Introduction
Emmanuel Opara in NUTRITION and DIABETES, 2005
AGEs independently increase the production of oxygen-derived free radicals and also autoactivate the AGE receptor (RAGE). AGEs are found in increased amounts in diabetic retinal vessels and renal glomeruli, and, as such, likely play a role in the microvascular complications of diabetes. AGEs were originally thought to arise from nonenzymatic reactions between extracellular proteins and glucose, but it now seems likely that intracellular hyperglycemia is the primary initiating event in the formation of both intracellular and extracellular AGE. The importance of AGEs in the pathogenesis of diabetic complications is indicated by the observation in animal models that AGE inhibitors partially prevented various functional and structural manifestations of diabetic microvascular disease in the retinal, kidney, and nerve. In a multicenter trial, the AGE inhibitor aminoguanidine slowed the progression of nephropathy in type 1 diabetic patients [30].
Diabetes and the Microcirculation
John H. Barker, Gary L. Anderson, Michael D. Menger in Clinically Applied Microcirculation Research, 2019
Several agents show promise for the future treatment of diabetic microvascular complications. The aldose reductase inhibitors, which inhibit polyol pathway activity, have shown marked benefits in experimental diabetes. In contrast, studies in human subjects have so far been disappointing and there have been problems with toxic side effects; however, most studies to date have looked at aldose reductase inhibitors in established microvascular disease and it may be that they are more effective in prevention. In neuropathy, regeneration and repair of myelinated fibers have been observed in sural nerve biopsy specimens from patients treated with sorbinil,66 and decreased glomerular hyperfiltration has been seen with ponalrestat.67 Another treatment that has shown great promise in experimental diabetes is inhibition of the advanced stages of protein glycation using aminoguanidine; however, no clinical trials have yet been reported using this agent.
Nerve and Retinal Changes in Experimental Diabetes
John H. McNeill in Experimental Models of Diabetes, 2018
The STZ-induced diabetic rat is the most extensively studied diabetic rat model. Early microangiopathic lesions, such as basement membrane thickening, loss of capillary pericytes, acellular capillaries, endothelial cell proliferation, and rare microaneurysms,244–248 are demonstrated. Euglycemia achieved by pancreatic islet cell transplantation can prevent microangiopathic changes in STZ diabetic rats.248,249 In STZ diabetic rats, increased permeability across the retinal pigment epithelium due to breakdown of the blood retinal barrier in association with structural alterations of the retinal pigment epithelium was observed. These changes are preventable by tight control of blood glucose by insulin therapy and syngeneic islet cell transplantation.250–252 Progressive intracellular AGE accumulation is associated with pericyte loss in STZ diabetic rats.253 Aminoguanidine, an inhibitor of nonenzymatic glycation, is only effective in preventing the late changes of diabetic retina, suggesting that AGE-associated changes are time dependent.
Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Bing Wang, Teng Liu, Zhongyu Wu, Lei Zhang, Jie Sun, Xiaojing Wang
To prepare the AGE reaction solution, 10 mg/ml of bovine serum albumin in 50 mM PBS (pH 7.4) was added to 0.2 M glucose, and 0.02% sodium azide was added to prevent bacterial growth. The reaction mixture (3 ml) was then mixed with various concentrations (0.5–1000 µg/ml) of the target compounds (1 ml) dissolved in DMSO. After incubating at 37 °C for 14 d, the fluorescence intensity of AGE was determined by a fluorospectrophotometer (PE, Cincinnati, OH) with excitation and emission wavelengths at 350 nm and 420 nm30, respectively. All experiments were run in triplicate. Aminoguanidine hydrochloride was used as a reference compound. The inhibition rate of AGEs formation and the IC50 value of each sample were calculated according to the formula. AC is the absorbance of control group (1.0 ml glucose +1.0 ml bovine serum albumin +1.0 ml sodium azide +1.0 ml DMSO); AB is the absorbance of blank group (1.0 ml PBS +1.0 ml bovine serum albumin +1.0 ml sodium azide +1.0 ml DMSO); AS is the absorbance of sample group (1.0 ml glucose +1.0 ml bovine serum albumin +1.0 ml sodium azide +1.0 ml target compound solution or aminoguanidine hydrochloride solution); ASB is the absorbance of sample blank group (1.0 ml PBS +1.0 ml bovine serum albumin +1.0 ml sodium azide +1.0 ml target compound solution or aminoguanidine hydrochloride solution).
3-Arylcoumarin inhibits vascular calcification by inhibiting the generation of AGEs and anti-oxidative stress
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
YuFei Li, Yinbo Pan, Liying Wang, Xiaojing Wang, Haiping Chu, Yan Li, Jie Sun, Yanling Mu
Cells were seeded on a 24-well plate at a density of 5.0 × 104 cells/well, and the normal control group (HASMCs normal culture), vehicle control group (HASMCs + 5‰ DMSO), and calcification induction group (HASMCs + 100 mg/L AGEs-BSA), negative control group (HASMCs + 100 mg/L AGEs-BSA +5‰ DMSO), positive control group (HASMCs + 100 mg/L AGEs-BSA +5‰ DMSO + AGH6.25 mg/L), compounds 1–44 In the interference group (HASMCs + 100 mg/L AGEs-BSA + 5‰ DMSO + compound 6.25 mg/L), after the cell culture of each group is completed, it is determined according to the alkaline phosphatase activity determination kit. (Note: Aminoguanidine hydrochloride is an inhibitor of AGEs production. Studies have shown that it can inhibit the glycosylation modification of proteins in the body and has obvious preventive and therapeutic effects on diabetic vascular complications18. After the MTT assay, DMSO at this concentration had no significant effect on cell proliferation rate).
Ezetimibe attenuates experimental diabetes and renal pathologies via targeting the advanced glycation, oxidative stress and AGE-RAGE signalling in rats
Published in Archives of Physiology and Biochemistry, 2023
Rabia Nabi, Sahir Sultan Alvi, Arunim Shah, Chandra P. Chaturvedi, Mohammad Faisal, Abdulrahman A. Alatar, Saheem Ahmad, M. Salman Khan
Although the implication of aminoguanidine, standard inhibitor of in-vitro AGEs formation (Nabi et al.2018), has showed various adverse effects in different experimental settings i.e. cell culture, animal models studies and human clinical trials in diabetic kidney disease (Bolton et al.2004, Nabi et al.2019b), the development of anti-AGE therapeutic approach remains open for the management of DN. Ezetimibe (EZ) is well reckoned for its pleiotropic pharmacological actions i.e. diminishing the circulatory lipid levels via inhibition of intestinal cholesterol absorption, maintaining redox balance, and inflammatory markers in diabetic and ASCVD patients (Sarigianni et al.2010, Giugliano et al.2018). However, a latest report suggested that administration of EZ also decreases the insulin resistance in patients suffering with metabolic syndrome (Nakamura et al.2019). Recently, we demonstrated that EZ exhibits strong in-vitro anti-glycation potential as well as also protects HEK-293 cells against LDL-AGEs-stimulated reactive oxygen species (ROS) generation and AGEs-RAGE-associated signalling (Nabi et al.2018, 2019b). Except our recent in-vitro findings, there is no report that documented the in-vivo effect of EZ on AGEs-induced diabetic microvascular complications. Therefore, in continuation of our above findings, the current in-vivo study was premeditated to uncover the protective role of EZ against the AGEs-related pathologies via targeting distinct biochemical markers and AGEs-RAGE-associated signalling in experimental diabetic rat model.
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