Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT2A/2Creceptors

2007 ◽  
Vol 293 (1) ◽  
pp. C328-C336 ◽  
Author(s):  
Yingjie Wang ◽  
Werner Beck ◽  
Reinhold Deppisch ◽  
Sally M. Marshall ◽  
Nicholas A. Hoenich ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Inflammatory Responses ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products

Advanced glycation end products (AGE) are substantially elevated in individuals with diabetes and/or chronic kidney disease (CKD). These patients are at greatly increased risk of cardiovascular events. The purpose of this study was to investigate the novel hypothesis that AGE elicit externalization of the platelet membrane phospholipid phosphatidylserine (PS). This contributes to hemostasis through propagation of the coagulation cascade leading to thrombus formation. Platelet-rich plasma (PRP) was prepared by differential centrifugation, and PS externalization was quantified by a fluorescence-activated cell sorter using annexin V-FITC. Human serum albumin (HSA)-AGE was generated by incubating HSA with glucose for 2, 4, or 6 wk, and total HSA-AGE was assessed by fluorescence intensity. The 2-wk HSA-AGE preparation (0–2 mg/ml) stimulated a concentration-dependent increase in PS externalization in a subpopulation of platelets that was threefold at 2 mg/ml. In contrast, the 4- and 6-wk preparations were maximal at 0.5 mg/ml and fivefold in magnitude. These effects mirrored the change in total HSA-AGE content of the preparations. The PS response was maximal at 10 min and inhibited by the PKC-δ inhibitor rottlerin and the serotonin [5-hydroxytryptamine (5-HT)]2A/2Creceptor antagonist ritanserin in a dose-dependent manner. Moreover, the 5-HT2A/2Creceptor agonist 1,2,5-dimethoxy-4-iodophenyl-2-aminopropane mimicked the effect of HSA-AGE on PS externalization. These data demonstrate, for the first time, that HSA-AGE stimulates PS externalization in a subpopulation of platelets via the 5-HT2A/2Creceptor. This may have important consequences for platelet involvement in inflammatory responses and the increased cardiovascular risk observed in individuals with diabetes and/or CKD.

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.

scholarly journals Higher levels of the soluble receptor for advanced glycation end products and lower levels of the extracellular newly identified receptor for advanced glycation end products were associated with lipid-lowering drugs in patients with type 1 diabetes: a comparative cross-sectional study

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Eva O. Melin ◽  
Jonatan Dereke ◽  
Magnus Hillman
Keyword(s):  
Type 1 Diabetes ◽  
Advanced Glycation End Products ◽  
Inflammatory Responses ◽  
Lipid Lowering ◽  
Advanced Glycation ◽  
Cross Sectional ◽  
Lipid Lowering Drugs ◽  
Glycation End Products ◽  
End Products

Abstract Background The receptors for advanced glycation end products (RAGE) are increased in atherosclerotic plaques. Soluble (s)RAGE decreases, whereas the extracellular newly identified receptor for advanced glycation end products (EN-RAGE) increases inflammatory responses mediated by RAGE. The aims were to explore whether sRAGE, EN-RAGE and the EN-RAGE/sRAGE ratio, were associated with the use of lipid-lowering drugs (LLD) and/or antihypertensive drugs (AHD) in patients with type 1 diabetes (T1D). Methods Cross-sectional design. T1D patients were consecutively recruited from one diabetes clinic. Blood samples were collected, supplemented with data from electronic health records. sRAGE and EN-RAGE were analysed by enzyme linked immunosorbent assays. An EN-RAGE/sRAGE ratio was calculated. Adjustments were performed with inflammatory and metabolic variables, s-creatinine, depression, smoking, physical inactivity, medication, and cardiovascular complications. Multiple regression analyses were performed. Results In this study 283 T1D patients (men 56%, 18–59 years) were included. One-hundred and thirty LLD users compared to 153 non-users had lower levels of the EN-RAGE/sRAGE ratio (P = 0.009), and 89 AHD users compared to 194 non-users had lower levels of sRAGE (P = 0.031). The use of LLD (inversely) (B coefficient − 0.158, P = 0.033) and the use of AHD (B coefficient 0.187, P = 0.023) were associated with the EN-RAGE/sRAGE ratio. sRAGE (Lg10) (per unit) (adjusted odds ratio (AOR) = 3.5, 95% CI = 1.4–9.1, P = 0.009), EN-RAGE (Lg10) (per unit) (inversely) (AOR 0.4, 95% CI = 0.2–1.0, P = 0.046), age (P <  0.001), and triglycerides (P <  0.029), were associated with LLD. sRAGE (Lg10) (per unit) (inversely) (AOR = 0.2, 95% CI = 0.1–0.5, P = 0.001), diabetes duration, triglycerides, s-creatinine, and systolic BP (all P values < 0.043), were associated with AHD. Conclusions Higher sRAGE levels and lower EN-RAGE levels were linked to the use of LLD, whereas lower sRAGE levels were linked to the use of AHD. No other variables but the use of LLD and the use of AHD were linked to the EN-RAGE/sRAGE ratio. This may be of major importance as sRAGE is an inhibitor and EN-RAGE is a stimulator of inflammatory processes mediated by RAGE.

