scholarly journals Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chih-Pei Lin ◽  
Po-Hsun Huang ◽  
Chi-Yu Chen ◽  
Meng-Yu Wu ◽  
Jia-Shiong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Calcium Deposition ◽  
Arterial Calcification ◽  
Advanced Glycation ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

AbstractDiabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

scholarly journals Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Attenuates Arterial Calcification By Downregulating Oxidative Stress-Induced Receptor for Advanced Glycation End Products in Low-Density Lipoprotein Receptor Knockout Mice

2021 ◽  
Author(s):  
Chih Pei Lin ◽  
Po-Hsun Huang ◽  
Chi-Yu Chen ◽  
Jia-Shiong Chen ◽  
Jaw-Wen Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Calcium Deposition ◽  
Advanced Glycation ◽  
Dipeptidyl Peptidase 4 ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Abstract Background: Plasma advanced glycation end products (AGEs) activates the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus patient vascular complications. Attenuating the activation of RAGE may exert a protective effect against the development of cardiovascular disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are a new class of oral hypoglycemic agents for the treatment of type 2 diabetes mellitus. Whether sitagliptin, a DPP-4 inhibitor, has a beneficial effect on vascular calcification remains undetermined. Methods: In the present study, we fed low-density lipoprotein receptor knockout (LDLR-/-) mice a high fat diet to induce diabetic mellitus and studied the effect of orally administered sitagliptin on the high fat diet fed LDLR-/- mice aorta medial calcification, RAGE expression, oxidative stress, aorta calcium content. Tumor necrosis factor (TNF)-α combined with S100A12 was used to induce HASMC oxidative stress, activation of NADPH, up-regulation of the bone markers and RAGE expression, and cell calcium deposition. Effect of sitagliptin, siRNA for RAGE and apocynin on blunting TNF-α and S100A12 induced HASMC oxidative stress, calcification and NADPH activation were also investigated. Results: Sitagliptin attenuated the HFD-induced LDLR-/- mice hyperlipidemia, hyperglycemia, increase in serum TNF-α, aorta calcium deposition and the expression of RAGE in the medial layer of the aorta. TNF-α combined with S100A12 stimulated HASMC RAGE expression, calcium deposition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activation, and up-regulation of bone marker (bone morphogenetic protein-2, Msh homeobox 2, and runt‑related transcription factor 2) expression. Sitagliptin and apocynin (APO), an NADPH oxidase inhibitor, suppressed the TNF-α+S100A12 treatment effects on the activation of NADPH oxidase and Nuclear factor (NF)-κB and the resultant oxidative stress, up-regulation of RAGE and bone markers expression and calcium deposition. Our findings suggest that sitagliptin imparts its protective effect by suppressing NADPH oxidase and NF-κB activation to blunt the up-regulation of RAGE expression.Conclusion: Our findings suggest that sitagliptin may suppress the initiation and progression of artery calcification by inhibiting the activation of NADPH oxidase and NF-κB and the resultant up-regulation of expression of RAGE.

Bombax ceiba (Linn.) calyxes ameliorate methylglyoxal-induced oxidative stress via modulation of RAGE expression: identification of active phytometabolites by GC-MS analysis

2020 ◽  
Vol 11 (6) ◽  
pp. 5486-5497
Author(s):  
Anusha Komati ◽  
Ajay Anand ◽  
Hussain Shaik ◽  
Mohana Krishna Reddy Mudiam ◽  
Katragadda Suresh Babu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Advanced Glycation End Products ◽  
Enzymatic Reactions ◽  
Advanced Glycation ◽  
Ms Analysis ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Non-enzymatic reactions between proteins and methylglyoxal (MG) result in the formation of advanced glycation end products (AGEs). Bombax ceiba calyx extract prevents the formation of AGEs.

Effects of Resveratrol on Receptor for Advanced Glycation End Products (RAGE) Expression and Oxidative Stress in the Liver of Rats with Type 2 Diabetes

2015 ◽  
Vol 30 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Mohammad Khazaei ◽  
Jamshid Karimi ◽  
Nasrin Sheikh ◽  
Mohammad Taghi Goodarzi ◽  
Massoud Saidijam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Advanced Glycation End Products ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
And Oxidative Stress ◽  
Rage Expression

scholarly journals Advanced Glycation End Products and Oxidative Stress in a Hyperglycaemic Environment

2021 ◽  
Author(s):  
Akio Nakamura ◽  
Ritsuko Kawahrada
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Advanced Glycation End Products ◽  
Reactive Oxygen ◽  
Protein Glycation ◽  
Oxygen Species ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
And Oxidative Stress

Protein glycation is the random, nonenzymatic reaction of sugar and protein induced by diabetes and ageing; this process is quite different from glycosylation mediated by the enzymatic reactions catalysed by glycosyltransferases. Schiff bases form advanced glycation end products (AGEs) via intermediates, such as Amadori compounds. Although these AGEs form various molecular species, only a few of their structures have been determined. AGEs bind to different AGE receptors on the cell membrane and transmit signals to the cell. Signal transduction via the receptor of AGEs produces reactive oxygen species in cells, and oxidative stress is responsible for the onset of diabetic complications. This chapter introduces the molecular mechanisms of disease onset due to oxidative stress, including reactive oxygen species, caused by AGEs generated by protein glycation in a hyperglycaemic environment.

Citrus Fruit Extracts Reduce Advanced Glycation End Products (AGEs)- and H2O2-Induced Oxidative Stress in Human Adipocytes

2010 ◽  
Vol 58 (20) ◽  
pp. 11119-11129 ◽  
Author(s):  
Deena Ramful ◽  
Evelyne Tarnus ◽  
Philippe Rondeau ◽  
Christine Robert Da Silva ◽  
Theeshan Bahorun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Advanced Glycation End Products ◽  
Citrus Fruit ◽  
Human Adipocytes ◽  
Advanced Glycation ◽  
Fruit Extracts ◽  
Glycation End Products ◽  
End Products

ONO-2506 alleviates lipopolysaccharide-induced hippocampal neuroinflammation and apoptosis

2019 ◽  
Author(s):  
Jian-yu Liu ◽  
Wei Fang ◽  
Shi-xia Cai ◽  
Ming-ying Dai ◽  
Bo Yao
Keyword(s):  
S100 Protein ◽  
Brain Cell ◽  
Potential Treatment ◽  
Advanced Glycation ◽  
High Concentration ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Neurotoxic Effects ◽  
Rage Expression

Abstract Background Sepsis associated encephalopathy has high mortality rate, but there is no targeted therapy to reduce brain damage in septic patients. In our previous study, we found that S100β concentration was higher in patients with SAE. At high concentration, S100β exerts neurotoxic effects through receptor for advanced glycation end products (RAGE). RAGE-activated signalling could induce the inflammatory response. And neuroinflammation is an important mechanism of SAE. So inhibiting S100β expression may be a potential treatment of SAE. ONO-2506 can inhibit the production and release of S100 protein from astrocytes. In this study, we administered ONO-2506 to mice in order to evaluate its effectiveness on neuroinflammation and apoptosis in hippocampus induced by lipopolysaccharides. Results We found administration with lipopolysaccharides increased the levels of S100β, RAGE, IL-β, TNF-α and the TUNEL positive brain cells in hippocampus tissue. The ONO-2506 30mg/kg and 90mg/kg could reduce the levels of neuroinflammation (IL-β and TNF-α), and alleviate the apoptosis in hippocampus. Conclusions ONO-2506 could reduce the neuroinflammation and alleviate brain cell apoptosis in hippocampus of LPS mice models. Moreover, the RAGE expression was inhibited after ONO-2506 treatment.

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