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1
Canning, Paul, Josephine V. Glenn, Daniel K. Hsu, Fu-Tong Liu, Tom A. Gardiner, and Alan W. Stitt. "Inhibition of Advanced Glycation and Absence of Galectin-3 Prevent Blood-Retinal Barrier Dysfunction during Short-Term Diabetes." Experimental Diabetes Research 2007 (2007): 1–10. http://dx.doi.org/10.1155/2007/51837.
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Breakdown of the inner blood-retinal barrier (iBRB) occurs early in diabetes and is central to the development of sight-threatening diabetic macular edema (DME) as retinopathy progresses. In the current study, we examined how advanced glycation end products (AGEs) forming early in diabetes could modulate vasopermeability factor expression in the diabetic retina and alter inter-endothelial cell tight junction (TJ) integrity leading to iBRB dysfunction. We also investigated the potential for an AGE inhibitor to prevent this acute pathology and examined a role of the AGE-binding protein galectin-3 (Gal-3) in AGE-mediated cell retinal pathophysiology. Diabetes was induced in C57/BL6 wild-type (WT) mice and in Gal-3−/−transgenic mice. Blood glucose was monitored and AGE levels were quantified by ELISA and immunohistochemistry. The diabetic groups were subdivided, and one group was treated with the AGE-inhibitor pyridoxamine (PM) while separate groups of WT and Gal-3−/−mice were maintained as nondiabetic controls. iBRB integrity was assessed by Evans blue assay alongside visualisation of TJ protein complexes via occludin-1 immunolocalization in retinal flat mounts. Retinal expression levels of the vasopermeability factor VEGF were quantified using real-time RT-PCR and ELISA. WT diabetic mice showed significant AGE -immunoreactivity in the retinal microvasculature and also showed significant iBRB breakdown (P<.005). These diabetics had higher VEGF mRNA and protein expression in comparison to controls (P<.01). PM-treated diabetics had normal iBRB function and significantly reduced diabetes-mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM-treated diabetics demonstrated near-normal configuration. Gal-3−/−mice showed significantly less diabetes-mediated iBRB dysfunction, junctional disruption, and VEGF expression changes than their WT counterparts. The data suggests an AGE-mediated disruption of iBRB via upregulation of VEGF in the diabetic retina, possibly modulating disruption of TJ integrity, even after acute diabetes. Prevention of AGE formation or genetic deletion of Gal-3 can effectively prevent these acute diabetic retinopathy changes.
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Muthenna, Puppala, Chandrasekhar Akileshwari, and G. Bhanuprakash Reddy. "Ellagic acid, a new antiglycating agent: its inhibition of Nϵ-(carboxymethyl)lysine." Biochemical Journal 442, no. 1 (January 27, 2012): 221–30. http://dx.doi.org/10.1042/bj20110846.
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Non-enzymatic glycation is a complex series of reactions between reducing sugars and amino groups of proteins. Accumulation of AGEs (advanced glycation end-products) due to non-enzymatic glycation has been related to several diseases associated with aging and diabetes. The formation of AGEs is accelerated in hyperglycaemic conditions, which alters the structure and function of long-lived proteins, thereby contributing to long-term diabetic complications. The present study describes AGE inhibition and the mechanism of action of a new antiglycating agent, EA (ellagic acid), a flavonoid present in many dietary sources. Inhibition of AGE formation by EA was demonstrated with different proteins, namely eye lens TSP (total soluble protein), Hb (haemoglobin), lysozyme and BSA, using different glycating agents such as fructose, ribose and methylglyoxal by a set of complementary methods. These results suggest that the antiglycating action of EA seems to involve, apart from inhibition of a few fluorescent AGEs, predominantly inhibition of CEL [Nϵ-(carboxyethyl)lysine] through scavenging of the dicarbonyl compounds. Furthermore, MALDI–TOF-MS (matrix-assisted laser-desorption ionisation–time-of-flight MS) analysis confirms inhibition of the formation of CEL on lysozyme on in vitro glycation by EA. Prevention of glycation-mediated β-sheet formation in Hb and lysozyme by EA confirm its antiglycating ability. Inhibition of glycosylated Hb formation in human blood under ex vivo high-glucose conditions signifies the physiological antiglycating potential of EA. We have also determined the effectiveness of EA against loss of eye lens transparency through inhibition of AGEs in the lens organ culture system. These findings establish the antiglycating potential of EA and its in vivo utility in controlling AGE-mediated diabetic pathologies.
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Rehman, Shahnawaz, Mohammad Faisal, Abdulrahman A. Alatar, and Saheem Ahmad. "Physico-chemical Changes Induced in the Serum Proteins Immunoglobulin G and Fibrinogen Mediated by Methylglyoxal." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 916–23. http://dx.doi.org/10.2174/1389203720666190618095719.
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Background: Non-enzymatic glycation of proteins plays a significant role in the pathogenesis of secondary diabetic complications via the formation of advanced glycation end products (AGEs) and increased oxidative stress. Methylglyoxal (MG), a highly reactive dicarbonyl of class α-oxoaldehyde that generates during glucose oxidation and lipid peroxidation, contributes to glycation. Objective: This comparative study focuses on methylglyoxal induced glycoxidative damage suffered by immunoglobulin G (IgG) and fibrinogen, and to unveil implication of structural modification of serum proteins in diabetes-associated secondary complications. Methods: The methylglyoxal induced structural alterations in IgG and fibrinogen were analyzed by UVvis, fluorescence, circular dichroism and Fourier transform infrared (FT-IR) spectroscopy. Ketoamine moieties, carbonyl contents, 5-Hydroxymethylfurfural (HMF) and malondyaldehyde were also quantified. Free lysine and arginine estimation, detection of non-fluorogenic carboxymethyllysine (CML) and fibril formation were confirmed by thioflavin T (ThT) assay. Results: Structural alterations, increased carbonyl contents and ketoamines were reported in MG glycated IgG and fibrinogen against their native analogues. Conclusion: The experiment results validate structural modifications, increased oxidative stress and AGEs formation. Thus, we can conclude that IgG-AGEs and Fib-AGEs formed during MG induced glycation of IgG and fibrinogen could impede normal physiology and might initiates secondary complications in diabetic patients.
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Furtak, Kh Ye, H. Ya Hachkova, and N. O. Sybirna. "The effect of Galega officinalis L. extract on the content of the advanced glycation end products and their receptors in rat leukocytes under experimental diabetes mellitus." Studia Biologica 15, no. 4 (December 2021): 49–58. http://dx.doi.org/10.30970/sbi.1504.672.
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Background. Diabetes mellitus intensifies non-enzymatic glycosylation (glycation) of biomolecules under conditions of chronic hyperglycemia and facilitates accumulation of advanced glycation end products. Disorders of the cells of various tissues are caused by binding of advanced glycation end products to the corresponding receptors, the level of receptors for advanced glycation end products increases under conditions of hyperglycemia. The interaction between receptors for advanced glycation end products and advanced glycation end products leads to the formation of excessive reactive oxygen species, changes in intracellular signaling, gene expression, increased secretion of pro-inflammatory cytokines and contributes to the development of diabetic complications. The search for factors of natural origin that will slow down the development of specific complications of diabetes, determines the feasibility of studies of the corrective ability of biologically active substances isolated from medicinal plants for the process of glycation of proteins in diabetes. Materials and methods. Experimental diabetes mellitus was induced by intraperitoneal administration of streptozotocin. Separation of blood leukocytes was performed in Ficoll density gradient. To determine the extent of advanced glycation end products and receptor for advanced glycation end products in leukocyte immunoperoxidase labeling was performed. Results. A decrease in the content of advanced glycation end products in leukocytes under conditions of experimental diabetes mellitus was found. The obtained data indicate a possible contravention of glucose uptake by leukocytes in the studied pathology. At the same time, an increase in exposure to the receptor for advanced glycation end products leukocyte membranes in response to chronic hyperglycemia has been demonstrated. The ability of alkaloid free fraction of Galega officinalis extract to reduce the content of receptors for end products of glycation on the membranes of immunocompetent cells in diabetic animals has been confirmed, which may be due to the presence of biologically active substances with hypoglycemic action in its composition. Conclusion. Corrective effect of alkaloid free fraction of Galega officinalis L. extract on the content of receptor for advanced glycation end products in diabetes mellitus is mediated by its normalizing effect on carbohydrate metabolism.
