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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- κ B 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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Vanesa Cepas et al.)

Advanced glycation end products (AGEs)-induced inflammation and degradation of aggrecan in human chondrocytes play an important role in the progression and development of osteoarthritis (OA). Azilsartan, an angiotensin II receptor antagonist, has been licensed for the treatment of high blood pressure. However, the effects of Azilsartan in OA and AGEs-induced damages in chondrocytes have not been previously reported. The injured chondrocytes model was established by incubating with 5 μmol/L AGEs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to evaluate the cell viability of treated SW1353 cells. The gene expression levels of interleukin-1α (IL-1α), tumor necrosis factor-β (TNF-β), IL-6, a disintegrin-like and metallopeptidase with thrombospondin type motif-4 (ADAMTS-4), ADAMTS-5, Aggrecan, and Sox-4 were evaluated using quantitative real-time polymerase chain reaction and their protein levels were determined using enzyme-linked immunosorbent assay or Western blot analysis. Mitogen-activated protein kinase p38 pathway was surveyed using phosp-p38 level and its specific inhibitor SB203580 was employed to block the p38 pathway. The overexpression of Sox4 plasmid was transfected into SW1353 cells to assess its regulation on ADAMTS-4 and ADAMTS-5. Azilsartan reduced AGEs-induced production of proinflammatory cytokines, such as IL-1α, TNF-β, and IL-6. Azilsartan prevented AGEs-induced expressions of ADAMTS-4 and ADAMTS-5 as well as the reduction of aggrecan. Mechanistically, AGEs treatment increased the expression of Sox4 in a dose-dependent manner. AGE treatment increased the level of phosphorylated p38. However, treatment with the p38 inhibitor SB203580 inhibited AGEs-induced expression of Sox4, suggesting that AGEs-induced expression of Sox4 is mediated by p38. Furthermore, Azilsartan suppressed AGEs-induced phosphorylation of p38 and expression of Sox4. Finally, the overexpression of Sox4 abolished the inhibitory effects of Azilsartan against the expressions of ADAMTS-4 and ADAMTS-5. Azilsartan treatment prevented AGEs-induced inflammatory response and degradation of aggrecan through inhibition of Sox4., (© 2021 Wiley Periodicals LLC.)

With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium-glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Jing Guo et al.)

Background: Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism and are consumed through the diet in high-fat and highly processed foods. They are associated with chronic inflammatory diseases, and evidence suggests that they play a role in carcinogenesis. The authors evaluated the association of dietary AGE intake and the risk of postmenopausal invasive breast cancer., Methods: This was a prospective cohort study of 183,548 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. The main outcome was incident invasive breast cancer. AGE intake was estimated from food-frequency questionnaires. Incident breast cancer cases were identified through state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals for developing breast cancer according to AGE intake quintiles. Multivariable regression models were adjusted for breast cancer risk factors., Results: The mean follow-up was 12.8 years, and 9851 breast cancers (1978 advanced stage) were identified. The median AGE daily intake was 5932 kilo units per 100 kilocalories (KU/1000 kcal). Women with higher intake tended to have lower education levels, higher body mass index, less physical activity, were current smokers, and had higher fat and meat intake. The highest quintile of AGE intake (compared with the lowest) was associated with an increased risk of breast cancer (HR, 1.09; 95% CI, 1.02-1.16; P = .03) after adjusting for breast cancer risk factors and particularly was associated with 37% of advanced-stage tumors (HR, 1.37; 95% CI, 1.09-1.74; P < .02) after adjusting for risk factors and fat and meat intake., Conclusions: Dietary AGEs may play a role in the development of postmenopausal breast cancer., (© 2020 American Cancer Society.)

To determine the most effective combination of neuroprotective and regenerative agents for cultured retinal neurons from advanced glycation end products- (AGEs-) induced degeneration, retinal explants of 7 adult Sprague-Dawley rats were three-dimensionally cultured in collagen gel and incubated in serum-free media and in 7 media; namely, AGEs, AGEs + 100  μ M citicoline, AGEs + 10 ng/mL NT-4, AGEs + 100  μ M TUDCA, AGEs + 100  μ M citicoline + TUDCA (doublet), and AGEs + 100  μ M citicoline + TUDCA + 10 ng/mL NT-4 (triplet) were examined. The number of regenerating neurites was counted after 7 days of culture, followed by performing TUNEL and DAPI staining. The ratio of TUNEL-positive cells to the number of DAPI-stained nuclei was calculated. Immunohistochemical examinations for the active form of caspase-9 and JNK were performed. All of the neuroprotectants increased the number of neurites and decreased the number of TUNEL-positive cells. However, the number of neurites was significantly higher, and the number of TUNEL-positive cells and caspase-9- and JNK-immunopositive cells was fewer in the retinas incubated with the combined three agents. Combination solutions containing citicoline, TUDCA, and NT-4 should be considered for neuroprotective and regenerative therapy for AGE-related retinal degeneration.

