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Introduction: Advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE) mediate renal function during diabetic and non-diabetic nephropathy development. Methylglyoxal-lysine dimer (MOLD), a typical toxic advanced glycation end product (TAGE), contributes to inflammatory responses during renal diseases. This study determines the effect of MOLD on inflammatory responses in mouse mesangial cells., Methods and Results: The murine mesangial cell line SV40 MES 13 is used to assess nuclear factor-kappa B (NF-κB) expression, reactive oxygen species (ROS) production, and mitochondria labeling. The interaction model between RAGE and MOLD is also determined. MOLD treatment of mesangial cells markedly increases RAGE expression and the linkage with V-type Ig domain of RAGE. MOLD induces ROS production and mitochondrial dysfunction. MOLD activates phosphatidylinositol 3-kinase-protein kinase B (PI3KB) and NF-κB signaling pathways. It is confirmed that these changes are reversed when ROS is suppressed. These effects may be regulated through mitogen-activated protein kinases and pro-inflammatory cytokines in circulatory inflammation responses., Conclusion: MOLD plays a major role in nephropathy via ROS production and mitochondrial dysfunction through direct association with RAGE. Further, the NF-kB and PI3K/AKT signaling pathways triggered by ROS mediate the inflammatory response to exacerbate MOLD-induced damages in inflammation-related diabetic and non-diabetic renal diseases., (© 2021 Wiley-VCH GmbH.)

Scope: The maintenance of interpodocyte slit diaphragm is critical in the sieving function of glomerular filtration barrier. Eucalyptol is a natural constituent in aromatic plants with antioxidant properties. This study investigates whether and how eucalyptol inhibits podocyte slit diaphragm malfunction in glucose-exposed podocytes and diabetic mouse kidneys., Methods and Results: Podocytes were incubated in media containing 33 mm glucose with 1-20 μm eucalyptol. The in vivo model employed db/db mice orally administrated with 10 mg kg -1 eucalyptol. Nontoxic eucalyptol enhanced podocyte expression of nephrin, podocin, FAT-1, CD2AP, and α-actinin-4 diminished by glucose. Oral administration of eucalyptol augmented the induction of the slit diaphragm proteins, α-actinin-4, and integrin β1 in diabetic kidneys, and ameliorated glomerular fibrosis and foot process effacement. Eucalyptol counteracted the receptor of advanced glycation end products (RAGE) induction in podocytes with glucose or AGE-BSA, and elevated the reduction of the slit diaphragm proteins by AGE-BSA. Eucalyptol attenuated the RAGE induction and AGE accumulation in diabetic kidneys. The blockade of ERK-c-Myc signaling enhanced the nephrin and CD2AP expression downregulated in AGE-exposed podocytes. These results indicate that eucalyptol blocked glucose-induced AGE-RAGE axis and podocyte injury through disturbing RAGE-ERK-c-Myc signaling., Conclusion: Eucalyptol may be a potent agent antagonizing diabetes-associated malformation of interpodocyte slit junction and podocyte actin cytoskeleton., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: Well-controlled glycation (generally limited to the early stages) has been proposed as a strategy to improve the physiochemical properties of dietary proteins, but the functional studies of glycation products are mostly on advanced glycation end-products (AGEs) rather than early glycation products (EGPs). Since cytokines are important modulators of various biological processes, this study aims to determine whether EGPs and AGEs affected immune homeostasis differentially and do so through modulating macrophage-derived factors., Methods and Results: Two systems (glycine-glucose and whey protein isolate (WPI)-glucose) are established to generate glycation products. They are applied to human macrophages (PMA-differentiated U937 cells), and cell viability and cytokine production are measured. Furthermore, EGPs, AGEs, and their conditioned medium (CM) from macrophages are applied to human prostate cancer (PCa) cells with different etiology (LNCaP and PC-3) and murine PCa cells (TRAMP-C2) to determine their direct and indirect effects on PCa cell proliferation. EGPs enhance the production of immunosuppressive cytokines, and this enhancement is associated with increased PCa cell proliferation. In contrast, AGEs inhibit macrophages to secret cytokines, but increase PCa cell proliferation directly., Conclusions: Our data suggest that EGPs promote the prostate tumor proliferation indirectly through modulating macrophages, while AGEs have a direct effect., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In vivo, advanced glycation endproducts (AGEs) are linked to various diseases, particularly those associated with diabetes. AGEs are also formed when many foods are thermally processed. The extent to which dietary AGEs are absorbed by the gastrointestinal (GI) tract and their possible role in the onset and promotion of disease are currently of considerable interest. This paper reviews information that supports the argument that dietary AGEs are not a risk to human health.

Thermal processing of food results in the formation of various novel compounds, among others advanced glycation endproducts (AGEs). AGEs result from nonenzymatic glycation reactions between reducing sugars and free amino groups of proteins, peptides, or amino acids. Due to their potential noxious effects, alimentary AGEs are also called glycotoxins. This review provides a summary of the available evidence on the health effects of exaggerated intake of thermally treated food. Data from experimental studies in rodents and from clinical studies in healthy volunteers and in patients suffering from selected diseases in which AGEs are of pathogenetic importance (diabetes, chronic renal failure) are summarized. It is concluded that, an exaggerated intake of thermally processed foods may exert in vivo diabetogenic and nephrotoxic effects, induce low-grade inflammation, enhance oxidative stress, and promote atherosclerosis.

We are interested in the regulation of intracellular calcium and the various diseases associated with an altered regulation of this second messenger. More recently, we also became interested in pathologies involving the Ca2+-binding S100 proteins and AGEs and their association with the multifunctional Receptor for Advanced Glycation Endproducts (RAGE).

The receptor for advanced glycation endproducts (RAGE) has a well-substantiated role in cell dysfunction and mechanisms of inflammatory disease. The physiological agonists of RAGE are less certain: S100/calgranulin proteins, high mobility group-1 protein HMGB1 and other proteins are candidate agonists. It increasingly appears unlikely proteins modified by advanced glycation endproducts are effective agonists in vivo. In the following debate, Professors Ann Marie Schmidt and Claus Heizmann gave arguments and evidences for and against the motion. Recent evidence suggesting the activation of RAGE impairs the enzymatic defence against glycation provided by glyoxalase 1 (Glo 1) suggests that studies of RAGE will continue to be of importance to our understanding of the physiological significance of protein glycation.

Physiological consequences resulting from protein-bound Maillard compounds in foods must be discussed carefully. This was the idea behind the debate, which is put for discussion by the papers by Sebekova and Somoza, who argued for the motion that dietary advanced glycation end products (AGEs) are a health risk, and by Ames, who provided evidence against the motion. In this two excellent reviews, numerous arguments based on papers published in high-impact journals are given for each of the opinions. The fact that no final conclusion can be drawn, may reflect the need for a more comprehensive examination of this issue in the future. For a deeper understanding of biological consequences resulting from heated foods, the relationships between well-defined biological effects and well-characterized chemical structures must be studied. Prerequisite for this is profound chemistry--pure compounds, exact concentrations, and unambiguous analytical techniques. A real "risk assessment" is much too complex than to leave it up to one discipline alone. It must be a comprehensive and interdisciplinary approach, joining the resources of biology, medicine, and chemistry.