Abstract
The habitual intake of large amounts of sugar, which has been implicated in the onset/progression of lifestyle-related diseases (LSRD), induces the excessive production of glyceraldehyde (GA), an intermediate of sugar metabolism, in neuronal cells, hepatocytes, and cardiomyocytes. Reactions between GA and intracellular proteins produce toxic advanced glycation end-products (toxic AGEs, TAGE), the accumulation of which contributes to various diseases, such as Alzheimer’s disease, non-alcoholic steatohepatitis, and cardiovascular disease. The cellular leakage of TAGE affects the surrounding cells via the receptor for AGEs (RAGE), thereby promoting the onset/progression of LSRD. We demonstrated that the intracellular accumulation of TAGE triggered numerous cellular disorders, and also that TAGE leaked into the extracellular space, thereby increasing extracellular TAGE levels in circulating fluids. Intracellular signaling and the production of reactive oxygen species are affected by extracellular TAGE and RAGE interactions, which, in turn, facilitate the intracellular generation of TAGE, all of which may contribute to the pathological changes observed in LSRD. In this review, we discuss the relationships between intracellular TAGE levels and numerous types of cell damage. The novel concept of the “TAGE theory” is expected to open new perspectives for research into LSRD.
Highlights
Our findings revealed the following: (i) seven distinct classes of Advanced glycation end-products (AGEs) structures are present in the blood of patients with HD-DN [6,34]; (ii) the neurotoxic effects of the serum fraction from HD-DN patients containing various AGE structures are completely neutralized by antibodies against toxic AGEs (TAGE) [11]; (iii) TAGE mimic the deleterious effects of AGE-rich serum purified from HD-DN on EC [51]; and (iv) TAGE are more cytotoxic than other AGEs due to their stronger binding affinities to receptor for AGEs (RAGE) [49,50]
We examined the relationship between impaired cerebral glucose metabolism and the pathogenesis of AD in human neuroblastoma SH-SY5Y cells treated with GA, a precursor of TAGE
Previous studies on AGEs reported that the effects of AGEs were associated with their extracellular binding to RAGE or accumulation in numerous tissues; further research on these molecules is needed to clarify the impact of the intracellular generation of TAGE
Summary
The turnover rates of chemically modified targets, and time have all been shown to influence the in vivo generation of AGEs. elevated concentrations of glucose were previously suggested to markedly affect the Maillard reaction, it is recognized as one of the least reactive sugars in biological organisms. The accumulation of TAGE in cells induces cell damage, resulting in their extracellular leakage into the blood, and increased levels in circulating fluids [32]. Interactions between extracellular TAGE and the receptor for AGEs (RAGE) alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules, and induce the generation of reactive oxygen species (ROS) in numerous types of cells [23], all of which may contribute to the pathological changes observed in LSRD. The close relationships between the generation/accumulation of intracellular TAGE and numerous types of cell damage are discussed
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