Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer’s disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.

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Advanced glycation end products (AGEs) are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

Abstract. An irreversible non-enzymatic reaction between carbohydrates and proteins results in the formation of advanced glycation end products (AGEs). AGEs have been demonstrated to be a risk factor of complications in patients with diabetes mellitus (DM). Previous studies have suggested that patients with DM exhibit a higher rate of metastasis of oral cancer and a lower cancer-associated survival rate. The receptor for AGEs (RAGE) has been associated with angiogenesis and an increase in cancer malignancy. Previous studies have suggested that AGE-RAGE regulates cell migration via extracellular signal-regulated kinase (ERK) phosphorylation. Nuclear factor-erythroid 2-related factor 2 (Nrf-2) is associated with the regulation of tumor protein p53 (p53) and the apoptotic response of oral cancer cells. AGEs are associated with oral cancer; however, the mechanism underlying this association remains to be elucidated. The present study hypothesized that AGEs regulate Nrf-2 and downstream pathways through ERK phosphorylation. The results of the current study demonstrated that AGEs inhibit the expression of Nrf-2, p53 and Bcl-2 associated x apoptosis regulator, and increase the expression of apoptosis regulator Bcl-x protein. The effect of AGEs was inhibited through the use of the PD98059. The present study demonstrated that AGEs regulate the downstream pathways Nrf-2 and Bcl-xl via ERK phosphorylation. It is suggested that AGEs regulate the survival of oral cancer cells via Nrf-2 and Bcl-xl through p53 regulation, which explains the poor prognosis of patients with DM who have oral cancer.

Diabetic cardiomyopathy has been shown to promote hypertrophy, leading to heart failure. Recent studies have reported a correlation between diabetic cardiomyopathy and oxidative stress, suggesting that the accumulation of advanced glycation end products (AGEs) induces the production of reactive oxygen species (ROS). In a clinical setting, AGEs have been shown to increase the risk of cardiovascular disease; however, the relationship between AGEs and cardiac hypertrophy remains unclear. This study sought to identify the role of AGEs in cardiac hypertrophy by treating H9c2 cells with glyceraldehyde-derived AGEs (200 μg/ml) or H2O2 (50 μM) for 96 h. Our results demonstrate that AGEs significantly increased protein levels and cell size. These effects were effectively blocked with PD98059 (10 μM; MEK/ERK inhibitor) pretreatment, suggesting that AGEs caused cell hypertrophy via the MEK/ERK pathway. We then treated cells with AGEs and H2O2 for 0-120 min and employed the Odyssey infrared imaging system to detect MEK/ERK phosphorylation. Our results show that AGEs up-regulated MEK/ERK phosphorylation. However, this effect was blocked by NAC (5 mM; ROS inhibitor), indicating that AGEs regulate MEK/ERK phosphorylation via ROS. Our findings suggest that glyceraldehyde-derived AGEs are closely related to cardiac hypertrophy and further identify a molecular mechanism underlying the promotion of diabetic cardiomyopathy by AGEs.