Search Results (302)

Objectives: To determine whether plasma concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are elevated in adults with prediabetes, we explored their association with tissue advanced glycation end-products (AGEs) and assessed the influence of Mediterranean diet adherence. Methods: This cross-sectional single-centre study included 92 adults with prediabetes and 86 age-/sex-matched normoglycaemic controls. Anthropometry, blood pressure, biochemical indices, and skin autofluorescence-derived AGEs were measured. Serum AEA and 2-AG were quantified by competitive ELISA, while Mediterranean diet adherence was assessed using the Mediterranean Diet Serving Score (MDSS). Results: Prediabetes was associated with higher AEA (p = 0.004) but not 2-AG (p = 0.520). Also, AEA correlated positively with AGE values (r = 0.36; p = 0.002) and increased across AGE-based cardiovascular risk categories. In multivariable models, both prediabetes status and AGE burden independently predicted AEA. Participants achieving MDSS ≥ 14 exhibited lower AEA (p = 0.038); 2-AG remained unaffected. Finally, the multivariable analysis confirmed that both prediabetes (β = 11.9; p = 0.005) and AGE values (β = 0.25; p = 0.003) are positively associated with plasma AEA levels, independent of age, sex, BMI, and fasting plasma glucose levels. Conclusions: Circulating AEA, but not 2-AG, is elevated in prediabetes and independently linked to cumulative AGE burden, suggesting early endocannabinoid activation contributes to cardiometabolic risk. High adherence to a Mediterranean diet may mitigate this dysregulation. Full article

Advanced glycation end-products (AGEs) are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids due to the consumption of high-carbohydrate diets; their production is also promoted by a sedentary lifestyle as well as cigarette smoking. Elevated levels of AGEs in the circulatory system and internal organs of the body are commonly observed in a number of cardiovascular diseases such as hypertension, diabetes, atherosclerosis, coronary artery disease, aortic aneurysm, atrial fibrillation, myocardial infarction, and heart failure, which are associated with the development of oxidative stress and myocardial inflammation. The adverse effects of AGEs on the cardiovascular system are elicited by both non-receptor mechanisms involving the cross-linking of extracellular and intracellular proteins, and by receptor-mediated mechanisms involving the binding of AGEs with advanced glycation end-product receptors (RAGEs) on the cell membrane. AGE–RAGE interactions along with the cross-linking of proteins promote the generation of oxidative stress, the production of inflammation, the occurrence of intracellular Ca²⁺-overload, and alterations in the extracellular matrix leading to the development of cardiovascular dysfunction. AGEs also bind with two other protein receptors in the circulatory system: soluble RAGEs (sRAGEs) are released upon the proteolysis of RAGEs due to the activation of matrix metalloproteinase, and endogenous secretory RAGEs (esRAGEs) are secreted as a spliced variant of endogenous RAGEs. While the AGE–RAGE signal transduction axis serves as a pathogenic mechanism, both sRAGEs and esRAGEs serve as cytoprotective interventions. The serum levels of sRAGEs are decreased in ischemic heart disease, vascular disease, and heart failure, as well as in other cardiovascular diseases, but are increased in chronic diabetes and renal disease. Several interventions which can reduce the formation of AGEs, block the AGE–RAGE axis, or increase the levels of circulating sRAGEs have been shown to exert beneficial effects in diverse cardiovascular diseases. These observations support the view that the AGE–RAGE axis not only plays a critical role in pathogenesis, but is also an excellent target for the treatment of cardiovascular disease. Full article

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements. Full article

Although emerging evidence suggests that epigenetic mechanisms contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM), data remain limited for patients with suboptimal metabolic control. The aim of this study was to assess global DNA methylation in patients with poorly controlled T2DM and to identify diabetes-related factors associated with DNA methylation levels. The study included 107 patients and 50 healthy controls. Global DNA methylation (5mC) was measured by UHPLC-DAD method. Pro-oxidant and antioxidant biomarkers, advanced glycation end-products, high-sensitivity C-reactive protein (hsCRP) and complete blood count were determined and leukocyte indices calculated. Patients had a significantly lower 5mC than controls (3.56 ± 0.31% vs. 4.00 ± 0.68%; p < 0.001), with further reductions observed in those with longer disease duration and diabetic foot ulcers. Oxidative stress and inflammatory biomarkers were higher in the patient group. DNA hypomethylation was associated with a higher monocyte-to-lymphocyte ratio and hsCRP, pro-oxidant–antioxidant balance, ischemia-modified albumin, and advanced oxidation protein products levels. Conversely, 5mC levels showed positive correlations with total antioxidant status and total sulfhydryl groups. Principal component analysis identified five key factors: proinflammatory, pro-oxidant, aging, hyperglycemic, and antioxidant. The pro-oxidant factor emerged as the sole independent predictor of global DNA hypomethylation in T2DM (OR = 2.294; p = 0.027). Our results indicate that global DNA hypomethylation could be a biomarker of T2DM progression, reflecting the complex interactions between oxidative stress, inflammation, and epigenetic modifications in T2DM. Full article

