ABSTRACT
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-ß-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-ß-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
Subject(s)
Cellular Senescence , Diabetes Mellitus, Experimental , Fibroblast Growth Factors , Inflammasomes , Mice, Inbred C57BL , Muscle, Smooth, Vascular , NLR Family, Pyrin Domain-Containing 3 Protein , PPAR gamma , Signal Transduction , Syk Kinase , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Syk Kinase/metabolism , Syk Kinase/genetics , PPAR gamma/metabolism , PPAR gamma/genetics , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Inflammasomes/metabolism , Mice , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Male , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathologyABSTRACT
PURPOSE: This systematic analysis was conducted to evaluate the efficacy and safety of pemetrexed based salvage chemotherapy for treatment of patients with metastatic colorectal cancer. METHODS: Clinical studies evaluating the efficacy and safety of pemetrexed based regimens on response and safety for patients with colorectal cancer were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. RESULTS: For pemetrexed based regimens, 4 clinical studies including 201 patients with advanced colorectal cancer were considered eligible for inclusion. The analysis suggested that, in all patients, pooled RR was 20.4% (41/201). Major adverse effects were neutropenia, anorexia, fatigue, and anemia. No treatment related death occurred with pemetrexed based treatment. CONCLUSION: This systematic analysis suggests that pemetrexed based regimens are associated with mild activity with good tolerability in treating patients with metastatic colorectal cancer.