Relationship of advanced glycation end-products in hypertension in diabetic patients: a systematic review / Relação dos produtos finais de glicação avançada na hipertensão de pacientes com diabetes: uma revisão sistemática

Abstract Diabetes mellitus and arterial hypertension are among the five risk factors that increase mortality in the world. Both are chronic, non-communicable diseases (NCDs), that have a pathophysiological association. Advanced glycation end products (AGEs), produced by the lack of glycemic control in diabetic patients, interact with their AGE receptors (AGER) resulting in increased arterial stiffness, inflammation and endothelial changes - which increases the risk of developing hypertension and other complications. We ran a systematic review in Pubmed, SciELO, Cochrane Library and Web of Science databases using keywords and Boolean operators to optimize the search, with the objective of assessing the mechanism of non-enzymatic glycation of proteins present in patients with diabetes and its correlation with the onset of hypertension, exposing all the endothelial and cellular damage caused by AGEs. We found 719 papers, of which 99 were read in full, and 26 met the eligibility criteria and were included in the present review. AGEs should be considered one of the main cardiometabolic risk factors. Reducing the AGE-AGER interaction will result in cardiovascular protection and increased life expectancy.

Resumo Diabetes mellitus e hipertensão arterial estão entre os cinco fatores de risco que elevam a mortalidade no mundo. Ambas são doenças crônicas não transmissíveis (DCNT) que têm associação fisiopatológica. Os produtos finais de glicação avançada (AGEs), produzidos pela falta de controle glicêmico nos pacientes diabéticos, interagem com seus receptores para AGEs (RAGE) resultando no aumento da rigidez arterial e da inflamação e em alterações endoteliais, fatores que intensificam o risco do desenvolvimento da hipertensão e de demais complicações. Realizou-se uma revisão sistemática nas bases de dados Pubmed, SciELO, Cochrane Library e Web of Science utilizando descritores e operadores booleanos para otimizar a busca, com o objetivo de fornecer o mecanismo da glicação não enzimática de proteínas presente em pacientes com diabetes e sua correlação com o aparecimento da hipertensão, expondo todo o dano endotelial e celular ocasionado pelos AGEs. Foram encontrados 719 artigos, dos quais 99 foram lidos na íntegra, e 26 atenderam aos critérios de elegibilidade e foram incluídos na presente revisão. Os AGEs devem ser considerados um dos principais fatores de risco cardiometabólico. A redução da interação AGE-RAGE resultará na proteção cardiovascular e no aumento da expectativa de vida.

Mechanism of advanced glycation end products inhibiting the proliferation of peripheral blood mononuclear cells and osteoblasts in rats / 北京大学学报(医学版)

OBJECTIVE@#To explore the mechanism of nuclear factor-kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B(PKB/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways after intervention of advanced glycosylation end products (AGEs) in peripheral blood mononuclear cells (PBMCs) and osteoblasts (OB) in rats, so as to provide certain experimental basis and theoretical basis for further research on the clinical treatment of periodontal tissue inflammation caused by diabetes mellitus.@*METHODS@#AGEs were prepared, PBMCs and OB were isolated and cultured in vitro. CCK-8 was used to detect the cell viability intervened by different concentrations and time of AGEs. Western blot and qRT-PCR were used to detect the expression changes of genes related to NF-κB, PI3K/PKB and MAPK signaling pathways.@*RESULTS@#OB and PBMCs were successfully isolated and cultured in vitro. The activity of PBMCs and OB cells was significantly correlated with the concentration, time and interaction of AGEs. With the increase of AGEs concentration and time, the activity of PBMCs and OB cells significantly decreased (P < 0.001). AGEs stimulation significantly increased the expression of NF-κB in PBMCs and the contents of tumor necrosis factor α(TNF-α), interleukin-1β(IL-1β) (P < 0.01). TNF-α, IL-1β levels were significantly reduced after inhibition of NF-κB pathway (P < 0.01). NF-κB p65, JNK, and p38 phosphorylated and non-phosphorylated proteins increased significantly after AGEs stimulation of OB (P < 0.05). The phosphorylated protein expression of IκB was significantly increased, while the expression of non-phosphorylated protein was decreased (P < 0.01).The expressions of NF-κB p65, JNK, and IκB were significantly increased at the mRNA levels, and the expressions of IκB mRNA were significantly decreased (P < 0.05). There was no difference in the expression of Akt in either phosphorylated or non-phosphorylated proteins or at the mRNA level (P>0.05). With the addition of MAPK signaling pathway inhibitors, the phosphorylation and non-phosphorylated protein expressions of NF-κB p65, p38 and JNK were significantly reduced, and the phosphorylated protein of IκB was significantly decreased and the non-phosphorylated protein was significantly increased compared with the group with AGEs alone (P < 0.05). The results of qRT-PCR showed that the expression of IκB increased significantly after the addition of the JNK pathway blocker (P < 0.05), and the expression of NF-κB p65, p38 and JNK decreased, but the difference was not significant (P>0.05). While NF-κB p65, p38 and JNK were significantly decreased and IκB was significantly increased in the AGEs group after the addition of the p38 pathway blocker (P < 0.05). At this time, there was still no significant change in the expression of Akt at the protein level and mRNA level (P>0.05).@*CONCLUSION@#AGEs inhibit the proliferation of PBMCs and OB, and the NF-κB and MAPK pathways are likely involved in regulating this process, but not the PI3K/PKB pathway.