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Ahmad, Saheem, Sultan Alouffi, Saif Khan, Mahvish Khan, Rihab Akasha, Jalaluddin Mohammad Ashraf, Mohd Farhan, Uzma Shahab, and Mohd Yasir Khan. "Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals." BioMed Research International 2022 (January 19, 2022): 1–15. http://dx.doi.org/10.1155/2022/5583298.
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Hundreds of millions of people around the globe are afflicted by diabetes mellitus. The alteration in glucose fixation process might result into hyperglycaemia and could affect the circulating plasma proteins to undergo nonenzymatic glycation reaction. If it is unchecked, it may lead to diabetes with increase in advanced glycation end products (AGEs). Therefore, the present study was designed to inhibit the diabetes and glycation by using natural antioxidant “ellagic acid” (EA). In this study, we explored the antidiabetes and antiglycation potential of EA in both in vitro (EA at micromolar concentration) and in vivo systems. The EA concentrations of 10 and 20 mg kg-1B.W./day were administered orally for 25 days to alloxan-induced diabetic rats, a week after confirmation of stable diabetes in animals. Intriguingly, EA supplementation in diabetic rats reversed the increase in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) level. EA also showed an inhibitory role against glycation intermediates including dicarbonyls, as well as AGEs, investigated in a glycation mixture with in vitro and in vivo animal plasma samples. Additionally, EA treatment resulted in inhibition of lipid peroxidation-mediated malondialdehyde (MDA) and conjugated dienes (CD). Furthermore, EA exhibited an antioxidant property, increased the level of plasma glutathione (GSH), and also helped to decrease histological changes evaluated by histoimmunostaining of animal kidney tissues. The results from our investigation clearly indicates the antiglycative property of EA, suggesting EA as an adequate inhibitor of glycation and diabetes, which can be investigated further in preclinical settings for the treatment and management of diabetes-associated complications.
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Ahmad, Saheem, Mohd Sajid Khan, Sultan Alouffi, Saif Khan, Mahvish Khan, Rihab Akashah, Mohammad Faisal, and Uzma Shahab. "Gold Nanoparticle-Bioconjugated Aminoguanidine Inhibits Glycation Reaction: An In Vivo Study in a Diabetic Animal Model." BioMed Research International 2021 (May 13, 2021): 1–10. http://dx.doi.org/10.1155/2021/5591851.
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Proteins undergo glycation resulting in the generation of advanced glycation end products (AGEs) that play a central role in the onset and advancement of diabetes-associated secondary complications. Aminoguanidine (AG) acts as an antiglycating agent by inhibiting AGE generation by blocking reactive carbonyl species (RCS) like, methylglyoxal (MGO). Previous studies on antiglycating behavior of AG gave promising results in the treatment of diabetes-associated microvascular complications, but it was discontinued as it was found to be toxic at high concentrations (>10 mmol/L). The current article aims at glycation inhibition by conjugating gold nanoparticles (Gnp) with less concentration of AG (0.5-1.0 mmol/L). The HPLC results showed that AG-Gnp fairly hampers the formation of glycation adducts. Moreover, the in vivo studies revealed AG-Gnp mediated inhibition in the production of total-AGEs and - N ε -(carboxymethyl)lysine (CML) in the diabetic rat model. This inhibition was found to be directly correlated with the antioxidant parameters, blood glucose, insulin, and glycosylated hemoglobin levels. Furthermore, the histopathology of AG-Gnp-treated rats showed good recovery in the damaged pancreatic tissue as compared to diabetic rats. We propose that this approach might increase the efficacy of AG at relatively low concentrations to avoid toxicity and might facilitate to overcome the hazardous actions of antiglycating drugs.
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Kuchurka, О. М., М. O. Chaban, O. V. Dzydzan, I. V. Brodyak, and N. O. Sybirna. "Leukocytes in type 1 diabetes mellitus: the changes they undergo and induce." Studia Biologica 16, no. 1 (April 11, 2022): 47–66. http://dx.doi.org/10.30970/sbi.1601.674.
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As leukocytes represent cellular and humoral immunity at the same time, they are a vital part of every immune process. This also stands for autoimmune processes and disorders, such as diabetes, specifically type 1 diabetes mellitus. Diabetes mellitus is one of the most widespread autoimmune diseases. Development of type 1 diabetes mellitus is mediated through complicated mechanisms of intercellular communication where leukocytes function as the key element, being both effectors and regulators. However, the immunocompetent cells are also affected by diabetic alterations, powered by chronic hyperglycemia. For example, the products of non-enzymatic interaction of glucose or other reducing sugars with either proteins or lipids, called advanced glycation end products, are associated with the development of long-term negative changes in diabetes. By binding to the receptors for advanced glycation end-products, they trigger the signaling pathways involved in expression of pro-inflammatory genes, which results in diabetic complications. As long as diabetes mellitus remains a global healthcare issue and several details of its pathogenesis are still to be discovered, it is important to analyze and investigate the peculiarities of alterations in leukocytes under type 1 diabetes mellitus, particularly the ones caused by advanced glycation end-products and their receptors.
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Ramesh, Pranav, Jian L. Yeo, Emer M. Brady, and Gerry P. McCann. "Role of inflammation in diabetic cardiomyopathy." Therapeutic Advances in Endocrinology and Metabolism 13 (January 2022): 204201882210835. http://dx.doi.org/10.1177/20420188221083530.
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The prevalence of type 2 diabetes (T2D) has reached a pandemic scale. Systemic chronic inflammation dominates the diabetes pathophysiology and has been implicated as a causal factor for the development of vascular complications. Heart failure (HF) is regarded as the most common cardiovascular complication of T2D and the diabetic diagnosis is an independent risk factor for HF development. Key molecular mechanisms pivotal to the development of diabetic cardiomyopathy include the NF-κB pathway and renin–angiotensin–aldosterone system, in addition to advanced glycation end product accumulation and inflammatory interleukin overexpression. Chronic myocardial inflammation in T2D mediates structural and metabolic changes, including cardiomyocyte apoptosis, impaired calcium handling, myocardial hypertrophy and fibrosis, all of which contribute to the diabetic HF phenotype. Advanced cardiovascular magnetic resonance imaging (CMR) has emerged as a gold standard non-invasive tool to delineate myocardial structural and functional changes. This review explores the role of chronic inflammation in diabetic cardiomyopathy and the ability of CMR to identify inflammation-mediated myocardial sequelae, such as oedema and diffuse fibrosis.
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Muthenna, P., C. Akileshwari, Megha Saraswat, and G. Bhanuprakash Reddy. "Inhibition of advanced glycation end-product formation on eye lens protein by rutin." British Journal of Nutrition 107, no. 7 (August 25, 2011): 941–49. http://dx.doi.org/10.1017/s0007114511004077.
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Formation of advanced glycation end products (AGE) plays a key role in the several pathophysiologies associated with ageing and diabetes, such as arthritis, atherosclerosis, chronic renal insufficiency, Alzheimer's disease, nephropathy, neuropathy and cataract. This raises the possibility of inhibition of AGE formation as one of the approaches to prevent or arrest the progression of diabetic complications. Previously, we have reported that some common dietary sources such as fruits, vegetables, herbs and spices have the potential to inhibit AGE formation. Flavonoids are abundantly found in fruits, vegetables, herbs and spices, and rutin is one of the commonly found dietary flavonols. In the present study, we have demonstrated the antiglycating potential and mechanism of action of rutin using goat eye lens proteins as model proteins. Under in vitro conditions, rutin inhibited glycation as assessed by SDS-PAGE, AGE-fluorescence, boronate affinity chromatography and immunodetection of specific AGE. Further, we provided insight into the mechanism of inhibition of protein glycation that rutin not only scavenges free-radicals directly but also chelates the metal ions by forming complexes with them and thereby partly inhibiting post-Amadori formation. These findings indicate the potential of rutin to prevent and/or inhibit protein glycation and the prospects for controlling AGE-mediated diabetic pathological conditions in vivo.
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Thornalley, P. J., A. C. McLellan, T. W. C. Lo, J. Benn, and P. H. Sönksen. "Negative Association between Erythrocyte Reduced Glutathione Concentration and Diabetic Complications." Clinical Science 91, no. 5 (November 1, 1996): 575–82. http://dx.doi.org/10.1042/cs0910575.
