scholarly journals Advanced glycation end products induce immature angiogenesis in in vivo and ex vivo mouse models

2020 ◽  
Vol 318 (3) ◽  
pp. H519-H533 ◽  
Author(s):  
Lixian Chen ◽  
Yun Cui ◽  
Bingyu Li ◽  
Jie Weng ◽  
Weiju Wang ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Advanced Glycation End Products ◽  
Ex Vivo ◽  
Aortic Ring ◽  
Treated Mouse ◽  
Mouse Retina ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE, ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation. NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.

scholarly journals Hyperglycemia and advanced glycation end products disrupt BBB and promote occludin and claudin-5 protein secretion on extracellular microvesicles

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Slava Rom ◽  
Nathan A. Heldt ◽  
Sachin Gajghate ◽  
Alecia Seliga ◽  
Nancy L. Reichenbach ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Connexin 43 ◽  
Ex Vivo ◽  
Advanced Glycation ◽  
Cerebral Microvessels ◽  
Glycation End Products ◽  
End Products ◽  
Bbb Permeability

Abstract Cognitive impairment is a well-known complication of diabetes mellitus (DM). Microvascular compromise was described one DM complication. Recently we showed blood brain barrier (BBB) permeability and memory loss are associated with diminution of tight junctions (TJ) in brain endothelium and pericyte coverage and inflammation in cerebral microvessels and brain tissue paralleling hyperglycemia in mice of both DM types. The current study demonstrates that exposure of brain microvessels to hyperglycemic conditions or advanced glycation end products (AGEs) ex vivo resulted in significant abnormalities in membranous distribution of TJ proteins. We found significant increase in the amount of extracellular vesicles (EVs) isolated from DM mice and enhanced presence of TJ proteins, occludin and claudin-5, on EVs. Exposure of BMVECs to high glucose and AGEs led to significant augmentation of ICAM and VCAM expression, elevated leukocyte adhesion to and migration across BMVEC monolayers, and increased BBB permeability in vitro. Pericytes exposed to hyperglycemia and AGEs displayed diminished expression of integrin α1, PDGF-R1β and connexin-43. Our findings indicate BBB compromise in DM ex vivo, in vitro and in vivo models in association with BMVEC/pericyte dysfunction and inflammation. Prevention of BBB injury may be a new therapeutic approach to avert cognitive demise in DM.

scholarly journals Inhibition of Receptor for Advanced Glycation End Products as New Promising Strategy Treatment in Diabetic Retinopathy

2019 ◽  
Vol 7 (23) ◽  
pp. 3921-3924 ◽  
Author(s):  
Irsan Saleh ◽  
Ziske Maritska ◽  
Nita Parisa ◽  
Rachmat Hidayat
Keyword(s):  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Advanced Glycation End Products ◽  
Negative Control ◽  
Advanced Glycation ◽  
Vegf Expression ◽  
White Rats ◽  
Glycation End Products ◽  
End Products

BACKGROUND: Extensive intracellular and extracellular formation of advanced glycation end-products (AGEs) is considered a causative factor for vascular injury triggered by hyperglycemia in diabetes. The hyperglycemia will cause accumulation of AGEs, damage to pericytes, nerve growth factor (NGF), glial acid fibrillary protein (GFAP) and increase in vascular endothelial growth factor (VEGF). AIM: This study aimed to assess the efficacy of RAGE inhibition in suppressing the development and progression of diabetic retinopathy through modulation of the inflammatory pathway involving NGF, GFAP, and VEGF. METHODS: The design was in vivo experimental study. Thirty white rats were induced with Alloxan monohydrate. Rats were divided into 5 groups, normal, negative control, groups with an anti-RAGE dose of 1 μg/uL, the dose of 10 μg/uL and 100 μg/uL. After 4 weeks of treatment, HbA1c, NGF, and GFAP levels were measured using ELISA. Quantification of VEGF expression was done using the ImageJ® application. Data was expressed with mean ± SD. Independent T-test with ANOVA and Tukey's post hoc was done. RESULTS: RAGE inhibitors yielded a significant decrease in blood glucose and HbA1c levels. VEGF and RAGE expression were reduced in anti-RAGE groups in various doses. Inhibition of RAGE reduced the damage of retinal pericytes, by reducing GFAP and increasing NGF, and reduced the formation of new blood vessels, by decreasing VEGF expression, in diabetic retinopathy. CONCLUSION: Inhibition of receptor for advanced glycation end-products (RAGE) was effective in suppressing the development and progression of diabetic retinopathy.

