Glucose-dependent Insulinotropic Polypeptide (GIP) Inhibits Signaling Pathways of Advanced Glycation End Products (AGEs) in Endothelial Cells via its Antioxidative Properties

Ojima, Ayako; Matsui, Takanori; Maeda, Sayaka; Takeuchi, Masayoshi; Yamagishi, Sho‐ichi

doi:10.1055/s-0032-1312595

Cited by 41 publications

(29 citation statements)

References 10 publications

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“…We have previously shown that antibody or antisense DNA raised against RAGE completely inhibits the AGE-evoked ROS generation in endothelial cells, while an anti-oxidant N -acetylcysteine or RAGE antibody itself blocks up-regulation of RAGE mRNA levels in AGE-exposed endothelial cells [21, 27, 28]. So our present study suggests that n-butanol extracts of noni may inhibit the deleterious effects of AGEs by breaking the vicious cycle between ROS generation and RAGE overexpression in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

N-butanol extracts of Morinda citrifolia suppress advanced glycation end products (AGE)-induced inflammatory reactions in endothelial cells through its anti-oxidative properties

Ishibashi

Matsui

Isami³

et al. 2017

BMC Complement Altern Med

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BackgroundAdvanced glycation end products (AGEs), senescent macroprotein derivatives formed during a normal aging process and acceleratedly under diabetic conditions, play a role in atherosclerotic cardiovascular disease. AGEs cause endothelial cell (EC) damage, an initial trigger for atherosclerosis through the interaction with a receptor for AGEs (RAGE). We have previously shown that n-butanol extracts of Morinda citrifolia (noni), a plant belonging to the family Rubiaceae, block the binding of AGEs to RAGE in vitro. In this study, we examined the effects of n-butanol extracts of noni on reactive oxygen species (ROS) generation and inflammatory reactions on AGE-exposed human umbilical vein ECs (HUVECs).MethodsHUVECs were treated with 100 μg/ml AGE-bovine serum albumin (AGE-BSA) or non-glycated BSA in the presence or absence of 670 ng/ml n-butanol extracts of noni for 4 h. Then ROS generation and inflammatory and gene expression in HUVECs were evaluated by dihydroethidium staining and real-time reverse transcription-polymerase chain reaction analyses, respectively. THP-1 cell adhesion to HUVECs was measured after 2-day incubation of AGE-BSA or BSA in the presence or absence of 670 ng/ml n-butanol extracts of noni.ResultsN-butanol extracts of noni at 670 ng/ml significantly inhibited the AGE-induced ROS generation and RAGE, intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 gene expressions in HUVECs. AGEs significantly increased monocytic THP-1 cell adhesion to HUVECs, which was also prevented by 670 ng/ml n-butanol extracts of noni.ConclusionsThe present study demonstrated for the first time that N-butanol extracts of noni could suppress the AGE-induced inflammatory reactions in HUVECs through its anti-oxidative properties via blocking of the interaction of AGEs with RAGE. Inhibition of the AGE-RAGE axis by n-butanol extracts of noni may be a novel nutraceutical strategy for the treatment of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

N-butanol extracts of Morinda citrifolia suppress advanced glycation end products (AGE)-induced inflammatory reactions in endothelial cells through its anti-oxidative properties

Ishibashi

Matsui

Isami³

et al. 2017

BMC Complement Altern Med

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“…We have previously found that GLP-1 or GIP limits endothelial and mesangial cells' susceptibility toward pro-oxidative and pro-inflammatory effects of AGEs by suppressing RAGE gene expression and oxidative stress generation through the elevation of cyclic AMP, whose effect could be augmented by the addition of DPP-4 inhibitor. [28][29][30][31] In addition, the AGE-RAGE axis evokes oxidative stress generation in various cell types via NADPH oxidase activity, which is blocked by cAMP-elevating agents. 3,32,33 Aortic AGEs and oxidative stress levels have been shown to decrease in diabetic RAGE and apolipoprotein E double knockout Figure 1 AGE-modified protein levels (a and b) and RAGE gene expression (c) in the kidneys of Control, DPP-4-deficient, STZ or DPP-4-deficient STZ rats at 9 weeks old.…”

