Search

IntroductionThe accumulation of tissue-advanced glycation end products in skin results from complex and consecutive reactions and can be measured by skin autofluorescence (SAF) reader devices. This overview discusses studies evaluating the utilization of SAF in screening renal and cardiac disease.Materials and methodsLiterature search was performed using Google Scholar, PubMed, Springer, Ovid, and ScienceDirect.ResultsSAF was an independent predictor of progression of chronic kidney disease (CKD) and was elevated in subjects on hemodialysis and peritoneal dialysis. Furthermore, SAF was significantly associated with cardiovascular events, cardiovascular mortality, and all-cause mortality in CKD patients. Other studies revealed a correlation between SAF and arterial stiffness, vascular damage, and subclinical atherosclerosis. A vegetarian diet was associated with lower SAF levels, whereas malnutrition was correlated with higher levels and increased mortality.ConclusionsSAF measurement may be useful in managing renal and cardiac disease. Future studies are needed to clarify the specific role of SAF in the management of CKD and its noninvasive office utilization to identify comorbidities in inflammatory diseases, such as psoriasis.

A total of 147 oral Kampo prescriptions, which are used clinically in Japan, were evaluated for their anti-glycation activity. Kakkonto demonstrated significant anti-glycation activity, prompting further analysis of its chemical constituents using LC-MS, which revealed the presence of two alkaloids, fourteen flavonoids, two but-2-enolides, five monoterpenoids, and four triterpenoid glycosides. To identify the components responsible for its anti-glycation activity, the Kakkonto extract was reacted with glyceraldehyde (GA) or methylglyoxal (MGO) and analyzed using LC-MS. In LC-MS analysis of Kakkonto reacted with GA, the peak intensity of ephedrine was attenuated, and three products from ephedrine-scavenging GA were detected. Similarly, LC-MS analysis of Kakkonto reacted with MGO revealed two products from ephedrine reacting with MGO. These results indicated that ephedrine was responsible for the observed anti-glycation activity of Kakkonto. Ephedrae herba extract, which contains ephedrine, also showed strong anti-glycation activity, further supporting ephedrine’s contribution to Kakkonto’s reactive carbonyl species’ scavenging ability and anti-glycation activity.

The consensus in aging is that inflammation, cellular senescence, free radicals, and epigenetics are contributing factors. Skin glycation through advanced glycation end products (AGEs) has a crucial role in aging. Additionally, it has been suggested that their presence in scars leads to elasticity loss. This manuscript reports fructosamine-3-kinase (FN3K) and fructosyl-amino acid oxidase (FAOD) in counteracting skin glycation by AGEs. Skin specimens were obtained (n = 19) and incubated with glycolaldehyde (GA) for AGE induction. FN3K and FAOD were used as monotherapy or combination therapy. Negative and positive controls were treated with phosphate-buffered saline and aminoguanidine, respectively. Autofluorescence (AF) was used to measure deglycation. An excised hypertrophic scar tissue (HTS) (n = 1) was treated. Changes in chemical bonds and elasticity were evaluated using mid-infrared spectroscopy (MIR) and skin elongation, respectively. Specimens treated with FN3K and FAOD in monotherapy achieved an average decrease of 31% and 33% in AF values, respectively. When treatments were combined, a decrease of 43% was achieved. The positive control decreased by 28%, whilst the negative control showed no difference. Elongation testing of HTS showed a significant elasticity improvement after FN3K treatment. ATR-IR spectra demonstrated differences in chemical bounds pre- versus post-treatment. FN3K and FAOD can achieve deglycation and the effects are most optimal when combined in one treatment. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:24 issue:10 ispartof: location:Switzerland status: published

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.

Podocyte injury leading to albuminuria is a characteristic feature of diabetic nephropathy (DN). Hyperglycemia and advanced glycation end products (AGEs) are major determinants of DN. However, the underlying mechanisms of podocyte injury remain poorly understood. The cytosolic protein TNFAIP2/M-Sec is required for tunneling nanotubes (TNTs) formation, which are membrane channels that transiently connect cells, allowing organelle transfer. Podocytes express TNFAIP2 and form TNTs, but the potential relevance of the TNFAIP2-TNT system in DN is unknown. We studied TNFAIP2 expression in both human and experimental DN and the renal effect of tnfaip2 deletion in streptozotocin-induced DN. Moreover, we explored the role of the TNFAIP2-TNT system in podocytes exposed to diabetes-related insults. TNFAIP2 was overexpressed by podocytes in both human and experimental DN and exposre of podocytes to high glucose and AGEs induced the TNFAIP2-TNT system. In diabetic mice, tnfaip2 deletion exacerbated albuminuria, renal function loss, podocyte injury, and mesangial expansion. Moreover, blockade of the autophagic flux due to lysosomal dysfunction was observed in diabetes-injured podocytes both in vitro and in vivo and exacerbated by tnfaip2 deletion. TNTs allowed autophagosome and lysosome exchange between podocytes, thereby ameliorating AGE-induced lysosomal dysfunction and apoptosis. This protective effect was abolished by tnfaip2 deletion, TNT inhibition, and donor cell lysosome damage. By contrast, Tnfaip2 overexpression enhanced TNT-mediated transfer and prevented AGE-induced autophagy and lysosome dysfunction and apoptosis. In conclusion, TNFAIP2 plays an important protective role in podocytes in the context of DN by allowing TNT-mediated autophagosome and lysosome exchange and may represent a novel druggable target. Abbreviations: AGEs: advanced glycation end products; AKT1: AKT serine/threonine kinase 1; AO: acridine orange; ALs: autolysosomes; APs: autophagosomes; BM: bone marrow; BSA: bovine serum albumin; CTSD: cathepsin D; DIC: differential interference contrast; DN: diabetic nephropathy; FSGS: focal segmental glomerulosclerosis; HG: high glucose; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LMP: lysosomal membrane permeabilization; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PI3K: phosphoinositide 3-kinase; STZ: streptozotocin; TNF: tumor necrosis factor; TNFAIP2: tumor necrosis factor, alpha-induced protein 2; TNTs: tunneling nanotubes; WT: wild type.

Jiao Wang,1– 3,* Wei Cai,4,* Jiao Yu,1 Honghong Liu,1 Shasha He,1 Lingyan Zhu,1– 3 Jixiong Xu1– 3 1Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, 330006, People’s Republic of China; 3Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, 330006, People’s Republic of China; 4Department of Medical Genetics and Cell biology, Medical College of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jixiong Xu, Email Jixiong.Xu@ncu.edu.cnObjective: This study aimed to explore the associations between gut microbiota characteristics and glycometabolic profiles in mice fed diets high in advanced glycation end products (AGEs).Methods: C57BL/6 mice were exposed to a heat-treated diet or exogenous AGEs for 24 weeks, and glucose metabolism was assessed via the intraperitoneal glucose-tolerance test (IPGTT). Serum AGE and lipopolysaccharide-binding protein (LBP) levels were quantified using ELISA kits. 16S rDNA sequencing was performed to analyze the changes in gut microbiota according to α- and β-diversity. Key operational taxonomic units (OTUs) were evaluated, and co-abundance groups (CAGs) were delineated using weighted correlation network analysis. Associations between CAGs and clinical parameters were analyzed using Spearman correlation; predictive functional analysis of gut microbiota was performed using Kyoto Encyclopedia of Genes and Genomes data.Results: We identified significant increases in fasting blood glucose (FBG) and fasting insulin levels, as well as homeostatic model assessment insulin resistance (HOMA-IR) and glucose area under the receiver operating characteristic curve from IPGTT, in the high-AGE diet groups relative to controls at week 24. Serum AGE and LBP levels were elevated, and the α- and β-diversity of gut microbiota reduced in high-AGE diet groups. We identified 92 key OTUs that clustered into six CAGs, revealing positive correlations between CAG2/3/5 and insulin levels and mice weight and negative correlations between CAG1/3/4/5 and AGE, FBG, and LBP levels and HOMA-IR in mice fed high-AGE diets. We observed a reduced abundance of butyrate-producing bacteria, including Bacteroidales_S24-7, Ruminococcaceae, and Lachnospiraceae, in mice fed high-AGE diets, with pathway analysis of gut microbiota revealing significantly enriched fructose and mannose metabolism.Conclusion: High-AGE diets altered the gut microbiota composition and structure, and induced insulin resistance in mice. In the pathogenesis of insulin resistance, the loss of butyrate-producing bacteria might impair the colonic epithelial barrier, thereby triggering chronic low-grade inflammation.Keywords: diet, advanced glycation end products, gut microbiota, insulin resistance

Water-soluble forms of α-tocopherol (TP) as an effective antioxidant were obtained by encapsulating it into nanoparticles (NPs) of amphiphilic copolymers of N-vinylpyrrolidone with triethylene glycol dimethacrylate (CPL1-TP) and N-vinylpyrrolidone with hexyl methacrylate and triethylene glycol dimethacrylate (CPL2-TP) synthesized by radical copolymerization in toluene. The hydrodynamic radii of NPs loaded with TP (3.7 wt% per copolymers) were typically ca. 50 or 80 nm depending on copolymer composition, media, and temperature. Characterization of NPs was accomplished by transmission electron microscopy (TEM), IR-, and 1H NMR spectroscopy. Quantum chemical modeling showed that TP molecules are capable to form hydrogen bonds with donor groups of the copolymer units. High antioxidant activity of both obtained forms of TP has been found by the thiobarbituric acid reactive species and chemiluminescence assays. CPL1-TP and CPL2-TP effectively inhibited the process of spontaneous lipid peroxidation as well as α-tocopherol itself. The IC50 values of luminol chemiluminescence inhibition were determined. Antiglycation activity against vesperlysine and pentosidine-like AGEs of TP water-soluble forms was shown. The developed NPs of TP are promising as materials with antioxidant and antiglycation activity and can be used in various biomedical applications.

