scholarly journals Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
Davide Maggi ◽  
Massimo Nicolò ◽  
Carlo E. Traverso ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Angiopoietin 2 ◽  
Angiopoietin 1

The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.

scholarly journals In Vitro Evaluation of the Toxicological Profile and Oxidative Stress of Relevant Diet-Related Advanced Glycation End Products and Related 1,2-Dicarbonyls

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Vanesa Cepas ◽  
Friederike Manig ◽  
Juan C. Mayo ◽  
Michael Hellwig ◽  
Debora Collotta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acids ◽  
Cell Death ◽  
Advanced Glycation End Products ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Advanced Glycation ◽  
Dicarbonyl Compounds ◽  
Glycation End Products ◽  
End Products

During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N- ε -(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.

scholarly journals Increased Expression of Tissue Factor and Receptor for Advanced Glycation End Products in Peripheral Blood Mononuclear Cells of Patients With Type 2 Diabetes Mellitus with Vascular Complications

2004 ◽  
Vol 5 (2) ◽  
pp. 163-169 ◽  
Author(s):  
A. E. Buchs ◽  
A. Kornberg ◽  
M. Zahavi ◽  
D. Aharoni ◽  
C. Zarfati ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Advanced Glycation End Products ◽  
Mononuclear Cells ◽  
Vascular Complications ◽  
Advanced Glycation ◽  
Peripheral Blood Mononuclear ◽  
Glycation End Products ◽  
End Products ◽  
Blood Mononuclear Cells

The aim of the study was to determine the correlation between the expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in patients with longstanding uncontrolled type 2 diabetes (T2D). TF and RAGE mRNAs as well as TF antigen and activity were investigated in 21 T2D patients with and without vascular complications. mRNA expression was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) in nonstimulated and advanced glycation end product (AGE) albumin–stimulated peripheral blood mononuclear cells (PBMCs). TF antigen expression was determined by enzyme-linked immunosorbent assay (ELISA) and TF activity by a modified prothrombin time assay. Basal RAGE mRNA expression was 0.2 ± 0.06 in patients with complications and 0.05 ± 0.06 patients without complications (P= .004). Stimulation did not cause any further increase in either group. TF mRNA was 0.58 ± 0.29 in patients with complications and 0.21 ± 0.18 in patients without complications (P= .003). Stimulation resulted in a nonsignificant increase in both groups. Basal TF activity (U/106PBMCs) was 18.4 ± 13.2 in patients with complications and 6.96 ± 5.2 in patients without complications (P= .003). It increased 3-fold in both groups after stimulation (P= .001). TF antigen (pg/106PBMCs) was 33.7 ± 28.6 in patients with complications, 10.4 ± 7.8 in patients without complications (P= .02). Stimulation tripled TF antigen in both groups of patients (P= .001). The RAGE/TF axis is up-regulated inT2Dpatients with vascular complications as compared to patients without complications. This suggests a role for this axis in the pathogenesis of vascular complications in T2D.

scholarly journals Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 6136-6144 ◽  
Author(s):  
Weifei Zhu ◽  
Wei Li ◽  
Roy L. Silverstein
Keyword(s):  
Diabetes Mellitus ◽  
Mouse Models ◽  
Advanced Glycation End Products ◽  
Vascular Complications ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Drug Induced ◽  
Glycation End Products ◽  
End Products

Abstract Diabetes mellitus has been associated with platelet hyperreactivity, which plays a central role in the hyperglycemia-related prothrombotic phenotype. The mechanisms responsible for this phenomenon are not established. In the present study, we investigated the role of CD36, a class-B scavenger receptor, in this process. Using both in vitro and in vivo mouse models, we demonstrated direct and specific interactions of platelet CD36 with advanced glycation end products (AGEs) generated under hyperglycemic conditions. AGEs bound to platelet CD36 in a specific and dose-dependent manner, and binding was inhibited by the high-affinity CD36 ligand NO2LDL. Cd36-null platelets did not bind AGE. Using diet- and drug-induced mouse models of diabetes, we have shown that cd36-null mice had a delayed time to the formation of occlusive thrombi compared with wild-type (WT) in a FeCl3-induced carotid artery injury model. Cd36-null mice had a similar level of hyperglycemia and a similar level of plasma AGEs compared with WT mice under this condition, but WT mice had more AGEs incorporated into thrombi. Mechanistic studies revealed that CD36-dependent JNK2 activation is involved in this prothrombotic pathway. Therefore, the results of the present study couple vascular complications in diabetes mellitus with AGE-CD36–mediated platelet signaling and hyperreactivity.

Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells

2001 ◽  
Vol 359 (3) ◽  
pp. 567-574 ◽  
Author(s):  
Karel OTERO ◽  
Fernando MARTÍNEZ ◽  
Amada BELTRÁN ◽  
Deyarina GONZÁLEZ ◽  
Beatriz HERRERA ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Advanced Glycation End Products ◽  
Biological Effects ◽  
Vascular Complications ◽  
Vascular Endothelial ◽  
Advanced Glycation ◽  
Cell Extracts ◽  
Vascular Endothelial Cadherin ◽  
Glycation End Products ◽  
End Products

Endothelial cell (EC) junctions regulate in large part the integrity and barrier function of the vascular endothelium. Advanced glycation end-products (AGEs), the irreversibly formed reactive derivatives of non-enzymic glucose–protein condensation reactions, are strongly implicated in endothelial dysfunction that distinguishes diabetes- and aging-associated vascular complications. The aim of the present study was to determine whether AGEs affect EC lateral junction proteins, with particular regard to the vascular endothelial cadherin (VE-cadherin) complex. Our results indicate that AGE-modified BSA (AGE-BSA), a prototype of advanced glycated proteins, disrupts the VE-cadherin complex when administered to ECs. AGE-BSA, but not unmodified BSA, was found to induce decreases in the levels of VE-cadherin, β-catenin and γ-catenin in the complex and in total cell extracts, as well as a marked reduction in the amount of VE-cadherin present at the cell surface. In contrast, the level of platelet endothelial cell adhesion molecule-1 (PECAM-1), which is located at lateral junctions, was not altered. Supplementation of the cellular antioxidative defences abolished these effects. Finally, the loss of components of the VE-cadherin complex was correlated with increases in vascular permeability and in EC migration. These findings suggest that some of the AGE-induced biological effects on the endothelium could be mediated, at least in part, by the weakening of intercellular contacts caused by decreases in the amount of VE-cadherin present.

scholarly journals Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

2021 ◽  
Author(s):  
Hao Tan ◽  
Wenjie Xu ◽  
Xiaoqian Ding ◽  
Huayu Ye ◽  
Yun Hu ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Nuclear Translocation ◽  
Bone Diseases ◽  
Advanced Glycation ◽  
Raw264.7 Macrophages ◽  
Macrophages Polarization ◽  
M1 Polarization ◽  
Glycation End Products ◽  
End Products ◽  
Signaling Axis

Abstract Advanced glycation end products (AGEs) aggregation and macrophages polarization both play essential roles in degenerative bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to understand the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. We found that RAW264.7 macrophages treated with AGEs highly expressed M1-associated genes and surface antigen markers CD86, and released a large amount of NO to the extracellular environment. Through the detection of osteoclast-related markers and TRAP staining, we revealed that the osteoclastogenesis of M1 macrophages could be markedly enhanced by AGEs. To explore the potential mechanisms of AGEs-mediated M1 polarization, we first demonstrated that AGEs effectively activated the transduction of Notch signaling pathway, including nuclear translocation of NICD1. Subsequently, it was observed that the M1 polarization effects induced by AGEs were significantly mitigated, when γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J were applied to block the signal transduction of Notch. In conclusion, our findings revealed a series of phenomena that AGEs induce macrophage M1 polarization and enhance its osteoclastogenesis ability, and Notch/NICD/RBP-J signaling axis is involved in the regulation of this polarization process.

scholarly journals Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression

2021 ◽  
Vol 10 (18) ◽  
pp. 4084
Author(s):  
Agnieszka Bronowicka-Szydełko ◽  
Łukasz Kotyra ◽  
Łukasz Lewandowski ◽  
Andrzej Gamian ◽  
Irena Kustrzeba-Wójcicka
Keyword(s):  
Thyroid Cancer ◽  
Cancer Progression ◽  
Advanced Glycation End Products ◽  
Intracellular Signaling ◽  
Anaplastic Thyroid Cancer ◽  
Carbonyl Stress ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.

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