In Vitro Evaluation of the Toxicological Profile and Oxidative Stress of Relevant Diet‐Related Advanced Glycation End Products and Related 1,2‐Dicarbonyls

Abstract

During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N- ε -(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.

The Influence of Intracellular Glutathione Levels on the Induction of Nrf2-Mediated Gene Expression by α-Dicarbonyl Precursors of Advanced Glycation End Products

“…The results also revealed subtle differences between the three α-dicarbonyls with MGO being the most potent in terms of scavenging by GSH, ROS production, induction of Nrf2-mediated gene expression, and the effects of GSH depletion on this potential. It is of interest to note that other studies report the toxicity of MGO to other cell lines [ 22 , 49 ]. Comparison of the toxicity data from these studies to the results of the present study reveals that U2OS cells appear less sensitive to the adverse effects of MGO.…”

Blood and Tissue Advanced Glycation End Products as Determinants of Cardiometabolic Disorders Focusing on Human Studies

“…AGEs with oxidant properties elevate oxidative stress and inflammatory responses by stimulating RAGE in the AGE formation process, leading to the risk of cardiometabolic disorders [107][108][109][110][111].…”

In Vitro Reactivity of the Glucose Degradation Product 3,4-Dideoxyglucosone-3-ene (3,4-DGE) towards Abundant Components of the Human Blood Circulatory System

“…Several harmful effects of 3,4-DGE have been observed in vitro, e.g., cytotoxicity against cell types, such as human podocytes [9] and leukocytes and especially neutrophils, which are involved in host defense against pathogens [10] but also against murine fibroblasts [11]. Possible reasons for the cytotoxicity of 3,4-DGE might be the depletion of cellular L-glutathione (GSH) [12] and, as reported lately, the induction of the nuclear factor-kappa B (NF-κB) pathway and production of reactive oxygen species (ROS) in human keratinocytes [13]. Additionally, impairment of enzyme activity has been described for bovine ribonuclease (RNase) A [11].…”