Niclosamide modulates phenotypic switch and inflammatory responses in human pulmonary arterial smooth muscle cells.

Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key steps of pulmonary vascular remodeling, leading to the development of pulmonary arterial hypertension (PAH) and right ventricular failure. Niclosamide (NCL), an FDA-approved anthelmintic, has been shown to regulate cell proliferation, migration, invasion, and apoptosis through a variety of signaling pathways. However, its role on modulating the phenotypic switch and inflammatory responses in PASMCs remains unclear. In this study, cell proliferation assay showed that NCL inhibited PDGF-BB induced proliferation of human PASMCs in a dose-dependent manner. Western blot analysis further confirmed a notable reduction in the expression of cyclin D1 and PCNA proteins. Subsequently, flow cytometry analysis demonstrated that NCL induced an increased percentage of cells in the G1 phase while promoting apoptosis in PASMCs. Moreover, both scratch wound assay and transwell assay confirmed that NCL decreased PDGF-BB-induced migration of PASMCs. Mechanistically, western blot revealed that pretreatment of PASMCs with NCL markedly restored the protein levels of SMA, SM22, and calponin, while reducing phosphorylation of P38/STAT3 signaling in the presence of PDGF-BB. Interestingly, macrophages adhesion assay showed that NCL markedly reduced recruitment of Calcein-AM labeled RAW264.7 by TNFα-stimulated PASMCs. Western blot revealed that NCL suppressed TNFα-induced expression of both of VCAM-1 and ICAM-1 proteins. Furthermore, pretreatment of PASMCs with NCL significantly inhibited NLRP3 inflammasome activity through reducing NLRP3, AIM2, mature interleukin-1ß (IL-ß), and cleaved Caspase-1 proteins expression. Together, these results suggested versatile effects of NCL on controlling of proliferation, migration, and inflammatory responses in PASMCs through modulating different pathways, indicating that repurposing of NCL may emerge as a highly effective drug for PAH treatment.

An updated meta-analysis of device related thrombus following left atrial appendage closure in patients with atrial fibrillation.

Aims: Device related thrombus (DRT) is a known complication of left atrial appendage closure (LAAC). However, the relation between DRT and elevated risk of ischemic events remains controversial. This study is sought to reassessed the incidence of DRT following LAAC and the relation between DRT and elevated risk of ischemic stroke and systemic embolism (SE) with latest clinical trials included. Methods: The PubMed, Embase, and Cochrane Library databases were systematically searched from their inception until April 2022 for studies that reported the incidence of DRT and compared the incidence of both stroke and SE between DRT patients and non-DRT patients. Results: In 59 eligible studies, the incidence of DRT was 366/12,845 (2.8%, ranging from 0 to 11%, I 2 = 64%). The incidence of DRT was not statistically different between single-seal device (SS) and dual-seal device (DS) in subgroup analysis [171/6,190 (2.8%) vs. 78/3,023 (3.6%); p = 0.93]. The pooled incidence of stroke (26 studies, 7,827 patients) in patients with and without DRT was 11.5% in DRT patients and 2.9% among non-DRT patients (OR: 5.08; 95% CI = 3.47-7.44). In the sensitivity analysis, DRT was associated with higher rate of stroke (12.1 vs. 3.2%; OR: 4.14; 95% CI = 2.69-6.38) and SE (16.0 vs. 3.8%; OR: 4.48; 95% CI = 3.04-6.62). Conclusion: The incidence of DRT was low and similar between SS and DS devices. DRT was associated with increased rates of ischemic events. The occurrence rate of ischemic events associated DRT was comparable between two occlusion mechanism devices. Systematic review registration: [https://www.crd.york.ac.uk/], identifier [CRD42022326179].

Detection and miss rates of autofluorescence imaging of adenomatous and polypoid lesions during colonoscopy: a systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: Autofluorescence imaging (AFI) is an endoscopic imaging technique used to increase the detection of premalignant gastrointestinal lesions, and it has gradually become popular in recent years. This meta-analysis was performed to examine whether AFI provides greater efficacy in the detection of adenomatous and polypoid lesions and can even prevent the failure to detect a single adenoma or polyp. The aim of the study was to systematically review the efficacy of AFI in increasing detection rates and decreasing miss rates. METHODS: Pertinent articles were identified through a search of databases up to December 2013 that included patients who had undergone two same-day colonoscopies (AFI and white light endoscopy [WLE]), followed by polypectomy. Fixed and random effects models were used to detect significant differences between AFI and WLE in regard to adenoma detection rate (ADR), polyp detection rate (PDR), adenoma miss rate (AMR), polyp miss rate (PMR), and procedural time. RESULTS: A total of 1199 patients from six eligible studies met the inclusion criteria. No significant differences were found in ADR (odds ratio [OR] 1.01; 95 % confidence interval [95 %CI] 0.74 - 1.37), PDR (OR 0.86; 95 %CI 0.57 - 1.30), or advanced ADR (OR 1.22; 95 %CI 0.69 - 2.17). The AMR (OR 0.62; 95 %CI 0.44 - 0.86) and PMR (OR 0.64; 95 %CI 0.48 - 0.85) by AFI were significantly lower than those by WLE. The procedural time of AFI was significantly longer than that of WLE (mean 8.00 minutes; 95 %CI 1.59 - 14.41). Subgroup meta-analysis for the other characteristics was not performed because of insufficiency of the primary data. CONCLUSIONS: AFI decreases AMR and PMR significantly compared with WLE but does not improve ADR or PDR. AMR and PMR may be decreased by using AFI in flat and small lesions or when less experienced endoscopists perform the procedure.