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1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy). 2. The presence of diabetic complications correlated positively with duration of diabetes and patient age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1c in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant. 3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with d-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients. 4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes. 5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to α-oxoaldehyde-mediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that α-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention of diabetic complications by supplementation of reduced glutathione and/or α-oxoaldehyde-scavenging agents now deserve investigation.
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Saraswat, Megha, P. Yadagiri Reddy, P. Muthenna, and G. Bhanuprakash Reddy. "Prevention of non-enzymic glycation of proteins by dietary agents: prospects for alleviating diabetic complications." British Journal of Nutrition 101, no. 11 (November 6, 2008): 1714–21. http://dx.doi.org/10.1017/s0007114508116270.
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The accumulation of advanced glycation endproducts (AGE) due to non-enzymic glycation of proteins has been implicated in several pathophysiologies associated with ageing and diabetes. The formation of AGE is accelerated in hyperglycaemic conditions, which alter the structure and function of long-lived proteins. Thus inhibition of the formation of AGE is believed to play a role in the prevention of diabetic complications. In the present study we evaluated the antiglycating effect of aqueous extracts of various plant-based foods. The effect of aqueous extracts of these agents in terms of their ability to prevent the accumulation of AGE due to fructose-mediatedin vitroglycation of eye lens soluble proteins was investigated. The degree of protein glycation in the absence and presence of dietary extracts was assessed by different complementary methods, i.e. non-tryptophan AGE fluorescence, AGE-induced cross-linking by SDS-PAGE and glyco-oxidative damage by carbonyl assay. Five out of the seventeen agents tested showed significant inhibitory potential againstin vitroprotein glycation in a dose-dependent manner. Prominent among them were ginger, cumin, cinnamon, black pepper and green tea, which inhibitedin vitroAGE formation to lens proteins 40–90 % at 1·0 mg/ml concentration. Assessing their potential to reduce the amount of glycated protein using boronate affinity chromatography and also their ability to prevent the formation of specific antigenic-AGE structures by immunodetection further substantiated the importance of ginger, cumin and cinnamon in reducing AGE burden. These findings indicate the potential of some dietary components to prevent and/or inhibit protein glycation. Thus these dietary agents may be able to be exploited for controlling AGE-mediated diabetic pathological conditionsin vivo.
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Abu El-Asrar, Ahmed M., Mohd Imtiaz Nawaz, Mohammad Mairaj Siddiquei, Abdullah S. Al-Kharashi, Dustan Kangave, and Ghulam Mohammad. "High-Mobility Group Box-1 Induces Decreased Brain-Derived Neurotrophic Factor-Mediated Neuroprotection in the Diabetic Retina." Mediators of Inflammation 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/863036.
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To test the hypothesis that brain-derived neurotrophic factor-(BDNF-) mediated neuroprotection is reduced by high-mobility group box-1 (HMGB1) in diabetic retina, paired vitreous and serum samples from 46 proliferative diabetic retinopathy and 34 nondiabetic patients were assayed for BDNF, HMGB1, soluble receptor for advanced glycation end products (sRAGE), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and TBARS. We also examined retinas of diabetic and HMGB1 intravitreally injected rats. The effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced changes in retinal BDNF expressions was studied. Western blot, ELISA, and TBARS assays were used. BDNF was not detected in vitreous samples. BDNF levels were significantly lower in serum samples from diabetic patients compared with nondiabetics, whereas HMGB1, sRAGE, sICAM-1, and TBARS levels were significantly higher in diabetic serum samples. MCP-1 levels did not differ significantly. There was significant inverse correlation between serum levels of BDNF and HMGB1. Diabetes and intravitreal administration of HMGB1 induced significant upregulation of the expression of HMGB1, TBARS, and cleaved caspase-3, whereas the expression of BDNF and synaptophysin was significantly downregulated in rat retinas. Glycyrrhizin significantly attenuated diabetes-induced downregulation of BDNF. Our results suggest that HMGB1-induced downregulation of BDNF might be involved in pathogenesis of diabetic retinal neurodegeneration.
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Peters, Verena, Benito Yard, and Claus Peter Schmitt. "Carnosine and Diabetic Nephropathy." Current Medicinal Chemistry 27, no. 11 (April 23, 2020): 1801–12. http://dx.doi.org/10.2174/0929867326666190326111851.
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Diabetic Nephropathy (DN) is a major complication in patients with type 1 or type 2 diabetes and represents the leading cause of end-stage renal disease. Novel therapeutic approaches are warranted. In view of a polymorphism in the carnosinase 1 gene CNDP1, resulting in reduced carnosine degradation activity and a significant DN risk reduction, carnosine (β-alanyl-L-histidine) has gained attention as a potential therapeutic target. Carnosine has anti-inflammatory, antioxidant, anti-glycation and reactive carbonyl quenching properties. In diabetic rodents, carnosine supplementation consistently improved renal histology and function and in most studies, also glucose metabolism. Even though plasma half-life of carnosine in humans is short, first intervention studies in (pre-) diabetic patients yielded promising results. The precise molecular mechanisms of carnosine mediated protective action, however, are still incompletely understood. This review highlights the recent knowledge on the role of the carnosine metabolism in DN.
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Haucke, Elisa, Alexander Navarrete Santos, Andreas Simm, Christian Henning, Marcus A. Glomb, Jacqueline Gürke, Maria Schindler, Bernd Fischer, and Anne Navarrete Santos. "Accumulation of advanced glycation end products in the rabbit blastocyst under maternal diabetes." REPRODUCTION 148, no. 2 (August 2014): 169–78. http://dx.doi.org/10.1530/rep-14-0149.
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Diabetes mellitus (DM) during pregnancy is one of the leading causes of perinatal morbidity and birth defects. The mechanism by which maternal hyperglycemia, the major teratogenic factor, induces embryonic malformations remains unclear. Advanced glycation end products (AGEs) are known to accumulate during the course of DM and contribute to the development of diabetic complications. Employing a diabetic rabbit model, we investigated the influence of maternal hyperglycemia during the preimplantation period on AGE formation (pentosidine, argpyrimidine, and Nε-carboxymethyllysine (CML)) in the reproductive tract and the embryo itself. As a consequence of type 1 DM, the AGE levels in blood plasma increased up to 50%, correlating closely with an AGE accumulation in the endometrium of diabetic females. Embryos from diabetic mothers had increased protein-bound CML levels and showed enhanced fluorescent signals for AGE-specific fluorescence in the blastocyst cavity fluid (BCF). The quantification of CML by HPLC–mass spectrometry (MS/MS) showed a higher amount of soluble CML in the BCF of blastocysts from diabetic rabbits (0.26±0.05 μmol/l) compared with controls (0.18±0.02 μmol/l). The high amount of AGEs in blastocysts from diabetic mothers correlates positively with an increased AGER (receptor for AGE (RAGE)) mRNA expression. Our study gives alarming insights into the consequences of poorly controlled maternal diabetes for AGE formation in the embryo. Maternal hyperglycemia during the preimplantation period is correlated with an increase in AGE formation in the uterine environment and the embryo itself. This may influence the development of the embryo through increased AGE-mediated cellular stress by RAGEs.
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Yamamoto, Yasuhiko, and Hiroshi Yamamoto. "Receptor for advanced glycation end-products-mediated inflammation and diabetic vascular complications." Journal of Diabetes Investigation 2, no. 3 (June 2011): 155–57. http://dx.doi.org/10.1111/j.2040-1124.2011.00125.x.
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Ren, Xiang, Ni-na Wang, Hui Qi, Yuan-yuan Qiu, Cheng-hong Zhang, Emily Brown, Hui Kong, and Li Kong. "Up-Regulation Thioredoxin Inhibits Advanced Glycation End Products-Induced Neurodegeneration." Cellular Physiology and Biochemistry 50, no. 5 (2018): 1673–86. http://dx.doi.org/10.1159/000494787.
