4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione has been researched along with Acute-Disease* in 3 studies
1 trial(s) available for 4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Acute-Disease
2 other study(ies) available for 4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Acute-Disease
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Specific deletion of glycogen synthase kinase-3β in the renal proximal tubule protects against acute nephrotoxic injury in mice.
Renal proximal tubular damage and repair are hallmarks of acute kidney injury. As glycogen synthase kinase-3β (GSK3β) is an important cellular regulator of survival and proliferation, we determined its role during injury and recovery of proximal tubules in a mercuric chloride-induced nephrotoxic model of acute kidney injury. Renal proximal tubule-specific GSK3β knockout mice exposed to mercuric chloride had improved survival and renal function compared to wild-type mice. Apoptosis, measured by TUNEL staining, Bax activation, and caspase 3 cleavage, was reduced in the knockout mice. The restoration of renal structure, function, and cell proliferation was also accelerated in the GSK3β knockout mice. This enhanced repair, evidenced by increased Ki-67 and BRDU staining, along with increased cyclin D1 and c-myc levels, was recapitulated by treatment of wild-type mice with the small-molecule GSK3 inhibitor TDZD-8 following injury. This confirmed that hastened repair in the knockout mice was not merely due to lower initial injury levels. Thus, inhibition of GSK3β prior to nephrotoxic insult protects from renal injury. Such treatment after acute kidney injury may accelerate repair and regeneration. Topics: Acute Disease; Acute Kidney Injury; Animals; Anti-Infective Agents, Local; Apoptosis; Cell Proliferation; Disease Models, Animal; Female; Gene Deletion; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Kaplan-Meier Estimate; Kidney Tubules, Proximal; Mercuric Chloride; Mice; Mice, Inbred C57BL; Mice, Knockout; Thiadiazoles | 2012 |
Effects of glycogen synthase kinase-3beta inhibition on the development of cerulein-induced acute pancreatitis in mice.
Glycogen synthase kinase (GSK)-3 is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. It also plays an important role in the pathophysiology of a number of diseases characterized by an enhanced or unregulated inflammatory response. Here we investigate the effects of GSK-3beta inhibition on the development of experimental acute pancreatitis induced by cerulein in mice.. Prospective, randomized study.. University-based research laboratory.. One-hundred and sixty anesthetized male CD mice.. Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 microg/kg). In the treatment group, the potent and selective GSK-3beta inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered 1 hr and 6 hrs after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL of 0.9% NaCl, intraperitoneally) and TDZD-8. In another set of experiments, mice were monitored for 24 days to determine their mortality rate.. The injection of cerulein resulted in acute necrotizing pancreatitis. TDZD-8 significantly reduced the degree of pancreas injury, amylase, and lipase serum levels (p < .01); nuclear factor-kappaB activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-1beta (p < .01); the expression of adhesion molecules and neutrophil accumulation (p < .01); the formation of oxygen and nitrogen-derived radicals (p < .01); the degree of lipid peroxidation (p < .01); the expression of transforming growth factor-beta and vascular endothelial growth factor (p < .01); and-ultimately-the mortality rate (p < .01).. Inhibition of GSK-3beta reduces the degree of cerulein-induced acute pancreatitis and the associated mortality rate in mice. Blocking protein kinase activity may be a novel approach to treatment of this inflammatory condition. Topics: Acute Disease; Animals; Cell Adhesion Molecules; Ceruletide; Cytokines; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred Strains; Neutrophil Activation; NF-kappa B; Oxidative Stress; Pancreatitis; Prospective Studies; Random Allocation; Survival Analysis; Thiadiazoles | 2007 |