Rubeosis faciei diabeticorum is not associated with oxidative stress and skin autofluorescence

Abstract Background Rubeosis faciei diabeticorum is a persistent facial erythema in patients with diabetes mellitus. The actual pathogenesis has not been studied. However, it is speculated to be a cutaneous diabetic microangiopathy. Objective Examine the correlation between the severity of facial erythema and the possible causes of microvascular diabetic complications, namely oxidative stress, hyperglycemia, and cutaneous accumulation of advanced glycation end-products . Methods Patients diagnosed with Type 2 diabetes mellitus (n = 32) were enrolled in the study. The facial erythema index was measured using the Mexameter MX18; cutaneous accumulation of advanced glycation end-products was estimated by measuring skin auto fluorescence with the AGE Reader (DiagnOptics Technologies B.V. - Groningen, Netherlands). Glycated haemoglobin, total antioxidant status, and malondialdehyde were measured in blood by TBARS assay. The correlation between the selected variables was assessed by Spearman's rank test; p ≤ 0.05 was considered statistically significant. Results There was a statistically significant correlation between total antioxidant status and the facial erythema index (ρ = 0.398, p = 0.024). Malondialdehyde, skin autofluorescence, glycated haemoglobin, body mass index, duration of diabetes, and age did not demonstrate statistically significant correlation with the facial erythema index. Study limitations This is an observational study. Elevation of total antioxidant status could have been caused by several factors that might have also influenced the development of rubeosis faciei, including hyperbilirubinemia and hyperuricemia. Conclusions The results contradicted expectations. Total antioxidant status correlated positively with facial erythema index; however, there was no correlation with oxidative stress and skin autofluorescence. Further investigations should be conducted to reveal the cause of total antioxidant status elevation in patients with rubeosis faciei.

The Role of Advanced Glycation End Products in Diabetic Vascular Complications

In cases of chronic hyperglycemia, advanced glycation end-products (AGEs) are actively produced and accumulated in the circulating blood and various tissues. AGEs also accelerate the expression of receptors for AGEs, and they play an important role in the development of diabetic vascular complications through various mechanisms. Active interventions for glucose and related risk factors may help improve the clinical course of patients by reducing AGEs. This review summarizes recent updates on AGEs that have a significant impact on diabetic vascular complications.

Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells

OBJECTIVE: Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity. METHODS: HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity. RESULTS: AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells. CONCLUSION: Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.

Reactive oxygen species inhibition improves the down-regulation of adiponectin in 3T3-L1 adipocytes induced by AGEs / 中华内分泌代谢杂志

Objective To investigate the effects of reactive oxygen species (ROS) inhibition on the down-regulation of adiponectin (ADPN) in mouse 3T3-L1 adipocytes by advanced glycation end-products (AGEs).Methods AGEs were prepared for incubating with cell.3T3-L1 preadipocytes were cultured in vitro and differentiated into mature adipocytes.Cell differentiation and lipid accumulation were determined by oil red O staining.After being intervened with AGEs,2',7'-dichlorofluorescein diacetate (DCFH-DA) was used as a reactive oxygen species (ROS) capture agent and the fluorescent intensity of 2',7 '-dichlorofluorescein (DCF) was detected by flow cytometry.Adiponectin expression under AGEs in 3T3-L1 adipocytes pretreated with N-acetyl-L-cysteine(NAC) or not was detected by real-time fluorescent PCR and ELISA.Results The level of ROS in 3T3-L1 adipocytes treated with AGEs was increased.mRNA and protein of ADPN were down-regulated.After inhibition with ROS,mRNA and protein expressions of ADPN injured by AGEs were ameliorated.Conclusion Exposure of 3T3-L1 adipocytes to AGEs induces oxidative stress in vitro,which decreases the expression of ADPN,and causes functional impairment of adipose cells and insulin resistance.