scholarly journals Influence of Dopamine on Fluorescent Advanced Glycation End Products Formation Using Drosophila melanogaster

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 453
Author(s):  
Ana Filošević Vujnović ◽  
Katarina Jović ◽  
Emanuel Pištan ◽  
Rozi Andretić Waldowski
Keyword(s):  
Drosophila Melanogaster ◽  
Advanced Glycation End Products ◽  
Model Organism ◽  
Covalent Modification ◽  
Advanced Glycation ◽  
Biomarkers Of Aging ◽  
Glycation End Products ◽  
End Products

Non-enzymatic glycation and covalent modification of proteins leads to Advanced Glycation End products (AGEs). AGEs are biomarkers of aging and neurodegenerative disease, and can be induced by impaired neuronal signaling. The objective of this study was to investigate if manipulation of dopamine (DA) in vitro using the model protein, bovine serum albumin (BSA), and in vivo using the model organism Drosophila melanogaster, influences fluorescent AGEs (fAGEs) formation as an indicator of dopamine-induced oxidation events. DA inhibited fAGEs-BSA synthesis in vitro, suggesting an anti-oxidative effect, which was not observed when flies were fed DA. Feeding flies cocaine and methamphetamine led to increased fAGEs formation. Mutants lacking the dopaminergic transporter or the D1-type showed further elevation of fAGEs accumulation, indicating that the long-term perturbation in DA function leads to higher production of fAGEs. To confirm that DA has oxidative properties in vivo, we fed flies antioxidant quercetin (QUE) together with methamphetamine. QUE significantly decreased methamphetamine-induced fAGEs formation suggesting that the perturbation of DA function in vivo leads to increased oxidation. These findings present arguments for the use of fAGEs as a biomarker of DA-associated neurodegenerative changes and for assessment of antioxidant interventions such as QUE treatment.

Dietary sugars and related endogenous advanced glycation end-products increase chromosomal DNA damage in WIL2-NS cells, measured using cytokinesis-block micronucleus cytome assay

Mutagenesis ◽  
2020 ◽  
Vol 35 (2) ◽  
pp. 169-177 ◽  
Author(s):  
Permal Deo ◽  
Caitlin L McCullough ◽  
Theodora Almond ◽  
Emma L Jaunay ◽  
Leigh Donnellan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Advanced Glycation End Products ◽  
Chromosomal Dna ◽  
Advanced Glycation ◽  
Age Related ◽  
Genome Damage ◽  
Glycation End Products ◽  
End Products ◽  
High Concentrations

Abstract This study investigated the effect of glucose and fructose, and advanced glycation end-products (AGEs) on genome damage in WIL2-NS cells, measured using the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. The effect of AGEs was investigated using the bovine serum albumin (AGE-BSA) model system induced either with glucose (Glu–BSA) or with fructose (Fru–BSA). Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed higher Nε-carboxymethyllysine (CML; 26.76 ± 1.09 nmol/mg BSA) levels in the Glu–BSA model. Nε-Carboxyethyllysine (CEL; 7.87 ± 0.19 nmol/mg BSA) and methylglyoxal-derived hydroimidazolone-1 (MG-H1; 69.77 ± 3.74 nmol/mg BSA) levels were higher in the Fru–BSA model. Genotoxic effects were measured using CBMN-Cyt assay biomarkers [binucleated(BN) cells with micronuclei (MNi), BN with nucleoplasmic bridges (NPBs) and BN with nuclear buds (NBuds)] following 9 days of treatment with either glucose, fructose, Glu–BSA or Fru–BSA. Fructose treatment exerted a significant genotoxic dose–response effect including increases of BN with MNi (R2 = 0.7704; P = 0.0031), BN with NPBs (R2 = 0.9311; P < 0.0001) and BN with NBuds (R2 = 0.7118; P = 0.0091) on cells, whereas the DNA damaging effects of glucose were less evident. High concentrations of AGEs (400–600 µg/ml) induced DNA damage; however, there was no effect on cytotoxicity indices (necrosis and apoptosis). In conclusion, this study demonstrates a potential link between physiologically high concentrations of reducing sugars or AGEs with increased chromosomal damage which is an important emerging aspect of the pathology that may be induced by diabetes. Ultimately, loss of genome integrity could accelerate the rate of ageing and increase the risk of age-related diseases over the long term. These findings indicate the need for further research on the effects of glycation on chromosomal instability and to establish whether this effect is replicated in humans in vivo.

scholarly journals Advanced Glycation End Products: Formation, Role in Diabetic Complications, and Potential in Clinical Applications

