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Key points Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO‐detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment. Diabetes was induced with streptozotocin. Fasting blood glucose, cognitive function, cerebral blood flow, neurovascular coupling (NVC), Glo1 activity, MGO and AGEs were assessed. In diabetes, MGO‐derived hydroimidazolone‐1 increased in the cortex, and was decreased in Glo1‐overexpressing mice compared to controls. Visuospatial memory was decreased in diabetes, but not in Glo1/diabetes. NVC response time was slightly increased in diabetes, and normalised in the Glo1‐overexpressing group. No impact of diabetes or Glo1 overexpression on blood–brain barrier integrity or vascular density was observed. Diabetes induced a mild visuospatial memory impairment and slightly reduced NVC response speed and these effects were mitigated by Glo1. This study shows a link between MGO‐related AGE accumulation and cerebrovascular/cognitive functions in diabetes. Modulation of the MGO–Glo1 pathway may be a novel intervention strategy in patients with diabetes who have cerebrovascular complications. Diabetes is associated with an increased risk of stroke, cognitive decline, depression and Alzheimer's disease, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a highly reactive by‐product of glycolysis, plays an important role in the development of diabetes‐associated microvascular dysfunction in the periphery and is detoxified by the enzyme glyoxalase 1. Diabetes reduced visuospatial memory in mice and slowed the neurovascular coupling response speed, which was improved by overexpression of glyoxalase 1. MGO formation and MGO‐derived advanced glycation endproduct (AGE) accumulation in the brain of diabetic mice are associated with a slight reduction in neurovascular coupling and mild cognitive impairment. The endogenous formation of MGO, and the accumulation of MGO‐derived AGEs, might be a potential target in reducing the risk of vascular cognitive impairment in people with diabetes. [ABSTRACT FROM AUTHOR]

Objective To investigate the mechanism by which methyltransferase-like 3 (METTL3) is involved in diabetes-induced endothelial cell apoptosis by promoting the N6-methyladenine (m6A) modification of forkhead box O (FOXO) 3 and its expression. Methods A model of advanced glycosylation end products (AGE)-induced damage in human aortic endothelial cells (HAEC) was constructed. HAEC were divided into 6 groups: cell control group, cell AGE group, cell control+negative control small interfering RNA (siRNA) group, cell AGE+negative control siRNA group, cell AGE+FOXO3 siRNA group, and cell AGE+METTL3 siRNA group, and 3 parallel groups were set in each group. The m6A modification profiles were detected and analyzed by methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and bioinformatics techniques. The m6A modification level of FOXO3 mRNA was detected by RNA-binding protein immunoprecipitation (RIP). Apoptosis was detected by flow cytometry. Real-time quantitative polymerase chain reaction (RT-PCR) was used to detect the expression level of FOXO3 mRNA, and Western blotting was used to detect the expression level of FOXO3, METTL3. Six 6-week-old ApoE knockout male mice were divided into simple atherosclerosis group and diabetic atherosclerosis group by randomized numerical table method. The protein expression of mouse FOXO3, METTL3 was detected by Western blotting, and the expression of mouse FOXO3 and METTL3 in endothelial cells was detected by immunofluorescence co-localization. Two independent samples t-test was used for intergroup comparison. Results Total m6A modification and m6A modification of FOXO3 were significantly higher in the cellular AGE group compared with the cellular control group (P<0.001), and the protein expression of FOXO3 and METTL3 was significantly higher (P<0.05). Protein expression of FOXO3 and METTL3 was significantly elevated in endothelial cells in the aortic plaque region of diabetic atherosclerotic mice compared with that of mice with simple atherosclerosis (P<0.05). Apoptosis was significantly reduced in the cell AGE+FOXO3 siRNA group compared to the cell AGE+negative control siRNA group (P<0.01). The m6A modification of FOXO3 (P<0.001) and FOXO3 protein expression were significantly decreased (P<0.05) and apoptosis was significantly reduced (P<0.001) in the cellular AGE+METTL3 siRNA group compared with the cellular AGE+negative control siRNA group. Conclusion AGE induces significant changes in m6A modification in HAEC, METTL3 is involved in diabetes-induced apoptosis in vascular endothelial cells by promoting m6A modification of FOXO3 mRNA and regulating its expression. [ABSTRACT FROM AUTHOR]

