Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure.

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure. Mesothelial cell loss is an initiating event for peritoneal fibrosis. We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E, driving downstream inflammatory responses, including the activation of macrophages. Moreover, pyroptosis is associated with elevated vascular endothelial growth factor A and C, two key factors in vascular angiogenesis and lymphatic vessel formation. GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure. Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action, and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy. Mechanistically, melatonin treatment maintains mitochondrial integrity in mesothelial cells, meanwhile activating mTOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate. These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress. Thus, Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

Ten-Year Outcomes of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Patients with Type 2 Diabetes Mellitus Suffering from Left Main Coronary Disease: A Meta-Analysis.

INTRODUCTION: In this meta-analysis, we aimed to systematically compare the 10-year outcomes of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in patients with type 2 diabetes mellitus (T2DM) suffering from left main coronary artery disease (LMCD). METHODS: Medical Literature Analysis and Retrieval System Online (MEDLINE), http://www.ClinicalTrials.gov , Excerpta Medica dataBASE (EMBASE), Cochrane Central, Web of Science, and Google scholar were searched for publications comparing 10-year outcomes of PCI versus CABG in patients with T2DM suffering from LMCD. Cardiovascular outcomes were considered as the clinical endpoints. Statistical analysis was carried out using RevMan software (version 5.4). Risk ratios (RR) with 95% confidence intervals (CI) were used to represent the data after analysis. RESULTS: Eight studies (three randomized trials and five observational studies) with a total number of 3835 participants with T2DM were included in this analysis; 2340 participants were assigned to the PCI group and 1495 participants were assigned to the CABG group. Results of this analysis showed that mortality (RR 0.85, 95% CI 0.73-1.00; P = 0.05), myocardial infarction (RR 0.53, 95% CI 0.35-0.80; P = 0.002), repeated revascularization (RR 0.34, 95% CI 0.26-0.46; P = 0.00001), and target vessel revascularization (RR 0.26, 95% CI 0.18-0.38; P = 0.00001) were significantly higher with PCI when compared to CABG in these patients with diabetes and LMCD. Major adverse cardiac and cerebrovascular events were also significantly higher with PCI at 10 years (RR 0.67, 95% CI 0.49-0.92; P = 0.01). However, CABG was associated with a significantly higher risk of stroke (RR 2.16, 95% CI 1.39-3.37; P = 0.0007). CONCLUSIONS: During a long-term follow-up time period of 10 years, PCI was associated with worse clinical outcomes compared to CABG in these patients with T2DM suffering from LMCD. However, a significantly higher risk of stroke was observed with CABG. This piece of information might be vital in order to carefully choose and prevent complications following revascularization in such patients.