Background/Objectives: Diabetes mellitus is defined as a group of metabolic diseases characterized by chronically elevated blood glucose levels. This condition influences the course of orthodontic treatment, as it affects various clinical aspects of the patient that must be taken into consideration prior to initiation. Therefore, achieving adequate control and management of diabetic patients undergoing orthodontic therapy is essential. This article presents a qualitative synthesis of studies addressing how diabetes affects orthodontic treatments, emphasizing the importance of understanding the necessary considerations prior to initiating treatment and how to manage potential complications. Methods: This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A database search was performed on 5 May 2025, in PubMed, Scopus, Scielo, and The Cochrane Library, using terms related to “diabetes mellitus” and “orthodontic treatments”. Studies meeting the search criteria were included, particularly those that were published in the past ten years and reported on the influence of diabetes on orthodontic treatment. The quality of the case–control studies was assessed using the Newcastle–Ottawa Scale (NOS); for cross-sectional studies, the Joanna Briggs Institute (JBI) critical appraisal checklist was used; and for experimental studies, the SYRCLE’s Risk of Bias Tool was applied. Results: Fourteen studies ultimately met the inclusion criteria. The evidence showed that diabetes increases gingival bleeding due to elevated levels of advanced glycation end-products (AGEs) and pro-inflammatory cytokines; reduces the efficiency of tooth movement; increases root resorption and affects bone remodeling; and compromises both periodontal and pulpal responses, thereby hindering tissue regeneration. It was also observed that the use of insulin or antidiabetic agents such as metformin may partially mitigate these adverse effects. Conclusions: This systematic review reveals a clear relationship between diabetes and various clinical aspects that influence the progression of orthodontic treatments. Nonetheless, further studies are needed to better understand the impact of this systemic condition on dental treatment outcomes. Full article

When breastfeeding is not possible, infant formulas may be used instead of human milk. However, harmful advanced glycation end-products (AGEs) may be formed during thermal processing of infant formulas. The exposure to AGEs at such an early age can lead to chronic diseases in the future. Therefore, the aim of this study was to develop a sensitive method to determine the content of AGEs in infant formulas. Twenty commercial infant formulas (initial and follow-on) in liquid and powder form were investigated using liquid chromatography with tandem mass spectrometry (LC-MS/MS) with a multistep sample pretreatment procedure. Five selected glycation products were analyzed: N^ε-carboxyethyllysine (CEL), N^ε-carboxymethyllysine (CML), furosine, glyoxal lysine dimer (GOLD), and methylglyoxal lysine dimer (MOLD). The mean contents of the tested glycation products did not differ significantly between the initial and follow-on formulas. No significant differences were found in the concentrations of the analyzed compounds from different manufacturers. However, the liquid formulas contained significantly more CML. The estimated dietary exposure to the tested compounds was in the range of 42.5–92.6 μg/day, except for furosine (almost 2 mg/day). The developed method enabled the determination of selected AGEs in complex matrices such as infant formulas. Consumption of liquid infant formulas can result in higher exposure to some AGEs. Full article

Thermal-processed foods like baked, smoked, and fried products are popular for their unique aroma, taste, and color. However, thermal processing can generate various contaminants via Maillard reaction, lipid oxidation, and thermal degradation, negatively impacting human health. This review summarizes the formation pathways, influencing factors, and tracing approaches of potential hazards in thermally processed foods, such as polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HAAs), furan, acrylamide (AA), trans fatty acids (TFAs), advanced glycation end-products (AGEs), sterol oxide. The formation pathways are explored through understanding high free radical activity and multiple active intermediates. Control patterns are uncovered by adjusting processing conditions and food composition and adding antioxidants, aiming to inhibit hazards and enhance the safety of thermal-processed foods. Full article