Met de toenemende vergrijzing in ons land zal er ook een toename plaatsvinden van het aantal ouderen met dementie. Dementie, met als voornaamste oorzaak de ziekte van Alzheimer, wordt in het algemeen vooral gezien als een ziekte waarbij cognitieve problemen optreden. Dat er ook al in een vroeg stadium motorische stoornissen optreden is veel minder bekend. Pas in een laat stadium worden de motorische problemen dusdanig groot dat de fysiotherapeut wordt ingeschakeld. Het is van belang om als fysiotherapeut kennis te hebben van de verschillende vormen van dementie en de daarmee gepaard gaande verschillen in motorische stoornissen. Daarnaast is het van belang om inzicht te krijgen in werkzame interventies en de juiste meetinstrumenten in te kunnen zetten. In deze masterclass wordt inzicht gegeven in de motorische problemen bij dementie (o.a. paratonie) en worden handvatten voor de praktijk gegeven.

Excessive consumption of cookies has been linked to harmful health outcomes owing to the presence of refined carbohydrates and heat-induced toxicants including end products of lipid peroxidation and dietary advanced glycation end products (dAGEs). To address this issue, this study explores the addition of dragon fruit peel powder (DFP), which is rich in phytochemicals and dietary fibers, to cookies as a potential solution to mitigate their adverse effects. The results indicate that adding DFP at 1%, 2%, and 5% w/w of raw cookie dough significantly improves the total phenolic and betacyanin contents and antioxidant activity, as evidenced by increased ferric-reducing antioxidant power. DFP incorporation also led to reductions in malondialdehyde and dAGEs (p < 0.05). Furthermore, the starch digestibility, hydrolysis index, and predicted glycemic index were all reduced in the presence of DFP, with the latter estimate being due to the higher content of undigested starch. Incorporating DFP in cookies resulted in significant changes in their physical properties, including texture and color. However, sensory evaluation indicates that the overall acceptability of the cookies was not negatively impacted by the addition of up to 2% DFP, suggesting that it is a viable option for enhancing the nutritional value of cookies without compromising their palatability. These findings suggest that DFP is a sustainable and healthier ingredient that can improve the antioxidant capacity of cookies while also mitigating the harmful effects of heat-induced toxins.

Background: Kidney transplant recipients (KTRs) represent a vulnerable group of patients who develop a number of comorbidities. Severe periodontitis (SP) is associated with the most common chronic systemic diseases including kidney diseases. The objective of this study was to explore the risk factors for SP in KTRs. Methods: In this study, KTRs were divided into those with or without periodontitis and in relation to the severity of periodontitis. A comprehensive medical and periodontal examination was performed and evaluated. Multivariate logistic regression was performed to examine possible risk factors for SP among KTRs. Results: A total of 100 KTRs was included in the analysis, of which 87% had periodontitis. Significant predictors of periodontitis were older age (OR (95% CI) = 1.07 (1.01-1.13), P = 0.016) and lower skeletal muscle mass (OR (95% CI) = 0.88 (0.78-0.99), P = 0.035). When examining periodontitis severity, predictors of SP (n = 21, 24%) were increased levels of uric acid (OR (95% CI) = 1.01 (1.00-1.02), P = 0.022) and dental plaque (OR (95% CI) = 1.04 (1.01-1.07), P = 0.013). In the subset analysis that included only KTRs with measured advanced glycation end products (AGE) (n = 47), 34% (n = 16) had SP. The predictors of SP were AGE (OR (95% CI) = 3.89 (1.28-11.82), P = 0.017) and dental plaque (OR (95% CI) = 1.07 (1.01-1.13), P = 0.028). Conclusions: KTRs with SP had significantly higher uric acid level and AGE, which may contribute to the systemic health status of this patient population.

Bone loss occurs in astronauts during long-term space flight, but the mechanisms are still unclear. We previously showed that advanced glycation end products (AGEs) were involved in microgravity-induced osteoporosis. Here, we investigated the improvement effects of blocking AGEs formation on microgravity-induced bone loss by using the AGEs formation inhibitor, irbesartan. To achieve this objective, we used a tail-suspended (TS) rat model to simulate microgravity and treated the TS rats with 50 mg/kg/day irbesartan, as well as the fluorochrome biomarkers injected into rats to label dynamic bone formation. To assess the accumulation of AGEs, pentosidine (PEN), non-enzymatic cross-links (NE−xLR), and fluorescent AGEs (fAGEs) were identified in the bone; 8-hydroxydeoxyguanosine (8-OHdG) was analyzed for the reactive oxygen species (ROS) level in the bone. Meanwhile, bone mechanical properties, bone microstructure, and dynamic bone histomorphometry were tested for bone quality assessment, and Osterix and TRAP were immunofluorescences stained for the activities of osteoblastic and osteoclastic cells. Results showed AGEs increased significantly and 8-OHdG expression in bone showed an upward trend in TS rat hindlimbs. The bone quality (bone microstructure and mechanical properties) and bone formation process (dynamic bone formation and osteoblastic cells activities) were inhibited after tail-suspension, and showed a correlation with AGEs, suggesting the elevated AGEs contributed to the disused bone loss. After being treated with irbesartan, the increased AGEs and 8-OHdG expression were significantly inhibited, suggesting irbesartan may reduce ROS to inhibit dicarbonyl compounds, thus suppressing AGEs production after tail-suspension. The inhibition of AGEs can partially alter the bone remodeling process and improve bone quality. Both AGEs accumulation and bone alterations almost occurred in trabecular bone but not in cortical bone, suggesting AGEs effects on bone remodeling under microgravity are dependent on the biological milieu.

The formation of advanced glycation end products (AGEs), including Nε-carboxymethyl-lysine (CML) and Nε-carboxyethyl-lysine (CEL), in a fish myofibrillar protein and glucose (MPG) model system at 80 °C and 98 °C for up to 45 min of heating were investigated. The characterization of protein structures, including their particle size, ζ-potential, total sulfhydryl (T-SH), surface hydrophobicity (H0), sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and Fourier transform infrared spectroscopy (FTIR), were also analyzed. It was found that the covalent binding of glucose and myofibrillar protein at 98 °C promoted protein aggregation when compared with the fish myofibrillar protein (MP) heated alone, and this aggregation was associated with the formation of disulfide bonds between myofibrillar proteins. Furthermore, the rapid increase of CEL level with the initial heating at 98 °C was related to the unfolding of fish myofibrillar protein caused by thermal treatment. Finally, correlation analysis indicated that the formation of CEL and CML had a significantly negative correlation with T-SH content (r = −0.68 and r = −0.86, p ≤ 0.011) and particle size (r = −0.87 and r = −0.67, p ≤ 0.012), but was weakly correlated with α-Helix, β-Sheet and H0 (r2 ≤ 0.28, p > 0.05) during thermal treatment. Overall, these findings provide new insights into the formation of AGEs in fish products based on changes of protein structure.

Multidisciplinary inpatient rehabilitation plays an important role in the recovery of patients with cardiovascular diseases (CVDs). Lifestyle changes, achieved by exercise, diet, weight loss and patient education programs, are the first steps to a healthier life. Advanced glycation end products (AGEs) and their receptor (RAGE) are known to be involved in CVDs. Clarification on whether initial AGE levels can influence the rehabilitation outcome is important. Serum samples were collected at the beginning and end of the inpatient rehabilitation stay and analyzed for parameters: lipid metabolism, glucose status, oxidative stress, inflammation and AGE/RAGE-axis. As result, a 5% increase in the soluble isoform RAGE (sRAGE) (T0: 891.82 ± 44.97 pg/mL, T1: 937.17 ± 43.29 pg/mL) accompanied by a 7% decrease in AGEs (T0: 10.93 ± 0.65 µg/mL, T1: 10.21 ± 0.61 µg/mL) was shown. Depending on the initial AGE level, a significant reduction of 12.2% of the AGE activity (quotient AGE/sRAGE) was observed. We found that almost all measured factors improved. Summarizing, CVD-specific multidisciplinary rehabilitation positively influences disease-associated parameters, and thus provides an optimal starting point for subsequent disease-modifying lifestyle changes. Considering our observations, the initial physiological situations of patients at the beginning of their rehabilitation stay seem to play a decisive role regarding the assessment of rehabilitation success.