2020 ◽  
Author(s):  
Rujman Khan ◽  
Xin Yee Ooi ◽  
Matthew Parvus ◽  
Laura Valdez ◽  
Andrew Tsin
Keyword(s):  
Diabetic Retinopathy ◽  
Advanced Glycation End Products ◽  
Diabetic Complications ◽  
Tanshinone Iia ◽  
Future Research ◽  
Advanced Glycation ◽  
Reactive Aldehydes ◽  
Glycation End Products ◽  
End Products ◽  
Lysine Residues

Hyperglycemic conditions and disruptions to glucose-regulating pathways lead to increased formation of highly reactive aldehydes, methylglyoxal and glyoxal, which react with certain arginine and lysine residues in proteins to form advanced glycation end products (AGEs). These AGEs damage the integrity of the retinal vasculature predominantly through two mechanisms: non-receptor-mediated damage, which pertains to the interaction with extracellular matrix and its functional properties, and receptor-mediated damage through AGE interactions with their receptors (RAGE) on pericytes and Muller cells. Damage occurring between AGE and RAGE potentially generates reactive oxygen species, inflammatory cytokines, and growth factors. Both mechanisms result in increased permeability of endothelial tight junctions, and this increased permeability can lead to leaking and eventually ischemia. Once this ischemia becomes significant, neovascularization can occur, the hallmark of proliferative diabetic retinopathy. Current pharmaceutical studies have shown the potential of AGE inhibitors, such as aminoguanidine, in decreasing AGE production, thus minimizing its effects in hyperglycemic conditions. Other pharmaceutical interventions, such as Tanshinone IIA, aim to protect cells from the impacts of AGEs. Future research will not only continue to understand the properties of AGEs and their effects on diabetes and diabetic complications like diabetic retinopathy but will also explore how they impact other diseases.

scholarly journals Use of Grape Pomace Phenolics to Counteract Endogenous and Exogenous Formation of Advanced Glycation End-Products

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1917 ◽  
Author(s):  
Pedapati S. C. Sri Harsha ◽  
Vera Lavelli
Keyword(s):  
Advanced Glycation End Products ◽  
Grape Pomace ◽  
Advanced Glycation ◽  
Sweetened Beverages ◽  
Glycation End Products ◽  
End Products ◽  
Food Applications ◽  
Double Blinded

The increase in consumption of “ultra-processed” foods has raised attention because of the possible adverse effects deriving from the Maillard reaction leading to the formation of toxic advanced glycation end-products (AGEs) during food processing. Additionally, the increasing trend and consumption of sugar-added foods and sweetened beverages is related to the endogenous formation of the same toxic compounds. However, ultra-processing in the context of food technology can bring challenges as well as a wealth of opportunities. Indeed, re-processing of grape pomace, a by-product of winemaking, can yield phenolic-rich fractions that efficiently counteract the effects of AGEs. In this review, the process of endogenous and exogenous AGE formation is illustrated. Then, the ability of grape phenolics to act as inhibitors of AGE formation is presented, including the efficacy ranking of various individual compounds measured in vitro and the outcome of in vivo double-blinded randomized crossover trials designed to prove the efficacy of grape phenolics as inhibitors of protein carbonylation. Finally, a survey of model functional foods added with grape phenolics, either to lower the dietary load of AGEs or to deliver antiglycation agents in vivo is listed in order to highlight the opportunity to develop safe and tailor-made “anti-AGEs” food applications.

scholarly journals Ethyl Pyruvate Prevents Renal Damage Induced by Methylglyoxal-Derived Advanced Glycation End Products

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Eunsoo Jung ◽  
Wan Seok Kang ◽  
Kyuhyung Jo ◽  
Junghyun Kim
Keyword(s):  
Advanced Glycation End Products ◽  
Ethyl Pyruvate ◽  
Renal Diseases ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Cross Links

The renal accumulation of advanced glycation end products (AGEs) is a causative factor of various renal diseases, including chronic kidney disease and diabetic nephropathy. AGE inhibitors, such as aminoguanidine and pyridoxamine, have the therapeutic activities for reversing the increase in renal AGE burden. This study evaluated the inhibitory effects of ethyl pyruvate (EP) on methylglyoxal- (MGO-) modified AGE cross-links with proteins in vitro. We also determined the potential activity of EP in reducing the renal AGE burden in exogenously MGO-injected rats. EP inhibited MGO-modified AGE-bovine serum albumin (BSA) cross-links to collagen (IC50=0.19±0.03 mM) in a dose-dependent manner, and its activity was stronger than aminoguanidine (IC50=35.97±0.85 mM). In addition, EP directly trapped MGO (IC50=4.41±0.08 mM) in vitro. In exogenous MGO-injected rats, EP suppressed AGE burden and MGO-induced oxidative injury in renal tissues. These activities of EP on the MGO-mediated AGEs cross-links with protein in vitro and in vivo showed its pharmacological potential for inhibiting AGE-induced renal diseases.

scholarly journals Diabetic threesome (hyperglycaemia, renal function and nutrition) and advanced glycation end products: evidence for the multiple-hit agent?