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Background/Aims: Diabetic retinopathy (DR) is one of the most serious complications of diabetes and is the leading cause of adult blindness in developed countries. Advanced glycation end products (AGEs) accumulation in diabetes is associated with its complications. Thioredoxin (Trx) is a small molecule (12kDa) antioxidant protein widely distributed in mammalian tissues, which has important biological functions including anti-apoptosis and transcriptional regulation. In a previous study, we found that Trx plays a key role in retinal neurodegeneration prior to the occurrence of endothelial damage in diabetic mice. In this study, our aim is to determine the effect of Trx on neurodegeneration induced by AGEs in order to identify new therapeutic targets for the clinical treatment and prevention of DR. Methods: In vivo, a high-fat diet and Streptozotocin (STZ) injection were used to generate a mouse model of diabetes. Histology was utilized to examine tissue morphology and measure the outer nuclear layer (ONL) thickness. Electroretinography (ERG) was used to assess retinal function and Western blot was used to examine protein expression. In vitro, three methods of Trx up-regulation were used, including a stable cell line that overexpresses Trx, treatment with Sulforaphane, and shRNA down-regulation Txnip. Cells were treated with AGEs, and level of apoptosis was performed to quantify this by flow cytometry and TUNEL. Quantitative Reverse Transcription PCR (qRT-PCR), Western blotting and immunofluorescence were used to measure gene and protein expression. Transmission electron microscopy (TEM) was used to observe autophagosomes. Results: We found that diabetic mice display decreased retinal function and reduced ONL thickness with AGEs accumulation and a reduction of Trx expression. Up-regulation Trx can prevent the ONL thickness decrease in diabetic mice, as observed by H&E staining. In vitro, up-regulation Trx resulted in decreased intracellular ROS generation, reduced apoptosis by inhibited autophagy. Conclusion: Up-regulating Trx inhibited neurodegeneration induced by AGEs. The underlying mechanism may be related to inhibit Txnip/mTOR pathway-mediated autophagy.
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Weinberg, Evgeny, Tal Maymon, and Miron Weinreb. "AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress." Journal of Molecular Endocrinology 52, no. 1 (November 6, 2013): 67–76. http://dx.doi.org/10.1530/jme-13-0229.
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Diabetic humans and animals exhibit lower bone mass and healing, resulting from diminished bone formation. We have recently reported that type 1 diabetic rats have fewer bone marrow osteoprogenitor cells, and since the formation of advanced glycation end products (AGEs) in bone increases in diabetes, we explored possible mechanisms involved in AGE-induced apoptosis of rat bone marrow stromal cells (BMSCs). BMSCs isolated from 4-month-old rats were exposed to 10–400 μg/ml AGE–BSA for 16 h and apoptosis was quantified with PI/annexin V staining and flow cytometry. Signaling mechanisms were evaluated by preincubating the cells with appropriate inhibitors. The formation of reactive oxygen species (ROS) was quantified by flow cytometric analysis of DCFDA fluorescence and the expression of genes by RT-PCR analysis. AGE–BSA at a concentration of 400 μg/ml increased the apoptosis of BMSCs two- to threefold, an effect completely blocked by a pan-caspase inhibitor. BSA or high concentrations of glucose had no effect. AGE–BSA-induced BMSC apoptosis was attenuated by a p38 inhibitor but not by an NF-κB inhibitor. Treatment with AGE–BSA induced the expression of several pro-apoptotic ligands and receptors, most notably tumor necrosis factor α (TNFα), TRAIL, lymphotoxin alpha, CD40, and TNFR2. Furthermore, AGE–BSA-induced apoptosis was completely blocked by pirfenidone, an inhibitor of TNFα production/secretion. Finally, AGE–BSA increased the production of ROS in BMSCs, and its apoptogenic effect was blocked by the antioxidant N-acetylcysteine (N-acetyl-l-cysteine). Thus, AGE–BSA increases the apoptosis of rat BMSCs via the activation of caspases, involving TNFα production/secretion, p38 MAPK signaling, and oxidative stress. We propose that increased protein glycation, such as that occurring under hyperglycemia, causes the apoptosis of BMSCs, which might significantly contribute to the development of osteopenia in diabetic animals.
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Bansal, Savita, Archana Burman, and Asok Kumar Tripathi. "Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1146–62. http://dx.doi.org/10.4239/wjd.v14.i8.1146.
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The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Chen, Qi, Zhida Shen, Yanjun Mao, Qinfeng Li, Yu Liu, Menghan Mei, Fuyu Qiu, and Meihui Wang. "Inhibition of microRNA-34a mediates protection of thymosin beta 4 in endothelial progenitor cells against advanced glycation endproducts by targeting B-cell lymphoma 2." Canadian Journal of Physiology and Pharmacology 97, no. 10 (October 2019): 945–51. http://dx.doi.org/10.1139/cjpp-2018-0743.
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The aim of our work was to test whether thymosin beta 4 protected endothelial progenitor cells against apoptosis induced by advanced glycation endproducts and investigate the underlying mechanism. Treatment with thymosin beta 4 or transfection with microRNA-34a inhibitor enhanced cell viability, reduced apoptosis, abated oxidative stress, and attenuated mitochondrial dysfunction in endothelial progenitor cells exposed to advanced glycation endproducts. Incubation with advanced glycation endproducts led to increased levels of microRNA-34a, which was attenuated by treatment with thymosin beta 4. Transfection with microRNA-34a reversed the beneficial effect of thymosin beta 4 against injuries induced by advanced glycation endproducts. The microRNA-34a could directly bind to the 3′UTRs of the mRNA of B-cell lymphoma 2, and thymosin beta 4 treatment upregulated B-cell lymphoma 2 expression in endothelial progenitor cells exposed to advanced glycation endproducts. More importantly, knockdown of B-cell lymphoma 2 abolished the protection of thymosin beta 4 and microRNA-34a inhibitor against advanced glycation endproducts. In conclusion, inhibition of microRNA-34a mediated protection of thymosin beta 4 in endothelial progenitor cells against advanced glycation endproducts by targeting B-cell lymphoma 2, which was helpful for understanding the therapeutic potential of thymosin beta 4 for diabetic patients.
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Bao, Zhengyang, Lihua Li, Yue Geng, Jinchuan Yan, Zhiyin Dai, Chen Shao, Zhen Sun, et al. "Advanced Glycation End Products Induce Vascular Smooth Muscle Cell-Derived Foam Cell Formation and Transdifferentiate to a Macrophage-Like State." Mediators of Inflammation 2020 (August 7, 2020): 1–12. http://dx.doi.org/10.1155/2020/6850187.
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Background. Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. Methods. Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. Results. In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. Conclusions. CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.
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Jensen, Louise J. N., Larry Denner, Bieke F. Schrijvers, Ronald G. Tilton, Ruth Rasch, and Allan Flyvbjerg. "Renal effects of a neutralising RAGE-antibody in long-term streptozotocin-diabetic mice." Journal of Endocrinology 188, no. 3 (March 2006): 493–501. http://dx.doi.org/10.1677/joe.1.06524.
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Advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non-receptor mediated pathway and through specific receptors for AGEs (e.g. RAGE). To explore a potentially specific role for RAGE in renal changes in type 1 diabetes, we examined the renal effects of a neutralising murine RAGE-antibody (ab) in streptozotocin (STZ)-diabetic mice, a model of type 1 diabetes. One group of STZ-diabetic mice was treated for two months with the RAGE-ab, while another STZ-diabetic group was treated for the same period with an irrelevant immunoglobulin G (IgG). Two groups of non-diabetic NMRI mice were treated with either RAGE-ab or isotype-matched IgG for two months. Placebo-treated STZ-diabetic mice showed an increase in kidney weight, glomerular volume, basement membrane thickness (BMT), urinary albumin excretion (UAE) and creatinine clearance (CrCl), when compared with non-diabetic controls. In RAGE-ab-treated STZ-diabetic mice, the increase in kidney weight and UAE was reduced, while the increase in CrCl was abolished. RAGE-ab administration in NMRI mice caused a reduction in liver weight and an increase in BMT. Renal messenger RNA (mRNA) for connective tissue growth factor and collagen IVα1 was increased in placebo-treated diabetic animals. RAGE-ab treatment had no impact on the expression of these factors. The renal effects of RAGE-ab administration in STZ-diabetic mice were seen without impact on body weight, blood glucose or food consumption. In conclusion, the present data support the hypothesis that RAGE is an important pathogenic factor in the renal changes in an animal model of type 1 diabetes.
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Simeoli, Raffaele, and Alessandra Fierabracci. "Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy." International Journal of Molecular Sciences 20, no. 18 (September 18, 2019): 4627. http://dx.doi.org/10.3390/ijms20184627.