Controversy exists regarding the association of dietary advanced glycation end products (dAGEs) with the risk of disease outcomes and mortality. We aimed to examine, prospectively, the association between dAGEs intake and the risk of overall and cause-specific mortality in the Golestan Cohort Study. The cohort was conducted between 2004 and 2008 in Golestan Province (Iran) recruiting 50,045 participants aged 40–75 years. Assessment of dietary intake over the last year was performed at baseline using a 116-item food frequency questionnaire. The dAGEs values for each individual were calculated based on published databases of AGE values of various food items. The main outcome was overall mortality at the time of follow-up (13.5 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cause-specific mortality were estimated according to the dAGEs quintiles. During 656, 532 person-years of follow-up, 5406 deaths in men and 4722 deaths in women were reported. Participants at the highest quintile of dAGE had a lower risk of overall mortality (HR: 0.89, 95% CI: 0.84, 0.95), CVD mortality (HR: 0.89, 95% CI: 0.84, 0.95), and death from other causes (HR: 0.89, 95% CI: 0.84, 0.95) compared to those in the first quintile after adjusting for confounders. We found no association of dAGEs with risk of mortality from cancer (all), respiratory and infectious diseases, and injuries. Our findings do not confirm a positive association between dAGEs and the risk of mortality in Iranian adults. There is still no agreement among studies investigating dAGEs and their health-related aspects. So, further high-quality studies are required to clarify this association.

Diabetic keratopathy (DK) is an important diabetic complication at the ocular surface. Chronic low-grade inflammation mediated by the NLRP3 inflammasome promotes pathogenesis of diabetes and its complications. However, the effect of the NLRP3 inflammasome on DK pathogenesis remains elusive. Wild-type (WT) and Nlrp3 knockout (KO) C57 mice were used to establish a type I diabetes model by intraperitoneal injection of streptozotocin. The effect of the NLRP3 inflammasome on diabetic corneal wound healing and never regeneration was examined by a corneal epithelial abrasion model. Western blot, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and pharmacological treatment were performed to investigate the regulatory mechanism of advanced glycation end products (AGEs) on NLRP3 inflammasome activation and corneal wound healing in vivo. The cultured mouse corneal epithelial cells (TKE2) were used to evaluate the effect and mechanism of AGEs on NLRP3 inflammasome activation in vitro. We revealed that NLRP3 inflammasome-mediated inflammation and pyroptosis contributed to DK pathogenesis. Under physiological conditions, the NLRP3 inflammasome was required for corneal wound healing and nerve regeneration. However, under a diabetic scenario, sustained activation of the NLRP3 inflammasome resulted in postponed corneal wound healing and impaired nerve regeneration. Mechanistically, the accumulated AGEs promoted hyperactivation of the NLRP3 inflammasome through ROS production. Moreover, genetically and pharmacologically blocking the AGEs/ROS/NLRP3 inflammasome axis significantly expedited diabetic corneal epithelial wound closure and nerve regeneration. Our results revealed that AGEs-induced hyperactivation of the NLRP3 inflammasome resulted in delayed diabetic corneal wound healing and impaired nerve regeneration, which further highlighted the NLRP3 inflammasome as a promising target for DK treatment.

Hodgkin lymphoma (HL) is today one of the most curable pediatric cancers. Despite survival rates now exceeding 90%, survivors of pediatric HL are still at higher risk to develop late effects of cancer therapy. Premature aging has been proposed as a paradigm to explain the onset of long-term complications in these subjects. High levels of advanced glycation end products (AGEs), together with chronic inflammation and oxidative unbalance, have been shown to be among the main factors contributing to aging. The present study aims to evaluate glycoxydation, inflammatory status, and oxidative stress in plasma and peripheral blood mononuclear cells (PBMC) obtained from 20 adult survivors of pediatric HL and 40 age- and sex-matched healthy controls. After the isolation of PBMC and the collection of plasma, we performed the analyses of gene expression by qRT-PCR and measured inflammatory and oxidative-stress markers. AGEs plasma levels, expressed as Nϵ-carboxymethyl-lysine and methylglyoxal hydroimidazolone, were markedly higher in HL survivors than in healthy subjects. HL survivors also showed a condition of higher oxidative stress, as demonstrated by an increased expression of NADPH oxidase on PBMC. Antioxidant defenses, evaluated in terms of alpha-tocopherol, GSSG/GSH ratio and catalase plasma levels, were strongly impaired in survivors. This pro-oxidative condition led to the over-expression of both NLRP3 and NFkB genes in PBMC and, consequently, to increased plasma levels of interleukin(IL)-1β and IL-6. Finally, the expression of the receptors for AGEs in PBMC confirmed the dysregulated AGE pathways. Data show AGEs accumulation in survivors of pediatric HL. The consequent activation of the receptor for AGEs leads to the persistent activation of intracellular signaling toward inflammation. These results suggest that the co-existence of AGEs accumulation, unbalanced oxidative status, and inflammation could play a role in the onset of late complications in HL survivors.

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 +/- 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in> 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using theAGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle.Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (beta: 0.08; 95% CI: 0.02, 0.13) and SAF (beta: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (beta: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF.Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Diabetes mellitus (DM) and chronic kidney disease are the diseases that have exceeded epidemic thresholds in terms of prevalence all over the world. That made it possible to classify them as non-communicable epidemics of the XXI century. Diabetic nephropathy (DN) is implicated with high levels of disablement and mortality. Advanced glycation end products (AGE) play a key role in the progression of DN. Increased formation of AGE occurs due to hyperglycemia under the conditions of diabetes. Moreover, there are additional factors in DN that increase the elaboration of AGE, such as high levels of oxidative stress and decreased renal clearance which slows down the AGE excretion. Both immediate effects of AGE and interaction of AGE with its cell-bound receptor (RAGE) result in a сascade of events that lead to further progression of DN. Thus, the research of the new therapeutic approaches targeted on the AGE-RAGE system is of great interest to slow progression of DN and improve the prognosis.

A declined salivary gland function is commonly observed in elderly people. Advanced glycation end products (AGEs) are believed to contribute to the pathogenesis of aging. Although physical exercise is shown to increase various organ functions in human and experimental models, it is not known whether it has a similar effect in the salivary glands. In the present study, we evaluated the AGEs burden in the salivary gland in the aging process and the protective effect of physical exercise on age-related salivary hypofunction. To accelerate the aging process, rats were peritoneally injected with D-galactose for 6 weeks. Young control rats and d-galactose-induced aging rats in the old group were not exercised. The rats in the physical exercise group ran on a treadmill (12 m/min, 60 min/day, 3 days/week for 6 weeks). The results showed that the salivary flow rate and total protein levels in the saliva of the d-galactose-induced aging rats were reduced compared to those of the young control rats. Circulating AGEs in serum and secreted AGEs in saliva increased with d-galactose-induced aging. AGEs also accumulated in the salivary glands of these aging rats. The salivary gland of aging rats showed increased reactive oxygen species (ROS) generation, loss of acinar cells, and apoptosis compared to young control mice. However, physical exercise suppressed all of these age-related salivary changes. Overall, physical exercise could provide a beneficial option for age-related salivary hypofunction.

Advanced glycosylation end products (AGEs) are continuously produced and accumulated in the bodies of diabetic patients. To effectively predict disease trends in diabetic patients, a corneal fluorescence detection device was designed based on the autofluorescence properties of AGEs, and corneal fluorescence measurements were performed on 83 volunteers. Multiple linear regression (MLR), extreme gradient boosting (XGBoost), support vector regression (SVR), and back-propagation neural network (BPNN) were used to predict the human AGE content. Physiological parameters which may affect corneal AGE content were collected for a correlation analysis to select the features that had a strong correlation with the corneal concentration of AGEs to participate in modeling. By comparing the predictive effects of the four models in the two cases of a single-input feature and a multi-input feature, it was found that the model with the single-input feature had a better predictive effect. In this case, corneal AGE content was predicted by a single-input SVR model, with the average error rate (AER), mean square error (MSE), and determination coefficient R-squared (R2) of the SVR model calculated as 2.43%, 0.026, and 0.932, respectively. These results proved the potential of our method and device for noninvasive detection of the concentration of AGEs in the cornea.

IntroductionProgression to type 1 diabetes has emerged as a complex process with metabolic alterations proposed to be a significant driver of disease. Monitoring products of altered metabolism is a promising tool for determining the risk of type 1 diabetes progression and to supplement existing predictive biomarkers. Methylglyoxal (MG) is a reactive product produced from protein, lipid, and sugar metabolism, providing a more comprehensive measure of metabolic changes compared to hyperglycemia alone. MG forms covalent adducts on nucleic and amino acids, termed MG-advanced glycation end products (AGEs) that associate with type 1 diabetes.MethodsWe tested their ability to predict risk of disease and discriminate which individuals with autoimmunity will progress to type 1 diabetes. We measured serum MG-AGEs from 141 individuals without type 1 diabetes and 271 individuals with type 1 diabetes enrolled in the Fr1da cohort. Individuals with type 1 diabetes were at stages 1, 2, and 3.ResultsWe examined the association of MG-AGEs with type 1 diabetes. MG-AGEs did not correlate with HbA1c or differ between stages 1, 2, and 3 type 1 diabetes. Yet, RNA MG-AGEs were significantly associated with the rate of progression to stage 3 type 1 diabetes, with lower serum levels increasing risk of progression.DiscussionMG-AGEs were able to discriminate which individuals with autoantibodies would progress at a faster rate to stage 3 type 1 diabetes providing a potential new clinical biomarker for determining rate of disease progression and pointing to contributing metabolic pathways.