2008 ◽  
Vol 67 (1) ◽  
pp. 60-74 ◽  
Author(s):  
Kateřina Kaňková
Keyword(s):  
Advanced Glycation End Products ◽  
Biological Properties ◽  
Advanced Glycation ◽  
Similar Chemical ◽  
Wide Range ◽  
Glycation End Products ◽  
End Products ◽  
Genes Encoding ◽  
Sugar Derivatives

Complex chemical processes termed non-enzymic glycation that operate in vivo and similar chemical interactions between sugars and proteins that occur during thermal processing of food (known as the Maillard reaction) are one of the interesting examples of a potentially-harmful interaction between nutrition and disease. Non-enzymic glycation comprises a series of reactions between sugars, α-oxoaldehydes and other sugar derivatives and amino groups of amino acids, peptides and proteins leading to the formation of heterogeneous moieties collectively termed advanced glycation end products (AGE). AGE possess a wide range of chemical and biological properties and play a role in diabetes-related pathology as well as in several other diseases. Diabetes is, nevertheless, of particular interest for several reasons: (1) chronic hyperglycaemia provides the substrates for extracellular glycation as well as intracellular glycation; (2) hyperglycaemia-induced oxidative stress accelerates AGE formation in the process of glycoxidation; (3) AGE-modified proteins are subject to rapid intracellular proteolytic degradation releasing free AGE adducts into the circulation where they can bind to several pro-inflammatory receptors, especially receptor of AGE; (4) kidneys, which are principally involved in the excretion of free AGE adducts, might be damaged by diabetic nephropathy, which further enhances AGE toxicity because of diminished AGE clearance. Increased dietary intake of AGE in highly-processed foods may represent an additional exogenous metabolic burden in addition to AGE already present endogenously in subjects with diabetes. Finally, inter-individual genetic and functional variability in genes encoding enzymes and receptors involved in either the formation or the degradation of AGE could have important pathogenic, nutrigenomic and nutrigenetic consequences.

scholarly journals Advanced glycation end products promote hepatosteatosis by interfering with SCAP-SREBP pathway in fructose-drinking mice

2013 ◽  
Vol 305 (6) ◽  
pp. G398-G407 ◽  
Author(s):  
Raffaella Mastrocola ◽  
Massimo Collino ◽  
Mara Rogazzo ◽  
Claudio Medana ◽  
Debora Nigro ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
De Novo ◽  
Regulatory Element ◽  
Plasma Lipid ◽  
De Novo Lipogenesis ◽  
Advanced Glycation ◽  
Sugary Drinks ◽  
Glycation End Products ◽  
End Products

Clinical studies have linked the increased consumption of fructose to the development of obesity, dyslipidemia, and impaired glucose tolerance, and a role in hepatosteatosis development is presumed. Fructose can undergo a nonenzymatic reaction from which advanced glycation end products (AGEs) are derived, leading to the formation of dysfunctional, fructosylated proteins; however, the in vivo formation of AGEs from fructose is still less known than that from glucose. In the present study C57Bl/6J mice received 15% (wt/vol) fructose (FRT) or 15% (wt/vol) glucose (GLC) in water to drink for 30 wk, resembling human habit to consume sugary drinks. At the end of the protocol both FRT- and GLC-drinking mice had increased fasting glycemia, glucose intolerance, altered plasma lipid profile, and marked hepatosteatosis. FRT mice had higher hepatic triglycerides deposition than GLC, paralleled by a greater increased expression and activity of the sterol regulatory element-binding protein 1 (SREBP1), the transcription factor responsible for the de novo lipogenesis, and of its activating protein SCAP. LC-MS analysis showed a different pattern of AGE production in liver tissue between FRT and GLC mice, with larger amount of carboxymethyl lysine (CML) generated by fructose. Double immunofluorescence and coimmunoprecipitation analysis revealed an interaction between CML and SCAP that could lead to prolonged activation of SREBP1. Overall, the high levels of CML and activation of SCAP/SREBP pathway associated to high fructose exposure here reported may suggest a key role of this signaling pathway in mediating fructose-induced lipogenesis.

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