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Diabetic neuropathy is a serious complication of chronic hyperglycemia in diabetes patients. This complication can involve both peripheral sensorimotor and autonomic nervous system. The precise nature of injury to the peripheral nerves mediated by chronic hyperglycemia is unknown; however, several mechanisms have been proposed including polyol pathway activation, enhanced glycation of proteins and lipids, increased oxidative stress, and cytokine release in the site of injury. MicroRNAs (miRNAs) are small non-coding RNAs that mediate RNA interference by post-transcriptionally modulating gene expression and protein synthesis. Therefore, they have been implicated in several developmental, physiological, and pathophysiological processes where they modulate the expression of different proteins. Recently, miRNAs gained an increasing attention also for their role as diagnostic test in many diseases due to their stability in serum and their easy detection. Furthermore, recent studies suggest that miRNAs may be involved in diabetic neuropathy although their role in the onset and the development of this complication is not fully understood. In this review, we discuss the most recent literature providing evidence for miRNAs role in diabetic neuropathy opening new pathways to improve both early diagnosis and treatment of this complication.
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Li, Limin, Shan Li, Ying Liu, Mingchao Zhang, and Ke Zen. "Podocyte-targeting autoimmunity promotes diabetic nephropathy progression." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 217.23. http://dx.doi.org/10.4049/jimmunol.204.supp.217.23.
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Abstract Diabetic nephropathy (DN) is the leading cause of kidney failure worldwide. High levels of advanced glycation end products (AGEs) derived from chronic hyperglycemia occur in diabetes. As AGEs are highly antigenic, it promotes us to hypothesize that AGEs may exert an autoimmune response in DN development. First, we demonstrated that podocytes have the ability to present antigens under inflammatory condition. Second, we confirmed the presence of AGEs-recognizing autoantibodies in the serum of DN patients, not nondiabetic individuals or diabetic patients without nephropathy. Third, we showed that the autoantobodies in sera of DN patients specifically identify kidney biopsies of DN patients, not nondiabetic individuals or diabetic patients without nephropathy. In particular, the autoantobodies recognize signal specificity in podocytes from DN patients. Finally, employing the kidney tissue sections from DN patients as antigen to screen serum samples from diabetic or DN patients, we found that significant DN patients (48%) but not diabetic patients without nephropathy (<5%) exhibited podocyte labeling with autoantibodies. These results suggest that podocyte-targeting autoimmunity may plays an important role in promoting immune-mediated DN progression.
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Yu, Ting, Yun Wang, Dong Qian, Xiaomeng Sun, Yurong Tang, Xiaoxue Shen, and Lin Lin. "Advanced Glycation End Products Impair Ca2+ Mobilization and Sensitization in Colonic Smooth Muscle Cells via the CAMP/PKA Pathway." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1571–87. http://dx.doi.org/10.1159/000482005.
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Background/Aims: Excessive production of advanced glycation end products (AGEs) has been implicated in diabetes-related complications. This study aimed to investigate the mechanism by which AGEs potentially contribute to diabetes-associated colonic dysmotility. Methods: Control and streptozotocin (STZ)-induced diabetic groups were treated with aminoguanidine (AG). The colonic transit time and contractility of circular muscle strips was measured. ELISA, immunohistochemistry and western blotting were used to measure Nε-carboxymethyl-lysine (CML) levels. Primary cultured colonic smooth muscle cells (SMCs) were used in complementary in vitro studies. Results: Diabetic rats showed prolonged colonic transit time, weak contractility of colonic smooth muscle strips, and elevated levels of AGEs in the serum and colon tissues. cAMP levels, protein kinase-A (PKA) activities, and inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) phosphorylation were increased in the colon muscle tissues of diabetic rats, whereas RhoA/Rho kinase activity and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were reduced. The inhibition of the production of AGEs (AG treatment) reduced these effects. In cultured colonic SMCs, AGE-BSA treatment increased IP3R3 phosphorylation and reduced intracellular Ca2+ concentration, myosin light chain (MLC) phosphorylation, RhoA/Rho kinase activity, and MYPT1 phosphorylation. The PKA inhibitor H-89 and anti-RAGE antibody inhibited the AGE-BSA–induced impairment of Ca2+ signaling and cAMP/PKA activation. Conclusion: AGEs/RAGE participate in diabetes-associated colonic dysmotility by interfering with Ca2+ signaling in colonic SMCs through targeting IP3R3-mediated Ca2+ mobilization and RhoA/Rho kinase-mediated Ca2+ sensitization via the cAMP/PKA pathway.
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Ren, X., H. Shao, Q. Wei, Z. Sun, and N. Liu. "Advanced Glycation End-products Enhance Calcification in Vascular Smooth Muscle Cells." Journal of International Medical Research 37, no. 3 (May 2009): 847–54. http://dx.doi.org/10.1177/147323000903700329.
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Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate in diabetes, are closely associated with vascular calcification in humans. In this study, the hypothesis that AGEs enhance calcification in cultured vascular smooth muscle cells (VSMCs) was tested. Using real-time polymerase chain reaction (PCR) and specific protein assays, it was demonstrated that rat aortic VSMCs incubated with AGEs exhibited an increased expression of the AGE receptor (RAGE) and typical bone proteins, such as osteopontin and alkaline phosphatase. Incubation with AGEs also enhanced calcium accumulation in VSMCs in time-and dose-dependent manners. These AGEs-mediated changes in VSMCs were partially attenuated by a neutralizing antibody to RAGE. The results suggest that AGEs that accumulate in diabetes could elicit the osteoblastic differentiation of VSMCs, thereby contributing to vascular calcification via the RAGE pathway. Interruption of the AGE-RAGE interaction might be a promising target for therapeutic intervention to prevent diabetic vascular calcification.
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Shaikh, Muniza, Salman Siddiqui, Humaira Zafar, Uzma Naqeeb, Fakiha Subzwari, Rehan Imad, Khalid M. Khan, and Muhammad I. Choudhary. "Antiglycation Activity of Triazole Schiff’s Bases Against Fructosemediated Glycation: In Vitro and In Silico Study." Medicinal Chemistry 16, no. 4 (May 20, 2020): 575–91. http://dx.doi.org/10.2174/1573406415666190212105718.
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Background: Advanced glycation end products (AGEs) are known to be involved in the pathophysiology of diabetic complications, neurodegenerative diseases, and aging. Preventing the formation of AGEs can be helpful in the management of these diseases. Objective: Two classes of previously synthesized traizole Schiff’s bases (4H-1,2,4-triazole-4- Schiff’s bases 1-14, and 4H-1,2,4-triazole-3-Schiff’s bases 15-23) were evaluated for their in vitro antiglycation activity. Methods: In vitro fructose-mediated human serum albumin (HSA) glycation assay was employed to assess the antiglycation activity of triazole Schiff’s bases. The active compounds were subjected to cytotoxicity analysis by MTT assay on mouse fibroblast (3T3) cell line. Molecular docking and simulation studies were carried out to evaluate the interactions and stability of compounds with HSA. Anti-hyperglycemic and antioxidant activities of selected non-cytotoxic compounds were evaluated by in vitro α-glucosidase inhibition, and DPPH free radical scavenging assays, respectively. Results: Compound 1 (IC50=47.30±0.38 µM) from 4H-1,2,4-triazole-4-Schiff’s bases has exhibited antiglycation activity comparable to standard rutin (IC50=54.5±0.05 µM) along with a stable RMSD profile in MD simulation studies. Compound 1 also exhibited a potent α-glucosidase inhibitory activity, and moderate antioxidant property. Other derivatives showed a weak antiglycation activity with IC50 values between 248.1-637.7 µM. Compounds with potential antiglycation profile were found to be non-cytotoxic in a cellular assay. Conclusion: The study identifies triazole Schiff’s bases active against fructose-mediated glycation of HSA, thus indicates their potential against late diabetic complications due to production of advancedend products (AGEs).
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Anago, Eugénie, Guilphados Djogbede, Ezéchiel Mahougnon Salomon Fiogbe, Gaétan Augustin Julien Segbo, and Dèwanou Casimir Akpovi. "Rôle de la glycation des protéines dans les complications et la thérapie du diabète: revue bibliographique." International Journal of Biological and Chemical Sciences 16, no. 6 (March 12, 2023): 2930–44. http://dx.doi.org/10.4314/ijbcs.v16i6.37.