Advanced glycation end-products (AGEs) and oxidative stress are recognized as central contributors to the pathogenesis of age-related or diabetic cataracts, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These glycation-related diseases are characterized by impaired redox balance and decreased glutathione (GSH) levels. This review aims to examine the mechanistic links between AGEs and GSH depletion across ocular tissues by integrating in vitro, ex vivo, in vivo, and clinical studies relevant to this topic. The multiple levels of evidence highlight GSH homeostasis as both a biomarker and therapeutic target in glycation-related ocular disorders. Therapeutic strategies aimed at restoring GSH homeostasis under glycation stress are categorized into four mechanistic domains: (I) promoting GSH supply and synthesis, (II) enhancing GSH recycling, (III) mitigating glycation stress, and (IV) reducing oxidative and nitrosative stress. Most of these strategies have been explored via different approaches, and experimental findings with various interventions have shown promise in restoring GSH balance and mitigating AGE-induced damage. A pathological link between GSH depletion and vascular endothelial growth factor (VEGF) overexpression is observed in DR and wet AMD. GSH-centered interventions act upstream to modulate redox homeostasis while anti-VEGF therapies target downstream angiogenesis. This study supports the rationale for a dual-targeting strategy that combines redox-based interventions with VEGF inhibition in glycation-related ocular diseases. Full article

In this study, the ranking of the multifaceted activity of rutin (Ru), quercetin (Q), and quercetin’s glucosides (Q3G, Q4′G and Q3,4′G) was addressed. The antioxidant potency was determined by electrochemical methods, whereas the ability of these compounds to inhibit angiotensin-converting enzyme (ACE) activity, acetylcholinesterase (AChE) activity, and advanced glycation endproduct (AGE) formation was examined in bovine serum albumin (BSA)/glucose and BSA/methylglyoxal (MGO) model systems to show their importance against hypertension, Alzheimer-type dementia, and diabetic complication, respectively. Then, the relationship between the biological activities of these compounds and their antioxidant potential provided by the cyclic voltammetry (CV) method was evaluated. The ranking of the ACE inhibitory activity was Q > Q3,4′G > Ru > Q3G > Q4′G. The correlation coefficient between ACE enzyme inhibitory activities and antioxidant potentials had a value of r = −0.68, thus clearly indicating the impact of antioxidant potential and chemical structure on ACE inhibitory activity. The ranking of the AChE enzyme inhibitory activity was Q ≈ Q3G ≈ Q4′G ≈ Ru > Q3,4′G, and the correlation between their antioxidant potentials and AChE inhibitory activities (r = −0.77) also indicated the impact of chemical structure. The quercetin glucosides displayed strong inhibitory capacity on AGE formation, as the ranking of anti-AGE activity in the BSA/MGO model system was Q3,4′G ≈ Q4′G ≈ Q3G > Ru ≈ Q > AG. The anti-AGE activity of rutin, quercetin, and quercetin’s glucosides was negatively correlated with their IC₅₀ values for ACE inhibition (r = −0.67) and AChE inhibition (r = −0.81), whereas no correlation was found between their ACE and AChE inhibition activities. These effects of rutin, quercetin, and quercetin’s glucosides expand our knowledge of the multifunctional activity of biologically active compounds of plant origin. Full article

Glycation in biological systems contributes to the development of chronic diseases, particularly under conditions of hyperglycemia and oxidative stress. This study evaluated the antiglycation and methylglyoxal (MGO)-trapping capacities of aqueous and methanolic extracts of carob flour. The methanolic extract exhibited significantly higher bioactive compounds, containing 1.4-fold more total phenolics and 1.6-fold more flavonoids than the aqueous extract, as well as 1.2- and 1.8-fold-higher antioxidant activity. Antiglycation activity was assessed using bovine serum albumin (BSA)–glucose and BSA–MGO in vitro models, where the methanolic extract consistently outperformed the aqueous extract. At 25 mg/mL, the formation of advanced glycation end-products was inhibited by 81.0% in the BSA–glucose model and nearly 70% in the BSA–MGO model. These findings were supported by lower IC₅₀ values for the methanolic extract (6.6 vs. 10.8 mg/mL and 9.4 vs. 16.6 mg/mL). MGO-trapping capacity was also higher for the methanolic extract, reaching 97% with 25 mg/mL after 168 h. The superior antiglycation and MGO-trapping activities of the methanolic extract are attributed to its higher content of gallic acid and other phenolic compounds with known bioactivities. These results highlight the potential of carob-based formulations as functional ingredients with preventive applications against glycation-associated pathologies. Full article