Background and Objectives: In the development of type 2 diabetes mellitus (T2DM) and its complications, genetic and environmental factors play important roles. Diabetic nephropathy (DN), one of the major microangiopathic chronic diabetic complications, is associated with an increased risk of major cardiovascular events and all-cause mortality. The present study was designed to investigate the possible modifying effect of glutathione transferase polymorphisms (GSTM1, GSTT1, GSTP1 rs1138272/rs1695, GSTO1 rs4925 and GSTO2 rs156697) in the susceptibility to T2DM and diabetic nephropathy. Materials and Methods: GSTM1 and GSTT1 deletion polymorphisms were determined by multiplex PCR, whereas GSTO1, GSTO2, and GSTP1 polymorphisms were determined by the real-time PCR in 160 T2DM patients and 248 age- and gender-matched controls. Advanced glycation end products (AGEs) were measured by ELISA. Results: Among six investigated GST polymorphisms, a significant association between the GST genotypes and susceptibility for development of diabetes mellitus was found for the GSTM1, GSTT1, GSTP1 (rs1138272) and GSTO1 polymorphisms. When the GST genotypes’ distribution in diabetes patients was assessed in the subgroups with and without diabetic nephropathy, a significant association was found only for the GSTO2 rs156697 polymorphism. Diabetic patients, carriers of the GSTM1 null, GSTT1 null and variant GSTO1*AA genotypes, had significantly increased levels of AGEs in comparison with carriers of the GSTM1 active, GSTT1 active and referent GSTO1*CC genotypes (p < 0.001, p < 0.001, p = 0.004, respectively). Conclusions: The present study supports the hypothesis that GST polymorphisms modulate the risk of diabetes and diabetic nephropathy and influence the AGEs concentration, suggesting the potential regulatory role of these enzymes in redox homeostasis disturbances.

Research background. The processing method generally affects the toxicity and biological activity of aged sorghum vinegar. This study investigates the changes in the intermediate Maillard reaction products of sorghum vinegar during ageing and the in vivo hepatoprotective effects of pure melanoidin obtained from it. Experimental approach. High-performance liquid chromatography (HPLC) and fluorescence spectrophotometry were utilized to quantify intermediate Maillard reaction products. The CCl4-induced liver damage in rats was used to evaluate the protective role of pure melanoidin in rat liver. Results and conclusions. Compared with the initial concentration, the 18-month ageing process caused a 1.2- to 3.3-fold increase in the concentrations of intermediate Maillard reaction products, i.e. 5-hydroxymethylfurfural (HMF), 5-methylfurfural (MF), methyglyoxal (MGO), glyoxal (GO) and advanced glycation end products (AGEs). The concentrations of HMF in the aged sorghum vinegar were 6.1-fold higher than the 450 μM limit standard for honey, implying the need for shortening the ageing of the vinegar in practice for safety concerns. Pure melanoidin (Mr>3.5 kDa) demonstrated significant protective effects against CCl4-induced rat liver damage, as evidenced by normalized serum biochemical parameters (transaminases and total bilirubin), suppressing hepatic lipid peroxidation and reactive oxygen species, as well as increasing glutathione amount and restoring antioxidant enzyme activities. Histopathological analysis revealed that melanoidin in vinegar reduced cell infiltration and vacuolar hepatocyte necrosis in rat liver. The findings demonstrated that a shortened ageing process should be considered in practice to ensure the safety of aged sorghum vinegar. Vinegar melanoidin is a potential alternative for the prevention of hepatic oxidative damage. Novelty and scientific contribution. This study demonstrates that the manufacturing process had a profound influence on the generation of vinegar intermediate Maillard reaction products. In particular, it revealed the in vivo hepatoprotective effect of pure melanoidin from aged sorghum vinegar, and provides insight into the in vivo biological activity of melanoidin., Pozadina istraživanja. Postupak pripreme često utječe na toksičnost i biološku aktivnost odležanog octa od sirka. U ovom su radu ispitane promjene u međuproduktima Maillardove reakcije u octu od sirka tijekom starenja, te in vivo hepatoprotektivni učinak čistog melanoidina izdvojenog iz dobivenog octa. Eksperimentalni pristup. Međuprodukti Maillardove reakcije određeni su visokodjelotvornom tekućinskom kromatografijom i fluorescencijskom spektrofotometrijom. Hepatoprotektivno djelovanje čistog melanoidina ispitano je na jetri šakora oštećenoj tetraklormetanom. Rezultati i zaključci. U usporedbi s početnom koncentracijom, koncentracija međuprodukata Maillardove reakcije u octu odležanom tijekom 18 mjeseci, i to 5-hidroksimetilfurfurala (HMF), 5-metilfurfurala (MF), metilglioksala (MGO), glioksala (GO) i konačnih produkata glikacije (engl. AGEs), porasla je za 1,2 do 3,3 puta. Koncentracija HMF-a u odležanom octu od sirka bila je 6,1 puta veća od dozvoljene granice od 450 μM u medu kao standardu, što znači da je u praksi potrebno skratiti vrijeme odležavanja octa radi postizanja sigurnosti njegove uporabe za potrošače. Čisti melanoidin (Mr>3,5 kDa) je učinkovito štitio jetru štakora od oštećenja izazvanih tetraklormetanom, što su potvrdili normalizirani biokemijski parametri seruma (aktivnost transaminaze i koncentracija ukupnih bilirubina), smanjena lipidna peroksidacija u jetri i manja količina reaktivnih spojeva kisika, te veća količina glutationa uz obnovljenu aktivnost enzima. Histopatološka analiza je pokazala da je melanoidin u octu smanjio staničnu infiltraciju i nekrozu hepatocita u jetri štakora. Rezultati pokazuju da bi u praksi trebalo razmotriti skraćeno vrijeme odležavanja octa od sirka, da bi on bio siguran za primjenu. Melanoidin iz octa može se koristiti umjesto lijekova za zaštitu jetre od oksidacijskog oštećenja. Novina i znanstveni doprinos. U radu je prikazano da postupak proizvodnje bitno utječe na stvaranje međuprodukata Maillardove reakcije u octu. Poglavito je prikazan in vivo hepatoprotektivni učinak čistog melanoidina iz odležanog octa od sirka, te je dan uvid u in vivo biološku aktivnost melanoidina.

In this study, sea cucumber (Holothuria scabra; Jaegar 1833) extracts and collagens were evaluated for inhibitory properties of protein-bound advanced glycation end products (AGEs). Processed dried sea cucumber with salt extract showed a significant lower IC₅₀ value for fluorescent AGEs (9.19 ± 7.68 μg mL-¹, P < 0.05) and fructosamine (503.47 ± 46.37 μg mL-¹, P < 0.05), respectively. Processed dried with and without salt extracts significantly reduced the Nε-epsilon-carboxymethyllysine (CML) and methylglyoxal-derived hydroimidazolone-1 (MG-H1) levels tested a 250 μg mL-¹. Smoked dried and fresh-dried extracts significantly reduced the Nɛ-epsilon-carboxyethyllysine (CEL) levels tested at 250 μg mL-¹. Pepsin-solubilised collagen and the crude collagen fibrils significantly reduced CML and MG-H1 levels whereas CEL levels were unchanged. Pearson's correlation analysis showed that protein-bound AGE and CML inhibition significantly correlated with the total phenolic and antioxidant activities, respectively. This study provides a strong rationale for further investigation aimed at identifying the active compounds responsible for the observed effects on biomarkers relevant to diabetes. Refereed/Peer-reviewed

Diabetes mellitus (DM) is a metabolic disease characterized by a high blood sugar level that can cause severe complications to the organism or even death when not treated. However, certain dietary habits and foods may have beneficial effects on this condition. A polyphenolic-rich extract (containing hyperoside, isoquercitrin, quercetin, ellagic acid, and vanillic acid) of Tageres erecta L. (T. erecta) was obtained from yellow and orange flowers using an ethanolic Soxhlet extraction. These extracts were screened for antidiabetic and anti-obesity properties using in vitro and in vivo procedures. The capacity to inhibit the enzymes lipase and α-glucosidase, as well as the inhibition of advance glycation end-products (AGEs) was tested in vitro. Caenorhabditis elegans (C. elegans) was used as an obesity in vivo model to assess extracts effects on fat accumulation using the wild-type strain N2 and a mutant with no N3 fatty acid desaturase activity BX24. Extracts from both cultivars (yellow and orange) T. erecta presented in vitro inhibitory activity against the enzymes lipase and α-glucosidase, showing lower IC50 values than acarbose (control). They also showed important activity in preventing AGEs formation. The polyphenol-rich matrices reduced the fat content of obese worms in the wild-type strain (N2) down to levels of untreated C. elegans, with no significant differences found between negative control (100% reduction) and both tested samples (p T. erecta flower effect. Our findings suggested that polyphenols from T. erecta can be considered candidate bioactive compounds in the prevention and improvement of metabolic chronic diseases such as obesity and diabetes.