The effect of advanced glycation end products on proliferation of bone marrow mesenchymal stem cells and related mechanism / 中华骨科杂志

Objective To explore the effect of advanced glycation end products (AGEs) on proliferation of bone marrow mesenchymal stem cells (MSCs) and related mechanism.Methods The bone marrow MSCs were isolated from male Sprague Dawley rats and cultured in vitro.The flow cytometer was used to identify the bone marrow MSCs by detecting positive labels (CD29 and CD90) and negative labels (CD34 and CD45).The advanced glycation end products-bovine serum albumin (AGE-BSA),one of the AGEs,was used in this study.The methyl thiazolyl tetrazolium (MTT) method was used to detect the effect of AGE-BSA on proliferation of the bone marrow MSCs.In MTT test,there were 3 groups:AGE-BSA group,BSA group,and control group.In AGE-BSA group,different doses of AGE-BSA (0,25,50,100 and 200 μg/ml) was used to stimulate the bone marrow MSCs for 6 h,12 h or 24 h.In BSA group,the 200 μg/ml BSA was used to stimulate the bone marrow MSCs for 6 h,12 h or 24 h.Gene chips detection was used to detect change of genes expression in bone marrow MSCs.Results The proliferation of the bone marrow MSCs could be inhibited by AGE-BSA,in a dose- and time-related manner.Compared with the BSA group,after being treated with 100 μg/ml AGE-BSA for 24 h or 200 μg/ml AGE-BSA for 12 h and 24 h,the proliferation of the bone marrow MSCs decreased obviously.The gene chips detection found that there were changes in expression of 17 genes in the bone marrow MSCs after being treated with AGE-BSA (200 μ.g/ml) for 12 h or 24 h,and the genes were same at the two time points.Among 17 genes,the expression of 12 genes increased,including four inflammatory factors (CCL3,CCL2,CCL4 and IL-1β),and 5 genes decreased.Conclusion AGE-BSA can inhibit the proliferation of bone marrow MSCs,which may be related to the onset of the diabetic osteoporosis.

Effect of pyridoxamine and telmisartan on kidneys oxidative stress in spontaneously hypertensive rats / 中华老年医学杂志

Objective To investigate the effects and the mechanism of telmisartan and pyridoxamine on oxidative stress in spontaneously hypertensive rats(SHR).Methods SHRs(male,20 weeks of age) were randomly divided into four groups (n＝ 12 for each):hypertension control (HC) group (2 ml of distilled water),telmisartan group[T,6 mg/(kg · d)],pyridoxamine group[P,200 mg/(kg · d)]and combined group(TP,6 mg/kg telmisartan and 200 mg/kg pyridoxamine per day).Treatments were continued for 16 weeks.The normal control group included 13 WKY rats and received gastric lavage with distilled water.SBP of tail artery was measured during the intervention ervey 2 weeks.The levels of AGEs,SOD and MDA were measured by ELISA,xanthine oxidase and thiobarbituric acid methods after the intervention.Expressiones of NF-κBp65,ERK1 and ERK2 in renal tissue were detected by immunohistochemistry.Expression of RAGE in the renal cortex was investigated by Western blot.Results SOD activity was decreased in the HC group.The levels of AGEs,MDA,RAGE and the activations of NF-κBp65 and ERK1/2 were increased in the HC group (t＝4.53,5.52,2.93,al1 P＜0.05).After the 16 weeks' intervention,SOD activity was elevated in T,P and TP groups compared to that in HC group (P＜0.05).The positive expressiones of NF-κBp65,ERK1 and ERK2 were significantly reduced in T,P and TP groups compared to those in HC group (F＝20.13、148.82、18.70,all P＜0.05).All the positive expressiones of NF-κBp65,ERK 1and ERK2 were lowest in the TP group versus T and P groups (t ＝ 3.58、2.84,P ＜ 0.05).Conclusions Telmisartan and pyridoxamine can alleviate the oxidative stress in spontaneously hypertensive rats,which may result from the blocking effect of Ang Ⅱ,the reduction of AGEs-RAGE and inhibiting the signal pathways of ROS,NF-κBp65 and ROS-ERK1/2.