Methylglyoxal is a reactive dicarbonyl intermediate in the advanced glycation end-product (AGE) pathway, and alterations in its levels have been detected in the plasma, cerebrospinal fluid, and brain parenchyma in various pathologies, particularly in diabetes. In this study, we investigate the effects of methylglyoxal (MGO) on murine brain microvascular endothelial cells at both physiological and pathological concentrations. We evaluate molecular parameters, including reactive oxygen species (ROS) production, cytosolic calcium signaling, and ATP synthesis, as well as cellular responses such as cytoskeletal remodeling, cell migration, adhesion, and permeability, across a concentration range of 0–1000 μM. At low concentrations (below ~250 μM), MGO does not induce oxidative stress; instead, it leads to an increase in cytosolic calcium levels and ATP production. At higher concentrations, however, MGO induces significant oxidative stress, which is accompanied by a marked decrease in cell viability, particularly at concentrations exceeding 500 μM. The modulation of key functional processes, including purinergic calcium signaling, actin filament synthesis, cell migration, and adhesion, reveals a threshold concentration beyond which cellular function is impaired due to oxidative stress. Below this threshold, the observed effects appear to be mediated primarily by non-oxidative mechanisms, likely involving protein glycation. In conclusion, our results suggest a dual action of methylglyoxal on brain endothelial cells, with distinct molecular mechanisms underlying its effects at physiological versus pathological concentrations. Full article

Background and Objectives: Gait and posture alterations are reported in patients with diabetic foot. We evaluated whether gait and postural parameters are associated with a well-known parameter, e.g., glycated hemoglobin levels in blood, and the salivary markers 1,5-anhydro-D-glucitol (1,5-AG) and Advanced Glycation End-Products (AGEs) measured in saliva samples. Materials and Methods: Gait and postural impairment was assessed using a wearable inertial sensor, and the evaluation of balance/gait and risk of fall was determined by the Tinetti Scale and Downton Index, respectively. Glycemic control was measured by glycated hemoglobin concentration and fasting glycemia. The salivary concentration of 1,5-AG and AGEs was measured using an enzyme-linked immunosorbent assay. Results: Eighty-five patients were evaluated, revealing significant associations (p < 0.05) between salivary 1,5-AG and sway path displacement along the medio-lateral axis (rho = 0.365, p = 0.017) and sway area (rho = 0.334, p = 0.031) during tandem position tests with eyes closed. Salivary AGEs were significantly associated with sway path displacement along the anterior–posterior axis (rho = 0.419, p = 0.004) and medio-lateral axis (rho = 0.436, p = 0.002) in the tests performed with eyes closed, feet close together, and foam pads, as well as with sway area (rho = 0.387, p = 0.007). The concentration of HbA1c was significantly correlated with sway path displacement along the anterior–posterior axis in the tests performed with eyes closed, feet close together, and foam pads (rho = 0.236, p = 0.043), as well as with sway area (rho = −0.236, p = 0.043). A significant difference was observed in the salivary AGE concentration between patients with previous ulcers versus those without (p = 0.035). By applying Bonferroni correction for multiple comparisons, the associations remained significant (p < 0.05) for AGE concentration in saliva and postural instability parameters. Conclusions: The results suggest a link between salivary glycemic control biomarkers, in particular AGEs and postural changes in patients with diabetic foot, indicating a new interesting filed for further studies on fall risk. Full article