Sporadic Alzheimer’s disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

In recent years, sodium butyrate has gained increased attention for its numerous beneficial properties. However, whether sodium butyrate could alleviate inflammatory damage by macrophage activation and its underlying mechanism remains unclear. The present study used an advanced glycosylation products- (AGEs-) induced inflammatory damage model to study whether sodium butyrate could alleviate oxidative stress, inflammation, and metabolic dysfunction of human monocyte-macrophage originated THP-1 cells in a PI3K-dependent autophagy pathway. The results indicated that sodium butyrate alleviated the AGEs-induced oxidative stress, decreased the level of reactive oxygen species (ROS), increased malondialdehyde (MDA) and mRNA expression of pro-inflammatory cytokines of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and increased the content of superoxide dismutase (SOD). Sodium butyrate reduced the protein expression of the NLR family, pyrin domain-containing protein 3 (NLRP3) and Caspase-1, and decreased the nucleus expression of nuclear factor-kappaB (NF-κB). Sodium butyrate decreased the expression of light-chain-associated protein B (LC3B) and Beclin-1, and inhibited autophagy. Moreover, sodium butyrate inhibited the activation of the PI3K/Akt pathway in AGEs-induced THP-1 cells. In addition, the metabolomics analysis showed that sodium butyrate could affect the production of phosphatidylcholine, L-glutamic acid, UDP-N-acetylmuraminate, biotinyl-5’-AMP, and other metabolites. In summary, these results revealed that sodium butyrate inhibited autophagy and NLRP3 inflammasome activation by blocking the PI3K/Akt/NF-κB pathway, thereby alleviating oxidative stress, inflammation, and metabolic disorder induced by AGEs.

Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent. We investigated the relationship between dietary intake of carboxymethyllysine (dCML) – an AGE prototype – and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study. Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia. 2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01–1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86–1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91–1.07)] or frailty [OR = 1.01 (0.83–1.22)] when non-frail subjects were used as reference. Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.

Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq Eugenia involucrata DC. is an underexplored native plant species, found in the Southern and Southeastern regions of Brazil. Recent studies report the presence of large amounts of phenolic compounds that potentially benefit human health in different parts (leaves, pulp, and seeds) of this species. Diabetes is characterized by hyperglycemia, which results in the glycation of proteins and excessive generation of reactive oxygen species (ROS) that lead to oxidative stress and the formation of advanced glycation end products (AGEs). Thus, one of the strategies for the treatment and/or protection of diabetes is to promote the reduction of blood glucose levels, through the inhibition of enzymes involved in carbohydrate digestion. So far, no study has been found in the literature on the effects of extracts from the pulp and seed E. involucrata towards enzymes involved in the digestion of carbohydrates and lipids. Therefore, the aim of this study was to investigate in vitro the anti-hyperglycemic and anti-obesogenic potential of phenolic compounds of ethanolic extracts from E. involucrata pulp and seed, through their ability to inhibit enzymes involved in the digestion of carbohydrates and lipids, and to evaluate the inhibition of AGEs formation, and the potential ability to neutralize reactive species of biological importance. The seed extract had higher content of total phenolic compounds (11,550.5 ± 633.0 µg. mL-1 ), being composed of phenolic acids and flavonoids, than the pulp extract (440.7 ± 28.1 µg. mL-1 ) that was composed of phenolic acids, flavonoids and anthocyanins. The IC50 values (µg of phenolic compounds. mL-1 ) revealed that the extracts had higher potency than acarbose towards the inhibition of α-amylase (0.2 ± 0.0 for pulp; 1.3 ± 0.2 for seed; 39.9 ± 3.9 for acarbose) and α-glucosidase (0.3 ± 0.0 for pulp; 1.5 ± 0.0 for seed; 2,019.0 ± 81.3 for acarbose), but lower potency than orlistat to inhibit pancreatic lipase (0.7 ± 0.0 for pulp; 0.6 ± 0.0 for seed; 0.1 ± 0.0 for orlistat). Extracts also inhibited (IC50 values as µg of phenolic compounds. mL-1 ) the formation of AGEs (6.8 ± 0.3 for pulp; 30.9 ± 1.7 for seed; 256.6 ± 13.7 for aminoguanidine) and were able to remove free radical species of biological relevance, namely peroxyl radical (0.02 ± 0.0 for pulp; 0.12 ± 0.0 for seed), hydroxyl radical (3.9 ± 0.0 for pulp; 4.5 ± 0.1 for seed). Despite the higher potency of phenolic compounds extracted from E. involucrata pulp towards all biological effects investigated when compared to the phenolics from seed extract, seed extraction has greater yield. Therefore, the concentration of phenolic compounds was 26 times higher in seed than pulp extract and seed extract had higher potency than pulp extract when taking into account the amount of pulp or seed that is necessary to obtain each extract. The results obtained in this study provide a basis for further studies in animal models and clinical studies for the development of new drugs or nutraceuticals, as well as food products with functional properties. A Eugenia involucrata DC. é uma espécie vegetal nativa subexplorada, presente nas regiões sul e sudeste do Brasil. Estudos recentes relatam a presença de grandes quantidades de compostos fenólicos potencialmente benéficos para a saúde humana em diferentes partes (folhas, polpa e sementes) desta espécie. O diabetes é uma doença caracterizada pela hiperglicemia, a qual resulta na glicação de proteínas e geração excessiva de espécies reativas de oxigênio (EROs) que leva ao estresse oxidativo e a formação de produtos finais de glicação avançada (AGEs), ambos envolvidos na patogênese da doença. Dessa forma, uma das estratégias de tratamento e/ou prevenção do diabetes é promover a redução dos níveis de glicose sanguínea, através da inibição de enzimas envolvidas no metabolismo de carboidratos e lipídeos. Até o presente momento não foi encontrado na literatura cientifica nenhum estudo realizado com extratos da polpa e semente de E. involucrata na inibição de enzimas envolvidas na digestão de carboidratos e lipídeos. Sendo assim, o objetivo deste estudo foi investigar in vitro o potencial anti-hiperglicêmico e anti-obesogênico de extratos etanólicos de polpa e semente de E. involucrata, por meio de sua capacidade de inibir enzimas envolvidas na digestão de carboidratos e lipídios, e avaliar a inibição da formação de AGEs, e a capacidade de neutralizar espécies reativas de importância biológica. O extrato de semente de E. involucrata apresentou maior teor compostos fenólicos totais (11.550,5 ± 633,0 µg. mL-1 ), compostos por ácidos fenólicos e flavonóides, que o extrato da polpa da fruta (440,7 ± 28,1 µg. mL-1 ), composto por ácidos fenólicos, flavonóides e antocianinas. Os valores de IC50 (expressos como µg de compostos fenólicos. mL-1 ) revelaram que os compostos fenólicos dos extratos de E. involucrata apresentaram potência superior a da acarbose para inibir as enzimas digestivas αamilase (IC50 polpa: 0,2 ± 0,0 µg. mL-1 ; IC50 semente: 1,3 ± 0,2 µg. mL-1 ; acarbose: 39,9 ± 3,9 µg. mL-1 ), α-glicosidase (IC50 polpa: 0,3± 0,0 µg. mL-1 ; IC50 semente: 1,5 ± 0,0 µg. mL-1 ; acarbose: 2.019,0 ± 81,3 µg. mL-1 ), mas inferior a do orlistat para inibir a lipase pancreática (IC50 polpa: 0,7 ± 0,0 µg. mL-1 ; IC50 semente: 0,6 ± 0,0 µg. mL-1 ; orlistat: 0,1 ± 0,0 µg. mL-1 ). Também inibiram a formação de AGEs (IC50 polpa: 6,8 ± 0,3 µg. mL-1 ; IC50 semente: 30,9 ± µg. mL-1 ), e foram capazes de remover espécies radicalares de importância biológica (radical peroxil: IC50 polpa: 0,02 ± 0,0 µg. mL-1 , IC50 semente: 0,12 ± 0,0 µg. mL-1 ; e radical hidroxil: IC50 polpa: 3,9 ± 0,0 µg. mL-1 , IC50 semente: 4,5 ± 0,1 µg. mL-1 ). Apesar dos compostos fenólicos extraídos da polpa da E. involucrata terem apresentado maior potência na inibição de enzimas digestivas e remoção de espécies reativas em comparação com fenólicos da semente da fruta, a extração da semente apresenta maior rendimento, resultando em concentração de fenólicos 26 vezes superior à do extrato da polpa, e maior potência do extrato de semente quando considerada a quantidade de polpa ou semente necessária para obtenção dos extratos. Os resultados obtidos neste estudo fornecem a base para estudos futuros em modelos in vivo e estudos clínicos visando a formulação de novos fármacos ou nutracêuticos, bem como de produtos alimentícios com propriedades funcionais.

α-Dicarbonyls and advanced glycation end products (AGEs) may contribute to the pathogenesis of insulin resistance by a variety of mechanisms. To investigate whether young insulin-resistant subjects present markers of increased dicarbonyl stress, we determined serum α-dicarbonyls-methylglyoxal, glyoxal, 3-deoxyglucosone; their derived free- and protein-bound, and urinary AGEs using the UPLC/MS-MS method; soluble receptors for AGEs (sRAGE), and cardiometabolic risk markers in 142 (49% females) insulin resistant (Quantitative Insulin Sensitivity Check Index (QUICKI) ≤ 0.319) and 167 (47% females) age-, and waist-to-height ratio-matched insulin-sensitive controls aged 16-to-22 years. The between-group comparison was performed using the two-factor (sex, presence/absence of insulin resistance) analysis of variance; multiple regression via the orthogonal projection to latent structures model. In comparison with their insulin-sensitive peers, young healthy insulin-resistant individuals without diabetes manifest alterations throughout the α-dicarbonyls-AGEs-sRAGE axis, dominated by higher 3-deoxyglucosone levels. Variables of α-dicarbonyls-AGEs-sRAGE axis were associated with insulin sensitivity independently from cardiometabolic risk markers, and sex-specifically. Cleaved RAGE associates with QUICKI only in males; while multiple α-dicarbonyls and AGEs independently associate with QUICKI particularly in females, who displayed a more advantageous cardiometabolic profile compared with males. Further studies are needed to elucidate whether interventions alleviating dicarbonyl stress ameliorate insulin resistance.

