Maxel rage 25 hl8/18/2023 ![]() (C) mRNA expression of pro-inflammatory factors, IL-1β, TNF-α and MCP-1, and anti-inflammatory factors, IL-10 and MRC1 was measured in human primary macrophages after stimulation with HG and recombinant human S100A9 (rhS100A9) for 6 hours (n=8 PBMC donors). (B) S100A9 levels in supernatants of human primary macrophages were measured by ELISA after administration with NG and HG condition for 24 hours (n = 17 PBMC donors). The graph shows the signal intensity of S100A9 / β-actin ratio (n = 7 PBMC donors). These blots from one donor are representative of the 7 PBMC donors. (A) mRNA and protein expression of S100A9 were measured in human primary macrophages after administration with normal glucose (NG 5 mmol/L glucose) and high glucose (HG 25 mmol/L glucose) by real-time quantitative polymerase chain reaction (qPCR) (left, administered for 6 hours, n = 16 PBMC donors) and Western blot (right, administered for 24 hours). ![]() Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within atherosclerotic plaques.Ītherosclerosis diabetes mellitus extracellular vesicles macrophages vascular calcification. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification. In addition, streptozotocin-induced diabetic Apoe -/-S100a9 -/- mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, P<0.001) in macrophages. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. ![]() 8 Department of Human Pathology, Sechenov First Moscow State Medical University, Russia (E.A.).7 Department of Biomedical Engineering, The City College of New York (L.C., S.W.).6 Institutes for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge (D.G.A.).5 Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University (A.M.S.).4 Regina Qu'Appelle Health Region, University of Saskatchewan, Regina, Canada (D.K.).3 Department of Biology, University of Regina, Saskatchewan, Canada (J.B.).2 Center for Interdisciplinary Cardiovascular Sciences (H.H., M.C.B., S.A.S., M.A., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.1 From the Center for Excellence in Vascular Biology (R.K., S.K., R.T., D.C.R., D.B.-G., L.S.A.P., G.K.S., P.L., M.A., K.C., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. ![]() For the bigger models F60H(L) ,F70H(L) ,The side plate holding the gear box is thinner and lighter ,but still retain its rigidity. The shaft coating has also been upgraded from brass to aluminum. The newly-designed handle shaft has an additional bearing to provide more and smoother cranking power. The modified EVA oval knobs are lighter weight and more user-friendly ![]() The side plate is now machined in an arc shape to provide more comfortable grip ![]()
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