Diets are currently characterized by elevated sugar intake, mainly due to the increased consumption of processed sweetened foods and drinks during the last 40 years. Diet is the main source of advanced glycation endproducts (AGEs). These are toxic compounds formed during the Maillard reaction, which takes place both in vivo, in tissues and fluids under physiological conditions, favored by sugar intake, and ex vivo during food preparation such as baking, cooking, frying or storage. Protein glycation occurs slowly and continuously through life, driving AGE accumulation in tissues during aging. For this reason, AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, kidney injury, and age-related and neurodegenerative diseases. AGEs are associated with an increase in oxidative stress since they mediate the production of reactive oxygen species (ROS), increasing the intracellular levels of hydrogen peroxide (H₂O₂), superoxide (O₂⁻), and nitric oxide (NO). The interaction of AGEs with the receptor for AGEs (RAGE) enhances oxidative stress through ROS production by NADPH oxidases inside the mitochondria. This affects mitochondrial function and ultimately influences cell metabolism under various pathological conditions. This short review will summarize all evidence that relates AGEs and ROS production, their relationship with diet-related diseases, as well as the latest research about the use of natural compounds with antioxidant properties to prevent the harmful effects of AGEs on health.

Neuroindole melatonin, a hormone synthesized during the night mainly—but not exclusively—by the pineal gland of all vertebrates, functions as an adapting signal to the light-dark cycle. Its antioxidant, neuroprotective, anti-inflammatory, and antitumor properties are all well-known and widely reported. Melanoma is one of the most common carcinomas among developed countries and a type of tumor particularly difficult to fight back in medium/advanced stages. In contrast to other types of cancer, influence of melatonin on melanoma has been scarcely investigated. Thus, we have chosen the murine melanoma model B16-F10 cell line to study antiproliferative and antitumoral actions of melatonin. For this purpose, we combined both, cell culture and in vivo models. Melatonin reduced either, growth rate or migration of B16-F10 cells. Furthermore, melanin synthesis was altered by melatonin, promoting its synthesis. Melatonin also induced a G2/M cell cycle arrest and altered the cytoskeletal organization. To corroborate these results, we tested the effect of melatonin in the in vivo model of B16-F10 cell injection in the tail vein, which causes numerous lung metastases. Two different strategies of melatonin administration were used, namely, in drinking water, or daily intraperitoneal injection. However, contrary to what occurred in cell culture, no differences were observed between control and melatonin treated groups. Results obtained led us to conclude that melatonin exerts an antiproliferative and anti-migrating effect on this melanoma model by interfering with the cytoskeleton organization, but this pharmacological effect cannot be translated in vivo as the indole did not prevent metastasis in the murine model, suggesting that further insights into the effects of the indole in melanoma cells should be approached to understand this apparent paradox.

Melatonin, N-acetyl-5-methoxytryptamine, is an indole mainly synthesized from tryptophan in the pineal gland and secreted exclusively during the night in all the animals reported to date. While the pineal gland is the major source responsible for this night rise, it is not at all the exclusive production site and many other tissues and organs produce melatonin as well. Likewise, melatonin is not restricted to vertebrates, as its presence has been reported in almost all the phyla from protozoa to mammals. Melatonin displays a large set of functions including adaptation to light: dark cycles, free radical scavenging ability, antioxidant enzyme modulation, immunomodulatory actions or differentiation–proliferation regulatory effects, among others. However, in addition to those important functions, this evolutionary ‘ancient’ molecule still hides further tools with important cellular implications. The major goal of the present review is to discuss the data and experiments that have addressed the relationship between the indole and glucose. Classically, the pineal gland and a pinealectomy were associated with glucose homeostasis even before melatonin was chemically isolated. Numerous reports have provided the molecular components underlying the regulatory actions of melatonin on insulin secretion in pancreatic beta-cells, mainly involving membrane receptors MTNR1A/B, which would be partially responsible for the circadian rhythmicity of insulin in the organism. More recently, a new line of evidence has shown that glucose transporters GLUT/SLC2A are linked to melatonin uptake and its cellular internalization. Beside its binding to membrane receptors, melatonin transportation into the cytoplasm, required for its free radical scavenging abilities, still generates a great deal of debate. Thus, GLUT transporters might constitute at least one of the keys to explain the relationship between glucose and melatonin. These and other potential mechanisms responsible for such interaction are also discussed here.

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.

Several epidemiological and preclinical studies suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) exert anticancer activity at multiple stages of colorectal cancer (CRC) progression. However, inconsistent clinical evidence and the lack of a clearly defined molecular mechanism underlying the antitumor effects of n-3 PUFAs have raised doubts about their efficacy as anticancer therapies. To address these issues, we investigated the effects of the n-3 PUFA docosahexaenoic acid (DHA) in a collection of CRC patient-derived tumor organoids (PDTOs), a powerful platform for functional analysis of patient-specific tumors. DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without inducing apoptosis. CRC-derived PDTOs exhibited pronounced sensitivity to DHA, irrespective of KRAS or TP53 mutational status, whereas organoids from normal colon tissue were less affected. Mechanistically, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation and partial rescue by ferroptosis inhibitors. Fluorescently labeled DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress. Moreover, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models. Together, these findings indicate that exploiting the intrinsic oxidative vulnerability of cancer cells with DHA may represent a promising, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.

Elevated levels of ROS are closely associated with impaired male fertility. Although spermatogenesis involves high mitochondrial oxygen consumption and consequent ROS generation, the precise mechanism by which oxidative stress contributes to sperm dysfunction remain poorly understood. Here we demonstrate for the first time that haplodeficiency of mitochondrial antioxidant enzyme SOD2/MnSOD show alterations in reproductive physiology. Colonies of Sod2+/- mice exhibited reduced litter size and prolonged breeding-to-parturition period, effects observed exclusively when males carried the transgene. Sod2 expression increased progressively along the spermatogenic lineage from spermatogonia to spermatozoa. Using transgenic mice expressing the mitochondrial biosensor mito-roGFP2-Orp1, we identified an inverse gradient of H2O2 consistent with expression of the mitochondrial antioxidant enzyme expression. Both, Sod2+/- haplodeficient and Sod2+/++ overexpressing mice displayed alterations in the spermatogenic series and in the seminiferous tubules stage distribution relative to wild type animals, but this was not correlated with a reduction in sperm count, motility, or viability. Notably, sperm form Sod2+/- mice exhibited reduced fertilization rate and significantly decreased early pre-embryonic viability during first stages following in vitro fertilization. Collectively, these findings indicate that impaired mitochondrial redox homeostasis due to Sod2 haplodeficiency compromises early embryonic development, leading to reduced reproductive success, and identify SOD2 as a potential marker of sperm functional quality.