Chronic oxidative stress in long-distance runners adversely affects conditioning. It is important to objectively assess and monitor oxidative stress, but measuring oxidative stress can be invasive or require skill to measure. Therefore, this study aimed to verify whether skin autofluorescence (SAF), a non-invasive, rapid, and easily calculable metric for calculating advanced glycation end products (AGEs), is useful as an oxidative stress biomarker. The subjects were 50 young Japanese male long-distance runners (aged 20.2 ± 1.2 years); 35 average-sized male university students (aged 19.8 ± 1.1 years) served as controls. The interactions and relationships between SAF and plasma pentosidine and oxidative stress markers (reactive oxygen metabolite-derived compounds [d-ROMs], biological antioxidant potential [BAP], and the BAP/d-ROMs ratio) in runners were examined, and SAF in the runners and controls was compared. The results suggest that plasma pentosidine in runners is associated with oxidative stress markers and that it can assess oxidative stress. However, as SAF was not associated with oxidative stress markers, it was not validated as one. In future, clarifying the factors affecting SAF may also clarify the relationship between SAF, plasma pentosidine, and oxidative stress markers.

Este estudo teve como objetivo analisar o perfil dietético de pacientes com síndrome metabólica, sob a ótica dos produtos de glicação avançada, e correlacionar com os parâmetros do perfil lipídico. Metodologia: Estudo transversal, retrospectivo, realizado com dados de prontuários de pacientes com SM atendidos no Núcleo de Pesquisa e Extensão em Genômica Nutricional e Disfunções Metabólicas - GENUT da Universidade do Estado da Bahia – UNEB e por demanda espontânea. A quantidade de produtos de glicação avançada foi quantificada a partir do recordatório 24h. Os dados obtidos foram analisados pelo Software R 4.0.4. Resultados: Houve predominância do sexo feminino (84,1%) e renda familiar de até dois salários-mínimos (40,8%). O consumo médio de AGE na dieta dos participantes do estudo foi de 7767 KU, superior ao recomendado de 7500 KU. Na comparação entre os grupos de alto e baixo consumo, encontrou-se diferença estatisticamente significante (p

Heat-processed food, like bread, containing high amounts of advanced glycation end products (AGEs), is controversially discussed regarding the effects on health and disease. In in vitro and in vivo experiments, AGEs can induce proinflammatory NF-κB and/or the anti-inflammatory NRF2 pathways. The aim of this study was to investigate how gene expression is influenced in vivo upon short as well as long-term feeding of mice with control and bread crust-food (BC). For that, the liver, kidney and heart from two days- and eight days-fed mice were isolated and gene arrays were performed. Fewer genes were affected in terms of expression after two days of BC feeding than after eight days. We observed, especially in the heart and to lesser extent in the liver, an induction of antioxidant response by BC. Among the significantly up-regulated genes identified in the heart were transcripts encoding for cardioprotective and antioxidative proteins like metallothionein 2, uncoupling protein 3 and pyruvate dehydrogenase kinase 4. In contrast, in the liver, genes encoding for inflammatory drivers like thioredoxin-interacting protein, lncRNA Mtss1 and ubiquitin-specific protease 2 were down-modulated. However, an increased expression of immunoglobulins was observed in the kidney. Furthermore, in vivo imaging analyses with NF-κB-luciferase-reporter mice uncovered a rather anti-inflammatory response, especially after three and seven days of the feeding study. Our results suggest that bread crust exerts antioxidant and anti-inflammatory effects in the model organism mouse in an organ-specific manner.

The aim of this study was to conduct a bibliometric analysis of the scientific articles on advanced glycation end products (AGEs) and obesity. English-language journal articles about AGEs and obesity were retrieved from the Scopus database. The OpenRefine application was used for data cleaning, the VOSviewer software program for analysis of the trends of year of publication, country, institution, journal, authors, references, and keywords. Microsoft Excel and Tableau Public were applied for the visualizing of the publication trends. Data collection was performed on 3 February 2022, from a total of 1170 documents. The Mann–Whitney test and Spearman test with software SPSS ver.28.0.1.1. were used to assess the relation between open access journal statuses, years of publications, and CiteScore. The results of the study showed that there was an increase in studies on processed foods, including AGEs and obesity. The United States was the country with the largest contribution in this field, with the highest number of citations. The Nutrients journal published the largest number of articles on this topic, particularly in the last two years. The present focus of the studies is on ultra-processed foods. The open access journals have younger medians of the year of publication and higher medians for number of citations than do closed access journals (p < 0.001 and p < 0.05, respectively). A strong negative association was seen between CiteScore and the year of publication (r = −0.64 [95% CI: −0.67, −0.60]), p < 0.001. We present this bibliometric analysis to furnish the most recent data on the description, visualization, and analysis of AGEs and obesity.

To compare advanced glycation end-products (AGE, RAGE) and 3-nitrotyrosine (3-HT) in patients with DM 1 after successful simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). To assess relationship between levels of AGE, RAGE, 3-HT and renal transplant (RT) function, carbohydrate and mineral metabolism.The study included 58 patients who received kidney transplantation in end-stage renal disease (ESRD). 36 patients received SPK. There were performed routine laboratory, examination of AGE, RAGE, 3-NT, parathyroid hormone (PTH), 25(OH)vitamin D, calcium, phosphorus, FGF23, osteoprotegerin (OPG), and fetuin-A levels.All patients after SPK reached normoglycemia (HbA1c 5.7 [5.3; 6.1] %; C-peptide 3.24 [2.29; 4.40] ng/ml) with the achievement of significant difference vs patients after KTA. Arterial hypertension (AH) was more frequent in recipients of SPK before transplantation than after (p=0.008). AH also persisted in greater number of cases in patients after KTA than after SPK. Patients after SPK had higher AGE (р=0.0003) and lower RAGE (р=0.000003) levels. OPG in patients after SPK was significantly higher (р=0.04). The correlation analysis revealed significant positive correlation between 3-HT and OPG (p0.05; r=0.30), RAGE and eGFR (r=-0.52), HbA1c (r=0.48), duration of AH (r=0.34), AGE with HbA1c (r=0.51).The results of the "metabolic memory" markers analysis may indicate their contribution to the persistence of the metabolic consequences of CKD and DM 1 after achievement of normoglycemia and renal function restoration and their possible participation in development of recurrent nephropathy, vascular calcification, and bone disorders.Цель. Сравнить состояние конечных продуктов гликирования (AGE, RAGE) и 3-нитротирозина (3-НТ) у пациентов с сахарным диабетом 1-го типа после успешной сочетанной трансплантации почки и поджелудочной железы (СТПиПЖ), изолированной трансплантации почки (ИТП). Оценить взаимосвязь уровней AGE, RAGE, 3-НТ с функцией ренального трансплантата, состоянием углеводного и минерального обмена. Материалы и методы. В исследование включили 58 пациентов после трансплантации почки по поводу терминальной стадии хронической болезни почек (36 реципиентов после СТПиПЖ). Всем больным проводились клинико-лабораторное обследование, определение уровней AGE, RAGE, 3-НТ, паратгормона, 25(ОН)витамина D, FGF23, остеопротегерина (ОПГ) и фетуина А. Результаты. У пациентов после СТПиПЖ наблюдалась нормогликемия (гликированный гемоглобин HbA1c 5,7 [5,3; 6,1] %; С-пептид 3,24 [2,29; 4,40] нг/мл) с достижением значимой разницы при сравнении с больными после ИТП. Артериальная гипертензия (АГ) значимо чаще наблюдалась у реципиентов СТПиПЖ до трансплантации, чем после (р=0,008), у больных после ИТП АГ также сохранялась чаще, чем у пациентов после СТПиПЖ. Соответственно, больные после СТПиПЖ гораздо реже нуждались в антигипертензивной терапии (р=0,001). Уровень AGE был значимо выше (р=0,0003), RAGE значимо ниже (р=0,000003) у пациентов после СТПиПЖ, ОПГ значимо больше у реципиентов СТПиПЖ (р=0,04). Обнаружена положительная корреляция 3-НТ с ОПГ (p0,05; r=0,30), RAGE с расчетной скоростью клубочковой фильтрации (r=-0,52), HbA1c (r=0,48), длительностью АГ (r=0,34), AGE с HbA1c (r=0,51). Заключение. Результаты анализа маркеров метаболической памяти могут отражать их вклад в персистенцию метаболических последствий хронической болезни почек и сахарного диабета 1-го типа после достижения нормогликемии и восстановления почечной функции после СТПиПЖ, участие в развитии возвратной нефропатии, сосудистой кальцификации и костных нарушений.