Correlation between serum vascular endothelial cells cadherin level and atherosclerosis in diabetic patients / 中华内分泌代谢杂志

To investigate the relationship among serum vascular endothelial cells(VE) -cadherin, advanced glycation end-products( AGE), and atherosclerotic lesion. 20 healthy subjects and 60 patients with diabetes mellitus,including 30 patients with carotid atherosclerosis (CI), were enrolled.Soluble VE-cadherin and AGE were determined using the enzyme-linked immunosorbent method (ELISA). The relationships among the concentration of soluble VE-cadherin, AGE, and the course of the disease, blood glucose, and blood lipid levels were analyzed with multivariant stepwise regression analysis. The levels of serum VE-cadherin and AGE in the patients with diabetes and CI were higher than those in control group( P＜0. 05 ). There was a significant difference in VE-cadherin between the diabetes group and the CI group( P＜0. 05 ). Serum VE-cadherin levels were positively correlated with serum AGE levels(r = 0. 69, P＜0. 01 ). AGE levels were positively correlated with the diabetes duration ( r = 0. 31, P =0. 02 ). The levels of serum VE-cadherin in diabetic patients are positively correlated with their serum AGE levels. The VE-cadherin seems to play an important role in the development of atherosclerosis caused by AGE.

Effects of advanced glycation end-products on matrix metalloproteinase 2 expression in INS-1 cells / 中华内分泌代谢杂志

Objective To explore the impact of advanced glycation end-products ( AGEs) on matrix metalloproteinase 2 ( MMP-2) expression in cultivated INS-1 cells. Method INS-1 cells were cultivated and MMP-2 expression was analyzed. Glycated serum was prepared for incubating with INS-1 cell. Reactive oxygen species (ROS) was detected by flow cytometry. The intracelluar MMP-2 expression was analyzed by RT-PCR, realtime PCR and Western blot. The MMP-2 cDNA was expressed in cultivated INS-1 cells. Result The level of ROS treated with AGEs was significantly higher than that in the control( P<0.05 ) , and the levels of MMP-2 and its protein expressions turned out as well( P<0. 05). Conclusion The results suggest that MMP-2 was expressed in INS-1 cells. Increased MMP-2 expression in ?cells may be induced by AGEs, suggesting that MMP-2 might play an important role in oxidative stress-mediated islet injury.

Serum matrix metalloproteinase-9 and advanced glycation end-products in diabetic patients with or without diabetic foot problems / 中华内分泌代谢杂志

Serum matrix metalloproteinase-9 (MMP-9)and advanced glycation end products (AGE)levels were measured in the diabetic patients with or without foot problems as well as in healthy retired people. In diabetic patients serum MMP-9 and AGE levels were significantly higher than those in healthy subjects. Median MMP-9 level in patients with diabetic foot was higher than that in diabetic patients without foot ulcers. Increased serum MMP-9 in diabetes might predict occurance of diabetic foot and poor wound healing of the foot ulcers.

The correlation of serum level of advanced glycation end products and the expression of receptor for advanced glycation end products in white blood cells with senile mental disorder / 中华老年医学杂志

Objective To investigate the correlation of serum advanced glycation end products (AGEs) and the expression of receptor for AGE (RAGE) with mental disorders in senile people. Methods All the subjects aged 65～67 years were divided into 4 groups: healthy control (31 cases), Alzheimer's disease (AD) (36 eases), vascular dementia (VD) (20 cases) and mental disorder (MD) (28 cases). Fluorospectrophotometry was carried out to measure the AGEs levels in serum samples, and reverse transcription polymerase chain reaction (RT-PCR) was used to determine the mRNA levels of RAGE in white blood cells. Results AGEs levels were 477. 1±36.2, 512. 6±33.2 and 415.2±32.5 AU/ml in AD, VD and MD group, respectively, which were higher than that in healthy control group (357.4±28. 2) AU/ml (F=3.77,P<0. 05). The mRNA levels of RAGE(RAGE/b- actin) were found to be 1.12±0.34, 1.27±0.41 and 1.18±0.42 in AD, VD and MD group, respectively, which were also significantly higher than that in healthy control group(0. 92±0. 37, F= 4. 07,P<0. 01). However, no significant differences were found in RAGE mRNA levels among the three groups of AD,VD and MD (F=0. 979,P>0. 05). The mRNA levels of RAGE in WBCs were found to be positively correlated with the serum AGEs levels (r=0. 442, P<0. 01). Conclusions Compared with patients in healthy control group, the serum AGEs levels and RAGE mRNA levels are significantly increased in patients with AD, VD and MD. The interaction between AGEs and RAGE may be involved in the pathogenesis of mental disorders in senile people.

