with support from a tertiary care hospital. Subjects: One hundred patients who underwent ablation for atrial fibrillation were recruited. Interventions: Participants were randomly allocated to a 12-week standard rehabilitation treatment (control group) or a comprehensive, domiciliary, mobile application-guided and tele-monitored cardiac rehabilitation program (intervention group) in a 1:1 fashion. Main outcome measures: The primary endpoint was the improvement in VO2peak. The secondary outcomes included adherence, physical activity, beliefs related to cardiovascular disease and exercise self-efficacy. Results: Ninety-seven patients completed follow-up. The mean VO2peak increased significantly in both the intervention group ( n = 49) (baseline vs 12 weeks: 19.1 ± 4.7 vs 27.3 ± 5.6 ml/(min kg), P < 0.01) and the control group ( n = 48) (baseline vs 12 weeks: 18.7 ± 4.9 vs 22.9 ± 6.3 ml/(min kg), P < 0.01). The results of the between-group analysis of aerobic capacity were significantly in favour of the intervention group. During the 12-week program, patients in the intervention group exhibited better adherence than those in the control group. Moreover, self-reported physical activity improved more in the intervention group than in the control group, as did the beliefs related to cardiovascular disease and exercise self-efficacy (all P < 0.01). Conclusions: Our domiciliary, mobile application-guided and tele-monitored cardiac rehabilitation program could lead to a more significant improvements in physical fitness, adherence and health beliefs than standard cardiac rehabilitation in patients who have undergone ablation for atrial fibrillation.
CYP24A1 is overexpressed in colorectal cancer, and the reason for the dysregulation of CYP24A1 in colorectal cancer is still unknown. In the present study, experiments were designed to test whether CYP24A1 inhibition facilitated the antiproliferative effect of 1,25(OH)D. In addition, the role of methylation in the regulation of CYP24A1 expression in human colorectal cancer was investigated. The expression of CYP24A1 in SW480 and Caco2 colorectal cancer cells was inhibited by RNAi. CYP24A1 inhibition significantly increased the antiproliferative effects of 1,25(OH)D in SW480 cells compared with 1,25(OH)D treatment alone (16.78% ± 2.08% vs. 33.53% ± 2.47%, p < 0.05). In addition, CYP24A1 inhibition sensitized Caco2 cells to 1,25(OH)D. We also found that CYP24A1 inhibition induced β-catenin to translocate from the nucleus to the plasma membrane in SW480 cells and enhanced the inhibitory effect of 1,25(OH)D on C-myc. Furthermore, CYP24A1 mRNA expression in Caco2 cells was increased after demethylation treatment, and the expression of CYP24A1 induced by 1,25(OH)D was significantly higher in cells treated with 5-aza-2'-deoxycytidine (DAC) than in an untreated group. In conclusion, inhibition of CYP24A1 expression enhances the antitumor effect of 1,25(OH)D in colorectal cancer, and DNA methylation is involved in the regulation of CYP24A1 expression in a cell-dependent manner.
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