Monu,1,2 Prachi Agnihotri,1 Mohd Saquib,1,2 Ashish Sarkar,1,2 Debolina Chakraborty,1,2 Uma Kumar,3 Sagarika Biswas1 1Council of Scientific and Industrial Research -Institute of Genomics & Integrative Biology (CSIR–IGIB), Delhi, 110007, India; 2Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; 3All India Institute of Medical Sciences, New Delhi, 110029, IndiaCorrespondence: Sagarika BiswasIntegrative and Functional Biology Department CSIR- Institute of Genomics & Integrative Biology, Mall Road, Delhi, 110 007, IndiaTel +91 11 27667602Fax +91-11-27667471; +9818004740Email sagarika.biswas@igib.res.inObjective: Rheumatoid arthritis (RA) is a chronic autoimmune, inflammatory joint disease. The identification of multifaceted etiological changes at the protein level in RA remains an important need. We aimed to identify differential proteins (DPs) and gene profiles to uncover inflammatory indicators and their association to RA pathogenesis.Methods: 2-DE and SWATH-MS were used to identify DPs in RA and healthy control plasma. Fluorescence phenylboronate gel electrophoresis (Flu-PAGE) with mass spectrometry was used for protein glycation in RA plasma. Disease specificity of identified DPs was confirmed by ELISA and Western blot analysis. The gene expressions of selected DPs were evaluated by qRT-PCR in PBMCs of RA, systemic lupus erythematosus (SLE), spondyloarthritis (SpA), and osteoarthritis (OA). The functional implication of glycated protein was determined by in- silico and validated by in vitro analysis in fibroblast-like synoviocytes.Results: A total of 150 DPs (127 increased and 23 decreased) were identified by 2-DE and SWATH-MS analysis in RA plasma compared to healthy control (HC). Nine proteins were identified as glycated by Flu-PAGE LC-MS/MS. Transthyretin (TTR), serotransferrin, and apolipoprotein-A1 (Apo-A1) were found to be differential and glycated. ELISA and Western blot results revealed the disease-specific increased expression of TTR and RAGE in RA. The qRT-PCR results signify the aberrant gene expression of TTR and RAGE, found to be associated with RA when compared with SLE, SpA, and OA PBMCs. TTR-RAGE interactions were predicted by in-silico and validated by in-vitro analysis using RA-FLS. The increased levels of pro-inflammatory cytokines IL-6, IL-1β, TNF-α, and differently expressed TTR and RAGE were confirmed in fibroblast-like synoviocytes under inflammatory conditions.Conclusion: Our findings showed that the level of TTR was increased in RA plasma, along with an altered glycation rate. TTR and RAGE aberrant gene expression in PBMCs are the key events associated with RA, and TNF-α activates the NF-KB pathways and promote TTR and RAGE differential expressions that may have pathogenic/inflammatory significance.Keywords: rheumatoid arthritis, differential proteins, post-translational modifications, transthyretin, advanced glycation end products, receptor for advanced glycation end products

Since lycopene has antioxidant activity, its combination with metformin may be useful to contrast diabetic complications related to oxidative stress. This study aimed to investigate the effects of metformin combined with lycopene on high-fat diet (HFD)-induced obese mice. Seventy-two C57BL-6J mice were divided into six groups: C (control diet-fed mice), H (HFD-fed mice for 17 weeks), H-V (HFD-fed mice treated with vehicle), H-M (HFD-fed mice treated with 50 mg/kg metformin), H-L (HFD-fed mice treated with 45 mg/kg lycopene), and H-ML (HFD-fed mice treated with 50 mg/kg metformin + 45 mg/kg lycopene). Treatments were administered for 8 weeks. Glucose tolerance, insulin sensitivity, fluorescent AGEs (advanced glycation end products), TBARS (thiobarbituric acid-reactive substances), and activities of antioxidant enzymes paraoxonase-1 (PON-1; plasma), superoxide dismutase, catalase and glutathione peroxidase (liver and kidneys) were determined. Metformin plus lycopene reduced body weight; improved insulin sensitivity and glucose tolerance; and decreased AGEs and TBARS in plasma, liver and kidneys. Combined therapy significantly increased the activities of antioxidant enzymes, mainly PON-1. Lycopene combined with metformin improved insulin resistance and glucose tolerance, and caused further increases in endogenous antioxidant defenses, arising as a promising therapeutic strategy for combating diabetic complications resulting from glycoxidative stress.

Advanced Glycation End Products (AGEs) have been positively correlated with inflammation in adults, while inconsistent evidence is available in children. We evaluated the association between urinary AGEs, measured by fluorescence spectroscopy, and biomarkers of subclinical inflammation in 676 healthy children/adolescents (age 11.8 ± 1.6 years, M ± SD) from the Italian cohort of the I.Family project. Urinary fluorescent AGEs were used as independent variable and high-sensitivity C-reactive protein (hs-CRP) was the primary outcome, while other biomarkers of inflammation were investigated as secondary outcomes. Participants with urinary AGEs above the median of the study population showed statistically significantly higher hs-CRP levels as compared to those below the median (hs-CRP 0.44 ± 1.1 vs. 0.24 ± 0.6 mg/dL, M ± SD p = 0.002). We found significant positive correlations between urinary AGEs and hs-CRP (p = 0.0001), IL-15 (p = 0.001), IP-10 (p = 0.006), and IL-1Ra (p = 0.001). At multiple regression analysis, urinary AGEs, age, and BMI Z-score were independent variables predicting hs-CRP levels. We demonstrated for the first time, in a large cohort of children and adolescents, that the measurement of fluorescent urinary AGEs may represent a simple, noninvasive, and rapid technique to evaluate the association between AGEs and biomarkers of inflammation. Our data support a role of AGEs as biomarkers of subclinical inflammation in otherwise healthy children and adolescents.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.

There is limited evidence on the associations between dietary patterns, body composition, and nonclassical predictors of worse outcomes such as advanced glycation end products (AGE) in kidney transplant recipients (KTRs). The aim of this cross-sectional study was to determine the level of AGE-determined cardiovascular (CV) risk in Dalmatian KTRs and possible associations between AGE, adherence to the Mediterranean diet (MeDi), and nutritional status. Eighty-five (85) KTRs were enrolled in this study. For each study participant, data were collected on the level of AGE, as measured by skin autofluorescence (SAF), Mediterranean Diet Serving Score (MDSS), body mass composition, anthropometric parameters, and clinical and laboratory parameters. Only 11.76% of the participants were adherent to the MeDi. Sixty-nine percent (69%) of KTRs had severe CV risk based on AGE, while 31% of KTRs had mild to moderate CV risk. The results of the LASSO regression analysis showed that age, dialysis type, dialysis vintage, presence of CV and chronic kidney disease, C- reactive protein level, urate level, percentage of muscle mass, and adherence to recommendations for nuts, meat, and sweets were identified as positive predictors of AGE. The negative predictors for AGE were calcium, phosphate, cereal adherence according to the MeDi, and trunk fat mass. These results demonstrate extremely low adherence to the MeDi and high AGE levels related CV risk in Dalmatian KTRs. Lifestyle interventions in terms of CV risk management and adherence to the MeDi of KTRs should be taken into consideration when taking care of this patient population.

Background: Diabetes is a serious health problem that results in high mortality rates worldwide. α-defensins are antimicrobial peptides of the innate immune system that contribute to inflammation. However, data on serum levels of α-defensin in patients suffering from type 2 diabetes are limited. Objectives: This study aimed to assess the possible changes in α-defensin serum levels in patients suffering from type 2 diabetes and to investigate its correlation with relevant biomarkers. Methodology: Analysis of serum α-defensin levels in 47 type 2 diabetics with diabetic neuropathy, 19 type 2 diabetics with no complications and 19 healthy control subjects by enzyme-linked immunosorbent assay was established. Furthermore, measurement of advanced glycation end products (AGEs) and fasting blood glucose (FBG) serum levels was performed, together with the lipid profile analysis. Results: The serum levels of α-defensin were higher in patients with and without diabetic neuropathy in comparison to control subjects. In addition, there was a significant correlation between α-defensin serum levels and AGEs and FBG serum levels as well as with the body mass index. Conclusions: α-defensins are significantly elevated in serum of type II diabetics, and correlate with AGEs serum levels indicating a crosstalk that may aggravate inflammation in type 2 diabetes. Keywords: Alpha defensing; Advanced glycation end products; Hyperglycemia; Inflammation; Innate immunity; Type 2 diabetes.

Sideritis sipylea Boiss. (Fam. Lamiaceae) is an endemic plant of the North Aegean Islands (Greece), commonly known as ironwort. Traditionally, its aerial parts have been used to relieve several ailments, especially gastrointestinal disorders, however, with scant knowledge about the pharmacological basis. In the present study, an endemic S. sipylea Greek species from Lesvos Island has been characterized for phytochemical composition and biological activities, in order to give a possible scientific basis to its traditional use and to highlight a further nutraceutical interest as a source of bioactive phytochemicals and extracts. Three different fractions obtained from a methanolic extract of S. sipylea aerial parts by using ethyl acetate with 10 (S10), 20 (S20), and 50% (S50) methanol as fractionation solvents were phytochemically characterized. Moreover, their antioxidant power and cytoprotective activity in different human cell lines were evaluated. The phytochemical analysis highlighted the presence of flavonoids, iridoids, and phenolic acids in all the tested samples. Particularly, the S10 fraction mainly contained iridoids, while S20 and S50 lavandulifolioside and chlorogenic acid, respectively. The fractions also showed antioxidant properties, S10 and S20 being the most potent. When assessed in human cholangiocytes, they counteracted the cytotoxicity of the tBOOH pro-oxidant agent, by reducing ROS levels and affecting GSH antioxidant system. The present findings highlight a possible interest in S10 and S20 fractions from S. sipylea as sources of bioactive molecules and stimulate further studies in order to characterize their possible application for nutraceutical and pharmaceutical purposes.