scholarly journals The Effect of Glyceraldehyde-Derived Advanced Glycation End Products on β-Tubulin-Inhibited Neurite Outgrowth in SH-SY5Y Human Neuroblastoma Cells

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2958
Author(s):  
Ryuto Nasu ◽  
Ayako Furukawa ◽  
Keita Suzuki ◽  
Masayoshi Takeuchi ◽  
Yoshiki Koriyama
Keyword(s):  
Neurite Outgrowth ◽  
Advanced Glycation End Products ◽  
Neurological Disorders ◽  
Neuroblastoma Cells ◽  
Advanced Glycation ◽  
Human Neuroblastoma ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products ◽  
Β Tubulin

Nutritional factors can affect the risk of developing neurological disorders and their rate of progression. In particular, abnormalities of carbohydrate metabolism in diabetes mellitus patients lead to an increased risk of neurological disorders such as Alzheimer’s disease (AD). In this study, we investigated the relationship between nervous system disorder and the pathogenesis of AD by exposing SH-SY5Y neuroblastoma cells to glyceraldehyde (GA). We previously reported that GA-derived toxic advanced glycation end products (toxic AGEs, TAGE) induce AD-like alterations including intracellular tau phosphorylation. However, the role of TAGE and their target molecules in the pathogenesis of AD remains unclear. In this study, we investigated the target protein for TAGE by performing two-dimensional immunoblot analysis with anti-TAGE antibody and mass spectrometry and identified β-tubulin as one of the targets. GA treatment induced TAGE-β-tubulin formation and abnormal aggregation of β-tubulin, and inhibited neurite outgrowth in SH-SY5Y cells. On the other hand, glucose-derived AGEs were also involved in developing AD. However, glucose did not make abnormal aggregation of β-tubulin and did not inhibit neurite outgrowth. Understanding the underlying mechanism of TAGE-β-tubulin formation by GA and its role in neurodegeneration may aid in the development of novel therapeutics and neuroprotection strategies.

scholarly journals DJC Suppresses Advanced Glycation End Products-Induced JAK-STAT Signaling and ROS in Mesangial Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Min Sun ◽  
Yan Li ◽  
Wenjie Bu ◽  
Jindong Zhao ◽  
Jianliang Zhu ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Oxidase Activity ◽  
Mesangial Cells ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Nadph Oxidase Activity ◽  
Glycation End Products ◽  
End Products ◽  
Anti Inflammatory