Section: Dpp-4 and Age-rage T Matsui Et Almentioning

confidence: 99%

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Matsui

Nakashima

Nishino

et al. 2015

Laboratory Investigation

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Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy. Sugars, including glucose and fructose, can react nonenzymatically with the amino groups of proteins, lipids and nucleic acids to form reversible Schiff bases, and then Amadori products. 1-3 These early glycation products undergo further complex reactions such as rearrangement, dehydration and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives called 'advanced glycation end products (AGEs)'. 1-3 The process of non-enzymatic glycation is also known as Maillard reaction, and formation and accumulation of AGEs in various tissues have progressed at a physiological aging and at an extremely accelerated rate under diabetes. [1][2][3] There is a growing body of evidence that AGEs and their receptor (RAGE) interaction evoke oxidative stress generation and inflammatory and fibrotic reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes. [4][5][6][7][8] Furthermore, RAGEoverexpressing diabetic mice have been shown to exhibit progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene. 9 Diabetic homozygous RAGE null mice displayed diminished albuminuria and glomerulosclerosis and failed to develop significantly increased mesan...

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“…In support of this hypothesis, we previously found that vildagliptin treatment is ineffective in lowering blood glucose levels in type 1 diabetic rats, but that it significantly reduces oxidative stress generation as well as ICAM-1 and PAI-1 gene expression in the thoracic aorta of this model [6]. Furthermore, therapeutic levels of GLP-1 and GIP, which are achieved by treatment with vildagliptin, have also been shown to suppress AGE-induced inflammatory and thrombogenic reactions in endothelial cells [15,16]. Whatever the mechanism, the present findings suggest that vildagliptin may potentially protect against retinal damage in patients with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Vildagliptin on Retinal Injury in Obese Type 2 Diabetic Rats

Maeda

Yamagishi²,

Matsui³

et al. 2013

Ophthalmic Res

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Background/Aims: Vildagliptin is an oral inhibitor of dipeptidyl peptidase-4, an enzyme mainly responsible for inactivating incretins, and one of the widely used drugs for the treatment of type 2 diabetes. However, effects of vildagliptin on retinal injury in diabetes remain unclear. We examined here whether oral administration of vildagliptin inhibited gene expression of inflammatory and thrombogenic parameters in Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), an animal model of obese type 2 diabetes. Methods: OLETF rats at 22 weeks of age were given vehicle or 3 mg/kg of vildagliptin for another 10 weeks. Gene expression was analyzed in quantitative real-time reverse transcription-polymerase chain reaction. Results: Vildagliptin significantly inhibited the increase in body weight and decreased average fasting blood glucose in the OLETF rats. Compared with 22-week-old OLETF rats, gene expression levels of vascular endothelial growth factor, intercellular adhesion molecule-1, plasminogen activator inhibitor-1 and pigment epithelium-derived factor were significantly increased in the retinas of OLETF rats at 32 weeks of age, all of which were inhibited by treatment with vildagliptin. Conclusions: The present study demonstrated for the first time that vildagliptin inhibited inflammatory and thrombogenic reactions in the retinas of obese type 2 diabetic rats. Vildagliptin may play a protective role against diabetic retinopathy.

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Glucose-dependent Insulinotropic Polypeptide (GIP) Inhibits Signaling Pathways of Advanced Glycation End Products (AGEs) in Endothelial Cells via its Antioxidative Properties

Cited by 41 publications

References 10 publications

N-butanol extracts of Morinda citrifolia suppress advanced glycation end products (AGE)-induced inflammatory reactions in endothelial cells through its anti-oxidative properties

N-butanol extracts of Morinda citrifolia suppress advanced glycation end products (AGE)-induced inflammatory reactions in endothelial cells through its anti-oxidative properties

Dipeptidyl peptidase-4 deficiency protects against experimental diabetic nephropathy partly by blocking the advanced glycation end products-receptor axis

Beneficial Effects of Vildagliptin on Retinal Injury in Obese Type 2 Diabetic Rats

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