AIM: To study the effect of thioltransferase (TTase) on oxidative stress in human lens epithelial cells (HLECs) induced by high glucose and advanced glycation end products (AGEs). METHODS: HLECs were treated with 35.5 mmol/L glucose or 1.5 mg/mL AGEs modified bovine serum albumin (AGEs-BSA) as the experimental groups, respectively. Cells were collected at the time point of 1, 2, 3, and 4d. The TTase activity were measured accordingly. TTase mRNA levels were detected by quantitative reverse transcription polymerase chain response (qRT-RCR) and its protein level was detected by Western blot. The siRNA was used to knock down the expression of TTase. The activity of catalase (CAT) and superoxide dismutase (SOD), the content of reactive oxygen species (ROS) and the ratio of oxidized glutathione/total glutathione (GSSG/T-GSH) were assessed in different groups, respectively. RESULTS: The level of TTase mRNA gradually increased and reached the top at 2d, then it decreased to the normal level at 4d, and the TTase activity increased from 2 to 3d in both high glucose and AGEs-BSA groups. The TTase expression elevated from 2d in high glucose group, and it began to rise from 3d in AGEs-BSA group. The activity of CAT and SOD showed a decrease and the content of ROS and the ratio of GSSG/T-GSH showed an increase in high glucose and AGEs-BSA group. These biochemical alterations were more prominent in the groups with TTase siRNA. CONCLUSION: High glucose and AGEs can increase ROS content in HLECs; therefore, it induces oxidative stress. This may result in the decreased GSH and increased GSSG content, impaired activity of SOD and CAT. The up-regulated TTase likely provides oxidation damage repair induced by high glucose and AGEs in the early stage.

Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. β‐catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of β‐catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked. In mechanism, phosphorylation of Y654 was blocked by Src inactivation, whereas phosphorylation of Y142 was reduced by a focal adhesion kinase inhibitor. β‐catenin Y654 phosphorylation induced by AGEs facilitated the dissociation of vascular endothelial (VE)‐cadherin/β‐catenin and the impairment of adherens junctions (AJs), whereas β‐catenin Y142 phosphorylation favoured the dissociation of β‐catenin and α‐catenin. Further investigation revealed that β‐catenin Y142 phosphorylation was required for AGEs‐mediated β‐catenin nuclear translocation, and this nuclear‐located β‐catenin subsequently activated the TCF/LEF pathway. This pathway promotes the transcription of the Wnt target, ADAM10 (a disintegrin and metalloprotease 10), which mediates VE‐cadherin shedding and leads to further impairment of AJs. In summary, our study showed the role of β‐catenin Y654 and Y142 phosphorylation in AGEs‐mediated endothelial hyperpermeability through VE‐cadherin/β‐catenin/α‐catenin dissociation and up‐regulation of ADAM10, thereby advancing our understanding of the underlying mechanisms of AGEs‐induced microvascular hyperpermeability.

The presence of excess glucose in blood is regarded as a sweet hurt for patients with diabetes. Human serum albumin (HSA) is the most abundant protein in human plasma, which undergoes severe non-enzymatic glycation with glucose in patients with diabetes; this modifies the structure and function of HSA. Furthermore, the advanced glycation end products produced by glycated HSA can cause pathological damage to the human body through various signaling pathways, eventually leading to complications of diabetes. Many potential glycation sites on HSA have different degrees of sensitivity to glucose concentration. This review provides a comprehensive assessment of the in vivo glycation sites of HSA; it also discusses the effects of glycation on the structure and function of HSA. Moreover, it addresses the relationship between HSA glycation and diabetes complications. Finally, it focuses on the value of non-enzymatic glycation of HSA in diabetes-related clinical applications.

Context: Oxidative stress and formation of advanced glycation end products (AGEs), due to glycation of proteins, lipids and nucleic acids are characteristic in diabetic patients. Palmatine, a protoberberine alkaloid bioactive isolated from Coscinium fenestratum (CF) stem extract, which previously has shown to possess antidiabetic and antioxidant properties and to be able to protect the kidney and liver in a STZ-diabetic induced rat model. Aims: To evaluate the in vitro and in vivo antioxidant and anti-AGE activity of palmatine. Methods: In vitro and in vivo studies were conducted to measure radical scavenging, reducing power, inhibition of lipid peroxidation, carbonyl trapping and metal ion chelation. In vitro antiglycation activity was done using bovine serum albumin-methylglyoxal (BSA-MGO), bovine serum albumin – glucose (BSA-GLU) and glycated hemoglobin. In vivo antioxidant and antiglycation activity were used to evaluate liver and kidney extracted from STZ-induced diabetic rat after treatment with palmatine. Results: The results showed palmatine blocked the formation of AGE as shown by the results of BSA-GLU, BSA-MGO, glycated hemoglobin and inhibited the free radicals generated by DPPH, nitric oxide, hydrogen peroxide, lipid peroxidation, FRAP and metal ion chelating. It was able to stimulate in vivo the activity of catalase, super oxide dismutase and glutathione peroxidase. Conclusions: Palmatine possess antioxidant and antiglycation properties, the mechanism of action seems to be via the blockage of free radical formation, decreasing of reactive carbonyl. Further research is ongoing to determine the effect of palmatine on glyoxalase 1 and aldose reductase pathway and interaction with receptor for AGE.

Background: Advanced glycation end products (AGEs) are involved in age-related diseases, but the interaction of gut microbiota with dietary AGEs (dAGEs) and tissue AGEs in the population is unknown. Objective: Our objective was to investigate the association of dietary and tissue AGEs with gut microbiota in the population-based Rotterdam Study, using skin AGEs as a marker for tissue accumulation and stool microbiota as a surrogate for gut microbiota. Design: Dietary intake of three AGEs (dAGEs), namely carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL), was quantified at baseline from food frequency questionnaires. Following up after a median of 5.7 years, skin AGEs were measured using skin autofluorescence (SAF), and stool microbiota samples were sequenced (16S rRNA) to measure microbial composition (including alpha-diversity, beta-dissimilarity, and taxonomic abundances) as well as predict microbial metabolic pathways. Associations of both dAGEs and SAF with microbial measures were investigated using multiple linear regression models in 1052 and 718 participants, respectively. Results: dAGEs and SAF were not associated with either the alpha-diversity or beta-dissimilarity of the stool microbiota. After multiple-testing correction, dAGEs were not associated with any of the 188 genera tested, but were nominally inversely associated with the abundance of Barnesiella, Colidextribacter, Oscillospiraceae UCG-005, and Terrisporobacter, in addition to being positively associated with Coprococcus, Dorea, and Blautia. A higher abundance of Lactobacillus was associated with a higher SAF, along with several nominally significantly associated genera. dAGEs and SAF were nominally associated with several microbial pathways, but none were statistically significant after multiple-testing correction. Conclusions: Our findings did not solidify a link between habitual dAGEs, skin AGEs, and overall stool microbiota composition. Nominally significant associations with several genera and functional pathways suggested a potential interaction between gut microbiota and AGE metabolism, but validation is required. Future studies are warranted, to investigate whether gut microbiota modifies the potential impact of dAGEs on health.

Background The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured as skin autofluorescence (SAF). Here, we assessed the correlation between SAF values and the complexity and severity of type 2 diabetes mellitus (T2DM) complications. Methods The basic clinical information of 825 patients with T2DM was collected through an electronic system, and SAF was measured by adapting a DM-Scan, a non-invasive optical signal detector. Diabetic complications were diagnosed based on clinical criteria by experienced doctors. Linear regression analysis was used to evaluate the independent determinants of SAF, and multiple logistic regression analysis was performed to assess independent determinants that influence the severity of the complications. Results SAF was significantly associated with the complexity of T2DM complications. Similarly, independent relationships between SAF and age (β = 0.389, P β = − 2.221, P = 0.004), 2-h C-peptide (β = − 0.182, P = 0.017), aminotransferase (ALT, β = − 0.158, P = 0.041), blood creatinine (BCr, β = 0.206, P = 0.009), and fatty liver (β = 0.161, P = 0.026) were observed. With the increasing number of complications, the SAF values increased significantly after adjusting for related risk factors. The SAF values correlated with diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy when compared with patients without any T2DM-associated complications. Moreover, the AGE-based diabetic complication risk score for each complication demonstrated a relationship with the presence or absence of certain complications. Conclusion SAF is an independent marker for diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy, and it is also a predictor of the complexity of T2DM complications. Moreover, the diabetic complication risk score is capable of predicting the risk of diabetic complications in patients with T2DM.

Objective: Life expectancy in patients suffering from affective disorders is considerably diminished. We investigated whether skin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, mediates the association between affective disorders and excess mortality. Methods: Included were 81,041 participants of the Lifelines cohort study. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed with the Mini-International Neuropsychiatric Interview. SAF was assessed as mediator in Cox proportional hazards models for all-cause or natural-cause mortality. Results: Mortality was increased in cases with major depression compared to controls (36.4 vs. 22.5 per 100,000 person years). Partial mediation by SAF of the association between affective disorders and mortality was shown (9.0-10.5%, P