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La fixation d’un ose, fréquemment le glucose, sur les protéines est une réaction biochimique courante entraînant la formation des produits avancés de la glycation (en anglais Advanced Glycation Endproducts, AGEs). L’hyperglycémie permanente observée pendant le diabète, provoque une élévation du taux de glycation des protéines, avec pour conséquence une altération de leurs fonctions. Plusieurs auteurs ont montré le lien entre l’accumulation des AGEs dans différents organes et les complications microvasculaires et macrovasculaires observées lors du diabète. D’autres travaux ont montré que ces complications diabétiques et plusieurs autres maladies métaboliques découlent d’une série de processus délétères initiée par les AGEs. Il s’agit de l’inflammation par le biais des récepteurs, les modifications conformationnelles des macromolécules aboutissant à des accumulations d’agrégats et à une réponse immunitaire médiée par l’immunogénicité des AGEs. Les principales approches thérapeutiques pour le traitement du diabète impliquent l’administration d'insuline, l'inhibition des enzymes de digestion des polysaccharides (alpha-amylase et alpha-glucosidase) et les inhibiteurs de la glycation. Plusieurs travaux ont prouvé qu’un nombre important de plantes, herbes aromatiques et épices possèdent des propriétés antiglycatives très intéressantes et pourront être envisagées pour élargir la gamme des molécules thérapeutiques.
The binding of a monosaccharide, frequently glucose, to proteins is a common biochemical reaction leading to the formation of advanced glycation end products (AGEs). The permanent hyperglycaemia observed during diabetes induces an increase in the glycation rate of proteins, with the consequent alteration of their functions. Several authors have demonstrated the link between the accumulation of AGEs in different organs and the microvascular and macrovascular complications observed in diabetes. Other work has shown that these diabetic complications and several other metabolic diseases stem from a series of deleterious processes initiated by AGEs. This is inflammation through receptors, conformational changes of macromolecules leading to accumulations of aggregates and an immune response mediated by the immunogenicity of AGEs. The main therapeutic approaches for the treatment of diabetes involve insulin administration, inhibition of polysaccharide digestion enzymes (alpha-amylase and alpha-glucosidase) and glycation inhibitors. Several works have proven that a large number of plants, aromatic herbs and spices have very interesting antiglycative properties and could be considered to expand the range of therapeutic molecules.
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Cheng, Meng-Ke, Yao-Yao Guo, Xiao-Nan Kang, Lu Zhang, Dan Wang, Hui-Hui Ren, and Gang Yuan. "Advances in cardiovascular-related biomarkers to predict diabetic peripheral neuropathy." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1226–33. http://dx.doi.org/10.4239/wjd.v14.i8.1226.
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The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Sandireddy, Reddemma, Veera Ganesh Yerra, Aparna Areti, Prashanth Komirishetty, and Ashutosh Kumar. "Neuroinflammation and Oxidative Stress in Diabetic Neuropathy: Futuristic Strategies Based on These Targets." International Journal of Endocrinology 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/674987.
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In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50–60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy. Mitochondria induced ROS and other oxidants are responsible for altering the balance between oxidants and innate antioxidant defence of the body. Oxidative-nitrosative stress not only activates the major pathways namely, polyol pathway flux, advanced glycation end products formation, activation of protein kinase C, and overactivity of the hexosamine pathway, but also initiates and amplifies neuroinflammation. The cross talk between oxidative stress and inflammation is due to the activation of NF-κB and AP-1 and inhibition of Nrf2, peroxynitrite mediate endothelial dysfunction, altered NO levels, and macrophage migration. These all culminate in the production of proinflammatory cytokines which are responsible for nerve tissue damage and debilitating neuropathies. This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy.
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Ohashi, Seiji, Hideharu Abe, Toshikazu Takahashi, Yasuhiko Yamamoto, Masayoshi Takeuchi, Hidenori Arai, Kazuhiro Nagata, et al. "Advanced Glycation End Products Increase Collagen-specific Chaperone Protein in Mouse Diabetic Nephropathy." Journal of Biological Chemistry 279, no. 19 (March 5, 2004): 19816–23. http://dx.doi.org/10.1074/jbc.m310428200.
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Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-β (TGF-β) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-β mRNA. Neutralizing antibody for TGF-β inhibited the overexpression of both HSP47 and type IV collagenin vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, bothin vivoandin vitro. The processes may be mediated by TGF-β.
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Dubey, Navneet Kumar, Hong-Jian Wei, Sung-Hsun Yu, David F. Williams, Joseph R. Wang, Yue-Hua Deng, Feng-Chou Tsai, Peter D. Wang, and Win-Ping Deng. "Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade." Aging and disease 10, no. 3 (2019): 483. http://dx.doi.org/10.14336/ad.2018.0616.
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Kennon, Amber M., and James A. Stewart. "Paracrine Signals in Calcified Conditioned Media Elicited Differential Responses in Primary Aortic Vascular Smooth Muscle Cells and in Adventitial Fibroblasts." International Journal of Molecular Sciences 24, no. 4 (February 10, 2023): 3599. http://dx.doi.org/10.3390/ijms24043599.
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Our goal was to determine if paracrine signals from different aortic layers can impact other cell types in the diabetic microenvironment, specifically medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts (AFBs). The diabetic hyperglycemic aorta undergoes mineral dysregulation, causing cells to be more responsive to chemical messengers eliciting vascular calcification. Advanced glycation end-products (AGEs)/AGE receptors (RAGEs) signaling has been implicated in diabetes-mediated vascular calcification. To elucidate responses shared between cell types, pre-conditioned calcified media from diabetic and non-diabetic VSMCs and AFBs were collected to treat cultured murine diabetic, non-diabetic, diabetic RAGE knockout (RKO), and non-diabetic RKO VSMCs and AFBs. Calcium assays, western blots, and semi-quantitative cytokine/chemokine profile kits were used to determine signaling responses. VSMCs responded to non-diabetic more than diabetic AFB calcified pre-conditioned media. AFB calcification was not significantly altered when VSMC pre-conditioned media was used. No significant changes in VSMCs signaling markers due to treatments were reported; however, genotypic differences existed. Losses in AFB α-smooth muscle actin were observed with diabetic pre-conditioned VSMC media treatment. Superoxide dismutase-2 (SOD-2) increased with non-diabetic calcified + AGE pre-conditioned VSMC media, while same treatment decreased diabetic AFBs levels. Overall, non-diabetic and diabetic pre-conditioned media elicited different responses from VSMCs and AFBs.
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Wang, Jin-Jun, Yuan-Yuan Yu, Pin-Yi Wang, Xian-Ming Huang, Xiao Chen, and Xi-Guang Chen. "Sequential treatment for diabetic foot ulcers in dialysis patients: A case report." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1323–29. http://dx.doi.org/10.4239/wjd.v14.i8.1323.
Full textAbstract:
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Kumar Pasupulati, Anil, P. Swathi Chitra, and G. Bhanuprakash Reddy. "Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy." Biomolecular Concepts 7, no. 5-6 (December 1, 2016): 293–309. http://dx.doi.org/10.1515/bmc-2016-0021.
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AbstractDiabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff’s base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
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KELLY, DARREN J., RICHARD E. GILBERT, ALISON J. COX, TINA SOULIS, GEORGE JERUMS, and MARK E. COOPER. "Aminoguanidine Ameliorates Overexpression of Prosclerotic Growth Factors and Collagen Deposition in Experimental Diabetic Nephropathy." Journal of the American Society of Nephrology 12, no. 10 (October 2001): 2098–107. http://dx.doi.org/10.1681/asn.v12102098.
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Abstract. Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-β1 (P< 0.01versuscontrol) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P< 0.01versuscontrol) in the tubulointerstitium.In situhybridization demonstrated a diffuse increase in both TGF-β1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-β1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P< 0.05). TGF-β1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.
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Bourajjaj, M., C. D. A. Stehouwer, V. W. M. van Hinsbergh, and C. G. Schalkwijk. "Role of methylglyoxal adducts in the development of vascular complications in diabetes mellitus." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1400–1402. http://dx.doi.org/10.1042/bst0311400.