Recently, the role of food and nutrition in preventing or delaying chronic disability in the elderly population has received great attention. Thanks to their ability to influence biochemical and biological processes, bioactive nutrients are considered modifiable factors capable of preserving a healthy brain status. A diet rich in vitamins and polyphenols and poor in saturated fatty acids has been recommended. In the prospective of a healthy diet, cooking methods should be also considered. In fact, cooking procedures can modify the original dietary content, contributing not only to the loss of healthy nutrients, but also to the formation of toxins, including advanced glycation end products (AGEs). These harmful compounds are adsorbed at intestinal levels and can contribute to the ageing process. The accumulation of AGEs in ageing ("AGE-ing") is further involved in the exacerbation of neurodegenerative and many other chronic diseases. In this review, we discuss food's dual role as both source of bioactive nutrients and reservoir for potential toxic compounds-paying particular attention to the importance of proper nutrition in preventing/delaying Alzheimer's disease. In addition, we focus on the importance of a good education in processing food in order to benefit from the nutritional properties of an optimal diet., Competing Interests: The authors confirm that this article content has no conflict of interests.

Diabetic nephropathy (DN) caused by advanced glycation end products (AGEs) may be associated with lipid accumulation in the kidneys. This study was designed to investigate whether Nε-(carboxymethyl) lysine (CML, a member of the AGEs family) increases lipid accumulation in a human renal tubular epithelial cell line (HK-2) via increasing cholesterol synthesis and uptake and reducing cholesterol efflux through endoplasmic reticulum stress (ERS). Our results showed that CML disrupts cholesterol metabolism in HK-2 cells by activating sterol regulatory element-binding protein 2 (SREBP-2) and liver X receptor (LXR), followed by an increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) mediated cholesterol synthesis and low density lipoprotein receptor (LDLr) mediated cholesterol uptake and a reduction in ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, ultimately causing lipid accumulation in HK-2 cells. All of these responses could be suppressed by an ERS inhibitor, which suggests that CML causes lipid accumulation in renal tubule cells through ERS and that the inhibition of ERS is a potential novel approach to treating CML-induced renal tubular foam cell formation.

Osteoarthritis is a highly prevalent disease, age being the main risk factor. The age-related accumulation of advanced-glycation-endproducts (AGEs) adversely affects the mechanical and biochemical properties of cartilage. The hypothesis that accumulation of cartilage AGEs in combination with surgically induced damage predisposes to the development of osteoarthritis was tested in vivo in a canine model. To artificially increase cartilage AGEs, right knee joints of eight dogs were repeatedly injected with ribose/threose (AGEd-joints). Left joints with vehicle alone served as control. Subsequently, minimal surgically applied cartilage damage was induced and loading restrained as much as possible. Thirty weeks after surgery, joint tissues of all dogs were analyzed for biochemical and histological features of OA. Cartilage pentosidine levels were ∼5-fold enhanced (p = 0.001 vs. control-joints). On average, no statistically significant differences in joint degeneration were found between AGEd and control-joints. Enhanced cartilage pentosidine levels did correlate with less cartilage proteoglycan release (R = -0.762 and R = -0.810 for total and newly-formed proteoglycans, respectively; p = 0.028 and 0.015 for both). The current data support the diminished cartilage turnover, but only a tendency towards enhanced cartilage damage in AGEd articular cartilage was observed. As such, elevated AGEs do not unambiguously accelerate the development of early canine OA upon minimal surgical damage., (Copyright © 2012 Orthopaedic Research Society.)

Advanced glycation end-products (AGEs) have been regarded as an initial motivating factor in the pathogenesis of endothelial dysfunction in diabetic complications. 4,4'-Diphenylmethane-bis(methyl) carbamate (DMPC), a carbamate compound, was isolated from Cortex Mori and its prevention effects against AGEs-induced endothelial dysfunction were studied. 4,4'-Diphenylmethane-bis(methyl) carbamate significantly reduced cell apoptosis to normal level at 10⁻⁹  mol/L concentration. Advanced glycation end-products up-regulated the expression of Bad and Bax and down-regulated Bcl-2 proteins, and pretreatment with DMPC significantly down-regulated Bad and Bax while up-regulating Bcl-2 expressions. In addition, ICAM (intercellular adhesion molecule)-1 and TGF (transforming growth factor)-β1 expressions in human umbilical vein endothelial cell (HUVEC) were significantly enhanced by AGEs. More importantly, these increases of ICAM-1 and TGF-β1 expressions were reduced meaningfully with the pretreatment of DMPC. All the results showed DMPC had prevention effects against the progression of AGE-induced endothelial dysfunction, and this compound might be a promising agent against endothelial dysfunction in diabetic vascular complications., (Copyright © 2011 John Wiley & Sons, Ltd.)

The formation of advanced glycation end products (AGEs) is observed in conditions such as diabetes mellitus and ageing, both associated with vascular disorders. AGEs form by the interaction of an aldose with NH2 of proteins, and the subsequent Amadori rearrangement leads to complex molecules. The heterogeneous class of AGE molecules is found in plasma, cells and tissues and accumulates in the vessel wall and the kidney. AGE reactions can generate reactive oxygen intermediates (ROIs), which can act as signal mediators and can be deleterious for molecules or cells. The AGEs and ROI-induced cellular dysfunctions can interfere with the gene expression of peptides and cytokines regulating cell proliferation and vascular functions. The interaction of AGEs with the AGE receptor (RAGE) is followed by a series of intracellular modifications that may be involved in the development of atherosclerosis. An attempt to minimize AGE formation and to limit ROI production by an appropriate therapy may result in the reduction or slowing of vascular disease in patients with diabetes mellitus.