The antidiabetic properties and anti-inflammatory effects of Danzhi Jiangtang Capsules (DJC) have been demonstrated in clinical and laboratory experiments. In this study, we explored whether DJC can ameliorate advanced glycation end products- (AGEs-) mediated cell injury and the precise mechanisms of DJC in treating diabetic nephropathy (DN). Western blot analysis was employed to assess the expressions of iNOS, COX2, and SOCS and the phosphorylation of JAK2, STAT1, and STAT3 in glomerular mesangial cells (GMCs) after treatment with DJC. TNF-α, IL-6, and MCP-1 were determined using double-antibody sandwich ELISA. ROS and NADPH oxidase activity were measured by DCFH-DA assay and lucigenin-enhanced chemiluminescence, respectively. DJC significantly reversed the AGEs-induced expression of COX2 and iNOS. Moreover, DJC inhibited the AGEs-induced JAK2-STAT1/STAT3 activation, resulting in the inhibition of inflammatory cytokines such as IL-6, MCP-1, and TNF-αin a concentration-dependent manner. The ability of DJC to suppress STAT activation was also verified by the observation that DJC significantly increased the SOCS3 protein level. DJC reversed the AGEs-induced accumulation of ROS and NADPH oxidase activity, thus confirming that DJC possesses antioxidant activity. The results suggest that the anti-inflammatory effects of DJC in GMCs may be due to its ability to suppress the JAK2-STAT1/STAT3 cascades and reduce ROS production.

scholarly journals Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases

2019 ◽  
Vol 20 (13) ◽  
pp. 3234
Author(s):  
Alexandra Eichhorst ◽  
Christoph Daniel ◽  
Rita Rzepka ◽  
Bettina Sehnert ◽  
Falk Nimmerjahn ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Diseases ◽  
Advanced Glycation End Products ◽  
Plasma Cells ◽  
Inflammatory Responses ◽  
Joint Inflammation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE−/− animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE−/− mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE−/− animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.

scholarly journals Shorter Telomere Length in Carriers of APOE-ε4 and High Plasma Concentration of Glucose, Glyoxal and Other Advanced Glycation End Products (AGEs)

2019 ◽  
Vol 75 (10) ◽  
pp. 1894-1898 ◽  
Author(s):  
Varinderpal S Dhillon ◽  
Permal Deo ◽  
Ann Chua ◽  
Phil Thomas ◽  
Michael Fenech
Keyword(s):  
Risk Factor ◽  
Telomere Length ◽  
Advanced Glycation End Products ◽  
Biological Aging ◽  
Advanced Glycation ◽  
Apoe Ε4 ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products ◽  
Ε4 Allele

Abstract Apolipoprotein-ε4 (APOE-ε4)—common variant is a major genetic risk factor for cognitive decline and Alzheimer's disease (AD). An accelerated rate of biological aging could contribute to this increased risk. Glycation of serum proteins due to excessive glucose and reactive oxygen species leads to the formation of advanced glycation end products (AGEs)—a risk factor for diabetes and AD, and decline in motor functioning in elderly adults. Aim of present study was to investigate impact of APOE-ε4 allele containing genotype and accumulation of AGEs in plasma on telomere length (TL). Results showed that TL is significantly shorter in APOE-ε4 carriers compared with non-APOE-ε4 carriers (p = .0003). Higher plasma glucose level was associated with shorter TL irrespective of APOE-ε4 allele containing genotype (r = −.26; p = .0004). With regard to AGEs, higher plasma glyoxal and fluorescent AGEs concentrations were inversely related to TL (r = −.16; p = .03; r = −.28; p = .0001), however, plasma Nε-(carboxymethyl)lysine levels didn't correlate with TL (r = −.04; p = .57). Results support the hypotheses that APOE-ε4 carriers have shorter telomeres than noncarriers and telomere erosion is increased with higher concentration of glucose, fluorescent AGEs, and glyoxal.

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.

Rehmannia glutinosa Suppresses Inflammatory Responses Elicited by Advanced Glycation End Products

Inflammation ◽  
2012 ◽  
Vol 35 (4) ◽  
pp. 1232-1241 ◽  
Author(s):  
Gui-Hyun Baek ◽  
Yong-Suk Jang ◽  
Seung-Il Jeong ◽  
Jaeho Cha ◽  
Myungsoo Joo ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Inflammatory Responses ◽  
Rehmannia Glutinosa ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products
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