Effects of advanced glycation end-products on differentiation of vascular endothelial cells from bone marrow stem cells of mice / 中华内分泌代谢杂志

The effects of advanced glycation end-products (AGEs) on number and activity of vascular endothelial cells (VEC) from hone marrow stem cells (BMSC) of mice were investigated. 100 μ/ml AGEs markedly inhibited differentiation of BMSC into VEC with decreased vascular endothelial growth factor receptor-2 positive cells, hut 20 μg/ml AGEs had no effect.

Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy

Advanced glycation endproducts (AGEs) have been reported to play a role in neointimal formation and increase the rate of in-stent restenosis (ISR) in the diabetic coronary artery disease patients treated with stents, but the potential pathogenic mechanisms of AGEs in vascular smooth muscle cell proliferation remain unclear. We sought to determine the AGEs related pathobiological mechanism of diabetic vasculopathy. Rat aortic smooth muscle cell (RAoSMC) culture was done with different concentrations of AGEs and proliferation was assessed. Immunohistochemistry for receptor of AGEs (RAGE) was performed with human carotid atheroma. Western blotting was performed to assess the activation of MAP kinase system in the cultured RAoSMC. AGEs increased RAoSMC proliferation and were associated with increased phosphorylation of ERK and p38 kinase by time and dose dependent manner. The MAP kinase activity was decreased by RNA interference for RAGE. AGEs stimulation increased reactive oxygen species (ROS) generation in cultured RAoSMC. From this study it is concluded that AGEs played a key role in RAoSMC proliferation via MAP kinase dependent pathways. Activation of vascular smooth muscle cell (VSMC) proliferation by MAP kinase system and increased formation of ROS may be the possible mechanisms of AGEs induced diabetic vasculopathy.

Effect of advanced glycation end products on inflammation in cultured cardiomyocytes / 中国病理生理杂志

AIM:To investigate the effect of advanced glycation end products on inflammation in cultured cardiomyocytes.METHODS: Primary cardiomyocytes were isolated from Sprague-Dawley neonatal (1 to 2 days old) rats ventricles. The insulin resistant cardiomyocyte model was established. Neonatal rat ventricular myocytes were exposed to AGEs for 24 hours. TNF-? mRNA and PPAR-? mRNA expressions were determined by RT-PCR. Activation of NF-?B in the cells was examined by using immunocytochemistry. The ultrastructure of the cells was detected by transmission electron microscope.RESULTS: The exprssion of TNF-? mRNA and the activation of NF-?B increased, the expression of PPAR-? mRNA decreased compared with control group (P

Effects of advanced glycation endproducts on proliferation of pericytes of bovine retinal capillary vessels and expression of transforming growth factor ? / 中华眼底病杂志

Objective To investigate the effects of advanced glycation endproducts (AGEs) on proliferation of pericytes of bovine retinal capillary vessels and expression of transforming growth factor ?(TGF-?). Methods [WTBZ]The proliferation of pericytes detected by methyl thiazolyl tetrazolium (MTT) colorimetric assay, cellular cycle of pericytes was analyzed by flow cytometry was used to analyze cell, and TGF-? protein expression of pericytes was observed by immunofluorescent staining. Results AGEs inhibited the proliferation of pericytes of bovine retinal capillary vessels, stopped the cellular cycle of pericytes in synthesis phase (S phase), increased the number of apoptotic cells obviously (P

Effects of advanced glycation end products on protein and mRNA expression of macrophage inflammatory protein-1? in cultured human umbilical vein endothelial cells / 中国病理生理杂志

AIM: To investigate the effects of advanced glycation end products (AGEs) on protein and mRNA expression of macrophage inflammatory protein-1? (MIP-1?) in cultured human umbilical vein endothelial cells(HUVECs). METHODS: HUVECs were cultured with AGEs at different concentrations for 24 h and at a concentration of 400 mg/L for different time.The levels of mRNA and protein expression of MIP-1? in cultured HUVEC were detected by in situ hybridization and Western blot, respectively. RESULTS: In situ hybridization showed that after exposure of HUVECs to AGEs at different concentrations (100 mg/L, 200 mg/L, 400 mg/L) for 24 h, the average integrated optical density values (18.76?3.17, 26.58?1.61, 34.23?2.25) of MIP-1? mRNA expression in HUVECs were higher than that in control group (13.83?1.24, P