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Various theories have been proposed to explain the hyperglycaemia-induced pathogenesis of vascular complications of diabetes, including detrimental effects of AGEs (advanced glycation end products) on vascular tissues. Increased formation of the very reactive dicarbonyl compound MGO (methylglyoxal), one of the side-products of glycolysis, and MGO-derived AGEs seem to be implicated in the development of diabetic vascular complications. Although the exact role of MGO and MGO adducts in the development of vascular complications is unknown, receptor-mediated activation of vascular cells by the MGO–arginine adduct hydroimidazolone, as well as intracellular modifications of protein by MGO, seem to be involved. The aim of this mini-review is to assess to what extent MGO is related to vascular complications in diabetes.
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Sohn, Eunjin, Junghyun Kim, Chan-Sik Kim, Yun Mi Lee, Kyuhyung Jo, So Dam Shin, Joo Hwan Kim, and Jin Sook Kim. "The Extract ofLitsea japonicaReduced the Development of Diabetic Nephropathy via the Inhibition of Advanced Glycation End Products Accumulation in db/db Mice." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/769416.
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Increasing evidence indicates that advanced glycation end products (AGEs) contribute to the pathogenesis of diabetic nephropathy. The aim of this study was to investigate the protective effect ofL. japonicaextract (LJE) against renal damage in the db/db mouse. LJE (100 or 250 mg/kg per day) was given to diabetic mice for 12 weeks. Body weight, blood glucose levels, glycated hemoglobin (HbA1c) levels, and proteinuria were examined. Inin vitroassay of the inhibition of AGE formation, immunohistochemical analysis of podocyte loss and AGE accumulations were performed. In 20-week-old db/db mice, severe hyperglycemia developed, and proteinuria was significantly increased. Diabetes induced markedly morphological alterations to the renal glomerular cells. AGE accumulations and podocyte loss were detected in renal glomeruli. LJE treatment significantly reduced proteinuria and AGE accumulations in diabetic mice. Moreover, the loss of nephrin, an important slit diaphragm component in the kidneys, was restored by LJE treatment. Our studies suggest that LJE might be beneficial for the treatment of diabetic nephropathy. The ability of LJE to attenuate proteinuria and podocyte dysfunction may be mediated by the inhibition of AGE accumulation in the context of diabetic nephropathy in db/db mice.
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Tam, Xystus H. L., Sammy W. M. Shiu, Lin Leng, Richard Bucala, D. John Betteridge, and Kathryn C. B. Tan. "Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in Type 2 diabetes." Clinical Science 120, no. 2 (October 8, 2010): 81–89. http://dx.doi.org/10.1042/cs20100256.
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The sRAGE [soluble RAGE (receptor for advanced glycation end-products)] lack the transmembrane and cytoplasmic domain of the full-length receptor and can function as a decoy for RAGE ligands. Recent evidence suggests that sRAGE may be a potential biomarker of RAGE-mediated pathology. The present study aimed to examine the relationship between RAGE expression in peripheral blood monocytes and circulating sRAGE and esRAGE (endogenous sRAGE, a splice variant of sRAGE) in Type 2 diabetes. Protein expression of RAGE and esRAGE in monocyte cell lysate was determined by Western blot in 53 diabetic patients and 52 controls. Monocyte cell-surface-bound full-length RAGE expression was measured using flow cytometry. Serum sRAGE, esRAGE and AGE (advanced glycation end products) were assayed by ELISA. The mean HbA1c (glycated haemoglobin) of the diabetic patients was 9.74% and serum AGEs was increased. Monocyte full-length RAGE expression was significantly higher in diabetic patients whereas esRAGE expression was reduced, and serum AGEs concentration was an independent determinant of monocyte cell surface full-length RAGE expression. Serum levels of sRAGE [573.3 (375.7–754.3) compared with 608.1 (405.3–940.8) pg/ml, P<0.05] and esRAGE [241.8 (154.6–356.6) compared with 286.5 (202.6–390.0) pg/ml, P<0.05; values are medians (interquartile range)] were decreased. There was an inverse association between monocyte RAGE expression and log(serum sRAGE) (r=−0.34, P=0.01) but not with esRAGE. In conclusion, despite an increase in full-length RAGE expression, esRAGE expression was down-regulated in the diabetic patients, and serum sRAGE and esRAGE was also reduced. Hence increased full-length RAGE levels are not associated with a similar increase in sRAGE isoforms levels.
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Kim, Chan-Sik, Junghyun Kim, Young Kim, Kyuhyung Jo, Yun Lee, Dong Jung, Ik Lee, Joo-Hwan Kim, and Jin Kim. "Improvement in Diabetic Retinopathy through Protection against Retinal Apoptosis in Spontaneously Diabetic Torii Rats Mediated by Ethanol Extract of Osteomeles schwerinae C.K. Schneid." Nutrients 11, no. 3 (March 4, 2019): 546. http://dx.doi.org/10.3390/nu11030546.
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Retinal apoptosis plays a critical role in the progression of diabetic retinopathy (DR), a common diabetic complication. Currently, the tight control of blood glucose levels is the standard approach to prevent or delay the progression of DR. However, prevalence of DR among diabetic patients remains high. Focusing on natural nutrients or herbal medicines that can prevent or delay the onset of diabetic complications, we administered an ethanol extract of the aerial portion of Osteomeles schwerinae (OSSCE), a Chinese herbal medicine, over a period of 17 weeks to spontaneously diabetic Torii (SDT) rats. OSSCE was found to ameliorate retinal apoptosis through the regulation of advanced glycation end product (AGE) accumulation, oxidative stress, and mitochondrial function via the inhibition of NF-κB activity, in turn, through the downregulation of PKCδ, P47phox, and ERK1/2. We further demonstrated in 25 mM glucose-treated human retinal microvascular endothelial cells (HRMECs) that hyperoside (3-O-galactoside-quercetin), quercitrin (3-O-rhamnoside-quercetin), and 2″-O-acetylvitexin (8-C-(2″-O-acetyl-glucoside)-apigenin) were the active components of OSSCE that mediated its pharmacological action. Our results provide evidence that OSSCE is a powerful agent that may directly mediate a delay in the development or disease improvement in patients of DR.
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Anandan, Satish, Murali Mahadevamurthy, Mohammad Azam Ansari, Mohammad A. Alzohairy, Mohammad N. Alomary, Syeda Farha Siraj, Sarjan Halugudde Nagaraja, et al. "Biosynthesized ZnO-NPs from Morus indica Attenuates Methylglyoxal-Induced Protein Glycation and RBC Damage: In-Vitro, In-Vivo and Molecular Docking Study." Biomolecules 9, no. 12 (December 16, 2019): 882. http://dx.doi.org/10.3390/biom9120882.
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The development of advanced glycation end-products (AGEs) inhibitors is considered to have therapeutic potential in diabetic complications inhibiting the loss of the biomolecular function. In the present study, zinc oxide nanoparticles (ZnO-NPs) were synthesized from aqueous leaf extract of Morus indica and were characterized by various techniques such as ultraviolet (UV)-Vis spectroscopy, Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). Further, the inhibition of AGEs formation after exposure to ZnO-NPs was investigated by in-vitro, in-vivo, and molecular docking studies. Biochemical and histopathological changes after exposure to ZnO-NPs were also studied in streptozotocin-induced diabetic rats. ZnO-NPs showed an absorption peak at 359 nm with a purity of 92.62% and ~6–12 nm in size, which is characteristic of nanoparticles. The images of SEM showed agglomeration of smaller ZnO-NPs and EDS authenticating that the synthesized nanoparticles were without impurities. The biosynthesized ZnO-NPs showed significant inhibition in the formation of AGEs. The particles were effective against methylglyoxal (MGO) mediated glycation of bovine serum albumin (BSA) by inhibiting the formation of AGEs, which was dose-dependent. Further, the presence of MGO resulted in complete damage of biconcave red blood corpuscles (RBCs) to an irregular shape, whereas the morphological changes were prevented when they were treated with ZnO-NPs leading to the prevention of complications caused due to glycation. The administration of ZnO-NPs (100 mg Kg−1) in streptozotocin(STZ)-induced diabetic rats reversed hyperglycemia and significantly improved hepatic enzymes level and renal functionality, also the histopathological studies revealed restoration of kidney and liver damage nearer to normal conditions. Molecular docking of BSA with ZnO-NPs confirms that masking of lysine and arginine residues is one of the possible mechanisms responsible for the potent antiglycation activity of ZnO-NPs. The findings strongly suggest scope for exploring the therapeutic potential of diabetes-related complications.