Glycation influences skin aging through non-enzymatic reactions between reducing sugars and proteins, forming advanced glycation end-products (AGEs) that accelerate skin deterioration. This study evaluates the curative anti-glycation effects of an injectable formulation combining dual-molecular-weight hyaluronic acid (low and mid/high) with trehalose in methylglyoxal-induced glycation in human skin explants. Thirty-six human skin explants were allocated across five experimental groups in a 12-day study. Glycation was induced using methylglyoxal (500 μM) on days 1 and 4, followed by curative product administration on day 5. CML (Nε-(carboxymethyl)lysine) immunohistochemistry was performed to assess glycation levels in the reticular dermis at days 6, 8, and 12, with quantitative analysis conducted through standardized image analysis. The formulation significantly reduced CML formation by 60% on day 6 compared to untreated controls (p < 0.001). Under methylglyoxal-induced glycation stress the product showed sustained curative effects, with CML reductions of 69% on day 6 (p = 0.008), 68% on day 8 (p = 0.012), and 61% on day 12 (p = 0.033) compared to methylglyoxal treatment alone. Cell viability remained unaffected throughout the study period across all experimental conditions. The tested injectable formulation exhibits significant and sustained curative anti-glycation properties in human skin explants for 12 days, effectively counteracting methylglyoxal-induced glycation damage without affecting cell viability. These findings advance anti-aging skin interventions, offering a novel approach to address glycation-induced skin damage with potential applications in clinical dermatology and aesthetic medicine. Full article

Background: Methylglyoxal (MGO), a reactive dicarbonyl compound, has been implicated in the formation of advanced glycation end-products (AGEs) and neuronal dysfunction. This study investigated the neuroprotective effects of the combination of trans-resveratrol and hesperidin (tRES-HESP) against MGO-induced neurotoxicity, focusing on memory dysfunction and depression-like behavior. Methods: Neuroblastoma 2a (N2a) cells were treated with MGO to induce neurotoxicity. The effects of tRES-HESP on cell viability, reactive oxygen species (ROS) production, apoptotic markers (BAX/Bcl 2 ratio, caspase 3 activity, and poly [ADP ribose] polymerase cleavage), and components of the glyoxalase system (glyoxalase-1, glyoxalase- 2, and receptors for AGEs) were assessed. The activation of the Kelch-like ECH-associated protein 1/Nuclear factor erythroid-2-related factor 2/Heme oxygenase-1 (Keap1/Nrf2/HO-1) pathway was also evaluated. In vivo, mice with MGO-induced depressive amnesia were treated with tRES-HESP (200 mg/kg) for eight weeks, and behavioral, biochemical, and histological assessments were performed. Results: tRES-HESP significantly reduced MGO-induced cytotoxicity, ROS production, and apoptosis in N2a cells. In addition, it restored the glyoxalase system and activated the Keap1/Nrf2/HO-1 pathway. In an in vivo model, tRES-HESP improved memory and depression-like behaviors, reduced cortisol and interleukin (IL)-6 levels, increased IL-10 levels, and lowered the expression of amyloid precursor protein and amyloid beta. Furthermore, tRES-HESP protected CA2/3 hippocampal subregions from MGO-induced damage. tRES-HESP exhibited neuroprotective effects through antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. Conclusions: Our results suggest that tRES-HESP is a potential dietary supplement for preventing cognitive decline and depression, particularly in neurodegenerative conditions such as Alzheimer’s disease. Further studies are required to assess its clinical relevance and efficacy in the human population. Full article

Advanced glycation end-products (AGEs) cause blood vessel damage and induce diabetic complications in various organs, such as the eyes, kidneys, nerves, and skin. As glycation stress causes aesthetic, physical, and functional changes in the skin, glycation-targeting skin anti-aging strategies are attracting attention in cosmetology and dermatology. The primary goal of this review is to understand the significance of glycation-induced skin aging and to examine the therapeutic potential of glycation-targeting strategies. This study covers experimental and clinical studies exploring various interventions to attenuate glycation-induced skin aging. Glycation stress decreases the viability of cells in culture media, the cell-mediated contraction of collagen lattices in reconstructed skin models, and the expression of fibrillin-1 at the dermo-epidermal junction in the skin explants. It also increases cross-links in tail tendon collagen in animals, prolonging its breakdown time. However, these changes are attenuated by several synthetic and natural agents. Animal and clinical studies have shown that dietary or topical administration of agents with antiglycation or antioxidant activity can attenuate changes in AGE levels (measured by skin autofluorescence) and skin aging parameters (e.g., skin color, wrinkles, elasticity, hydration, dermal density) induced by chronological aging, diabetes, high-carbohydrate diets, ultraviolet radiation, or oxidative stress. Therefore, the accumulating experimental and clinical evidence supports that dietary supplements or topical formulations containing one or more synthetic and natural antiglycation agents may help mitigate skin aging induced by AGEs. Full article