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Hayashi, Kenjiro, Koichi Sato, Seishi Ochi, Shuhei Kawano, Seiichi Munesue, Ai Harashima, Yu Oshima, Kumi Kimura, Takashi Kyoi, and Yasuhiko Yamamoto. "Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation." International Journal of Molecular Sciences 23, no. 10 (May 20, 2022): 5757. http://dx.doi.org/10.3390/ijms23105757.
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Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) are implicated in inflammatory reactions and vascular complications in diabetes. Signaling pathways downstream of RAGE are involved in NF-κB activation. In this study, we examined whether ethanol extracts of Saururus chinensis (Lour.) Baill. (SE) could affect RAGE signaling and vascular relaxation in streptozotocin (STZ)-induced diabetic rats. Treatment with SE inhibited AGEs-modified bovine serum albumin (AGEs-BSA)-elicited activation of NF-κB and could compete with AGEs-BSA binding to RAGE in a dose-dependent manner. Tumor necrosis factor-α (TNF-α) secretion induced by lipopolysaccharide (LPS)—a RAGE ligand—was also reduced by SE treatment in wild-type Ager+/+ mice as well as in cultured peritoneal macrophages from Ager+/+ mice but not in Ager−/− mice. SE administration significantly ameliorated diabetes-related dysregulation of acetylcholine-mediated vascular relaxation in STZ-induced diabetic rats. These results suggest that SE would inhibit RAGE signaling and would be useful for the improvement of vascular endothelial dysfunction in diabetes.
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Juneja, Deven, Prashant Nasa, Ravi Jain, and Omender Singh. "Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1314–22. http://dx.doi.org/10.4239/wjd.v14.i8.1314.
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The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Wu, Tsung-Tien, Ying-Ying Chen, Hui-Yu Chang, Ya-Hsin Kung, Ching-Jiunn Tseng, and Pei-Wen Cheng. "AKR1B1-Induced Epithelial–Mesenchymal Transition Mediated by RAGE-Oxidative Stress in Diabetic Cataract Lens." Antioxidants 9, no. 4 (March 25, 2020): 273. http://dx.doi.org/10.3390/antiox9040273.
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Purpose: Cataracts are a major cause of visual acuity deterioration in diabetes mellitus (DM) in developed and developing countries. Studies have demonstrated that overproduction of AKR1B1 and receptor for advanced glycation end products (RAGE) plays a major role in the pathogenesis of diabetic cataracts, but it is unclear whether the prevalence of diabetic cataracts is related to epithelial–mesenchymal transition (EMT) in lens epithelial cells. This study aimed to analyze the role of EMT in cataract formation of DM patients. Methods: Immunofluorescence and immunohistochemistry assays were used to estimate AKR1B1, RAGE, AMPK, and EMT levels in epithelial human lens of DM or non-DM cataracts. Results: Immunohistochemical staining demonstrated that pathologic phases and N-cadherin expression levels were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Immunofluorescent staining showed that AKR1B1 and RAGE were significantly higher in epithelial human lens of DM (+) compared to DM (−) cataracts. Interestingly, acetyl superoxide dismutase 2 (AcSOD2) levels were significantly higher in DM patients’ lens epithelial cells (LECs), whereas AMPKT172 phosphorylation was significantly increased in non-DM patients. This indicates that AMPKT172 might be related to superoxide reduction and diabetic cataract formation. Conclusions: Our results suggest that AKR1B1 overexpression can decrease AMPK activation, thereby increasing AcSOD2 and RAGE-induced EMT in epithelial human lens of DM cataracts. These novel findings suggest that AKR inhibitors may be candidates for the pharmacological prevention of cataracts in patients with DM.
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Lee, Jae Hyuk, Lalita Subedi, and Sun Yeou Kim. "Effect of Cysteine on Methylglyoxal-Induced Renal Damage in Mesangial Cells." Cells 9, no. 1 (January 17, 2020): 234. http://dx.doi.org/10.3390/cells9010234.
Full textAbstract:
Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a key precursor of the formation of advanced glycation end products (AGEs). MGO and MGO-AGEs were reportedly increased in patients with diabetic dysfunction, including diabetic nephropathy. The activation of glyoxalase-I (GLO-I) increases MGO and MGO-AGE detoxification. MGO-mediated glucotoxicity can also be ameliorated by MGO scavengers such as N-acetylcysteine (NAC), aminoguanidine (AG), and metformin. In this study, we noted that l-cysteine demonstrated protective effects against MGO-induced glucotoxicity in renal mesangial cells. l-cysteine prevented MGO-induced apoptosis and necrosis, together with a reduction of reactive oxygen species (ROS) production in MES13 cells. Interestingly, l-cysteine significantly reduced MGO-AGE formation and also acted as an MGO-AGE crosslink breaker. Furthermore, l-cysteine treatment accelerated MGO catabolism to D-lactate via the upregulation of GLO-I. The reduction of AGE formation and induction of AGE breakdown, following l-cysteine treatment, further supports the potential use of l-cysteine as an alternative for the therapeutic control of MGO-induced renal complications in diabetes, especially against diabetic nephropathy.
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Su, Bao-Lin, Liang-Liang Wang, Liang-You Zhang, Shu Zhang, Qiang Li, and Gang-Yi Chen. "Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1234–48. http://dx.doi.org/10.4239/wjd.v14.i8.1234.
Full textAbstract:
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Liu, I.-Min, Thing-Fong Tzeng, Shorong-Shii Liou, and Chia Ju Chang. "Beneficial Effect of Traditional Chinese Medicinal Formula Danggui-Shaoyao-San on Advanced Glycation End-Product-Mediated Renal Injury in Streptozotocin-Diabetic Rats." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/140103.
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The present study was undertaken to characterize the effects of Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, on diabetic nephropathy. Streptozotocin-induced diabetic rats were orally administrated DSS (2.8 g kg−1per day) for 12 consecutive weeks. DSS partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-hour urinary albumin excretion rate, and creatinine clearance as well as the kidney hypertrophy (kidney weight/body weight ratio) and glomerular mesangial matrix expansion were ameliorated after 12 weeks of DSS treatment. The increased expression of nuclear factor-κB as well as transforming growth factor-β1and the progressive accumulation of type IV collagen in kidney of diabetic rats were also attenuated by DSS. Not only the elevated levels of advanced glycation end products (AGEs) andNε-(carboxymethyl)lysine but also the higher levels of lipid peroxidation products in kidney of diabetic rats were ameliorated by DSS. Decreased activity of superoxide diamutase and glutathione peroxidase in kidney of diabetic rats was enhanced by DSS. These data demonstrated that the renoprotective effects of DSS in STZ-diabetic rats not only were attributable to regulate plasma glucose to attenuate AGEs expression in diabetic glomeruli but also likely reflected its antioxidant activity.
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Puddu, Alessandra, François Mach, Alessio Nencioni, Giorgio Luciano Viviani, and Fabrizio Montecucco. "An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes." Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/591056.
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Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreaticβ-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.
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Zhan, Hui-Qin, Ji-Lin Zhou, Jun Zhang, De Wu, and Chun-Yan Gu. "Conbercept combined with laser photocoagulation in the treatment of diabetic macular edema and its influence on intraocular cytokines." World Journal of Diabetes 14, no. 8 (August 15, 2023): 1271–79. http://dx.doi.org/10.4239/wjd.v14.i8.1271.
Full textAbstract:
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a nonhomogeneous, chemically diverse group of compounds formed nonenzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Su, Wen, Weiping Li, Hui Chen, Huirong Liu, Haixia Huang, and Hongwei Li. "Advanced Glycation End Products Impair Voltage-Gated K+ Channels-Mediated Coronary Vasodilation in Diabetic Rats." PLOS ONE 10, no. 11 (November 12, 2015): e0142865. http://dx.doi.org/10.1371/journal.pone.0142865.
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Liu, I.-Min, Thing-Fong Tzeng, Shorong-Shii Liou, and Chia Ju Chang. "Angelica Acutiloba Root Alleviates Advanced Glycation End-Product-Mediated Renal Injury in Streptozotocin-Diabetic Rats." Journal of Food Science 76, no. 7 (August 22, 2011): H165—H174. http://dx.doi.org/10.1111/j.1750-3841.2011.02310.x.
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