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity. [ABSTRACT FROM AUTHOR]

Objectives: Intrapulpal calcifications can occur in the dental pulp of patients with diabetes. We focused on the association between ectopic calcifications in the dental pulp and advanced glycation end products (AGEs) in Spontaneously Diabetic Torii (SDT)‐fatty rats, an obese type 2 diabetic rat model, to determine the mechanism of calcification with pulp stone in the dental pulp. Materials and Methods: Pathologic calcification in the dental pulp of SDT‐fatty rats was observed using electron microscopy and immunohistochemical analysis. Moreover, mechanical analysis of periapical region of molar tooth against occlusal force was performed. Results: In SDT‐fatty rats, pathogenic pulpal calcifications occurred during blood glucose elevation after 6 weeks, and granular calcification was observed in the dental pulp after 11 weeks. Pentosidine, a major AGE, and the receptor for AGEs were strongly expressed in the dental pulp of SDT‐fatty rats. S100A8, TNF‐α, and IL‐6 also showed positive response in the dental pulp of the SDT‐fatty rat, which indicated pulpal inflammation. Blood flow disorder and hypoxic dental pulp cells were also observed. In silico simulation, strain from occlusal force concentrates on the root apex. Conclusions: Glycation makes blood vessels fragile, and occlusal forces damage the vessels mechanically. These are factors for intrapulpal calcification of diabetes. [ABSTRACT FROM AUTHOR]

Introductions: Cystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Onset is often insidious, so screening for early detection of glycemic abnormalities is important. Continuous glucose monitoring (CGM) has been validated in people with CF and has been shown to detect early glycemic variability otherwise missed on 2-hour oral glucose tolerance testing (OGTT). We previously reported that CGM measures of hyperglycemia and glycemic variability are superior to hemoglobin A1c (HbA1c) in distinguishing those with and without CFRD. However, little is known about the long-term predictive value of CGM measures of glycemia for both the development of CFRD and their effect on key clinical outcomes such as weight maintenance and pulmonary function. In addition, there have been no studies investigating advanced glycation endproducts (AGE) assessed by skin autofluorescence in people with CF. Methods: In this prospective observational study, CGM and HbA1c were measured at 2 to 3 time points 3 months apart in 77 adults with CF. Participants who did not have CFRD at the time of enrollment underwent OGTT at the baseline visit, and all participants had AGE readings at baseline. Follow up data including anthropometric measures, pulmonary function and CFRD status were collected by review of medical records 1- and 2-years after the baseline visits. We applied multivariable linear regression models correlating glycemic measures to change in key clinical outcomes (weight, BMI, FEV1) accounting for age, gender and elexacaftor/tezacaftor/ivacaftor (ETI) use. We also conducted logistic regression analyses comparing baseline glycemic data to development of CFRD during the 2-year follow up period. Results: Of the 77 participants, 25 had pre-existing CFRD at the time of enrollment, and six participants were diagnosed with CFRD by the OGTT performed at the baseline visit. When adjusting for age, gender, and ETI use, multiple CGM measures correlated with weight and BMI decline after one year but not after two years. CGM and HbA1c at baseline did not predict decline in FEV1 (p>0.05 for all). In the 46 participants without a diagnosis of CFRD at baseline, two participants were diagnosed with CFRD over the following two years, but CGM measures at baseline did not predict progression to CFRD. Baseline AGE values were higher in individuals with CFRD and correlated with multiple measures of dysglycemia (HbA1c, AG, SD, CV, TIR, % time >140, >180, >250) as well as weight. AGE values also correlated with FEV1 decline at year 1 and weight decline at year 1 and year 2. Conclusions: Several key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD (n=2) during the follow up period and the initiation of ETI by many participants, affecting their trajectory in weight and pulmonary function. These results provide additional data supporting the potential role for CGM in identifying clinically significant dysglycemia in CF. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD and to understand the implications of AGE measures in this patient population. [ABSTRACT FROM AUTHOR]

IntroductionsCystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Onset is often insidious, so screening for early detection of glycemic abnormalities is important. Continuous glucose monitoring (CGM) has been validated in people with CF and has been shown to detect early glycemic variability otherwise missed on 2-hour oral glucose tolerance testing (OGTT). We previously reported that CGM measures of hyperglycemia and glycemic variability are superior to hemoglobin A1c (HbA1c) in distinguishing those with and without CFRD. However, little is known about the long-term predictive value of CGM measures of glycemia for both the development of CFRD and their effect on key clinical outcomes such as weight maintenance and pulmonary function. In addition, there have been no studies investigating advanced glycation endproducts (AGE) assessed by skin autofluorescence in people with CF.MethodsIn this prospective observational study, CGM and HbA1c were measured at 2 to 3 time points 3 months apart in 77 adults with CF. Participants who did not have CFRD at the time of enrollment underwent OGTT at the baseline visit, and all participants had AGE readings at baseline. Follow up data including anthropometric measures, pulmonary function and CFRD status were collected by review of medical records 1- and 2-years after the baseline visits. We applied multivariable linear regression models correlating glycemic measures to change in key clinical outcomes (weight, BMI, FEV1) accounting for age, gender and elexacaftor/tezacaftor/ivacaftor (ETI) use. We also conducted logistic regression analyses comparing baseline glycemic data to development of CFRD during the 2-year follow up period.ResultsOf the 77 participants, 25 had pre-existing CFRD at the time of enrollment, and six participants were diagnosed with CFRD by the OGTT performed at the baseline visit. When adjusting for age, gender, and ETI use, multiple CGM measures correlated with weight and BMI decline after one year but not after two years. CGM and HbA1c at baseline did not predict decline in FEV1 (p>0.05 for all). In the 46 participants without a diagnosis of CFRD at baseline, two participants were diagnosed with CFRD over the following two years, but CGM measures at baseline did not predict progression to CFRD. Baseline AGE values were higher in individuals with CFRD and correlated with multiple measures of dysglycemia (HbA1c, AG, SD, CV, TIR, % time >140, >180, >250) as well as weight. AGE values also correlated with FEV1 decline at year 1 and weight decline at year 1 and year 2ConclusionsSeveral key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD (n=2) during the follow up period and the initiation of ETI by many participants, affecting their trajectory in weight and pulmonary function. These results provide additional data supporting the potential role for CGM in identifying clinically significant dysglycemia in CF. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD and to understand the implications of AGE measures in this patient population.

ABSTRACT: Objective: The aim of this study was to compare peri-implant clinical and radiographic status and levels of advanced glycation endproducts (AGEs) in peri-implant sulcular fluid (PISF) in waterpipe users and cigarette smokers. Methods: Waterpipe users, cigarette smokers, and never smokers were included. Demographic details were collected using a questionnaire. Characteristics of implants (dimensions, jaw location, depth of placement, insertion torque, and duration in function) were recorded. Peri-implant modified plaque and gingival indices (mPI and mGI), probing depth (PD), and crestal bone loss (CBL) were recorded in all groups. Volume of PISF and levels of AGEs were determined using standard techniques. Sample-size estimation was done on data from a pilot investigation, and correlation between clinicoradiographic and immunoinflammatory parameters was assessed using logistic regression models. Probability values

of the study.

Background: Dark circles affect subjects of all ages and in all skin types. They can be treated by various methods, particular by topical solutions. This investigation was directed towards exploring the effect of gentiopicroside (GP) on the skin around the eyes. For this, an extract of Gentiana lutea (GIE) containing GP (65% by dry matter) was evaluated on oxidant and angiogenesis parameters using in vitro and ex‐vivo studies. A clinical experimentation was also realized. Methods: The effect of GIE at different concentrations on antioxidant gene was evaluated in vitro by RT‐qPCR after treatment of NHDF. The effect of 2.93 μg mL−1 GIE on the release of VEGF‐A and VEGF‐C by NHDF was also studied. The effect of 87.9 μg mL−1 GIE was also evaluated on pseudotube formation in a coculture system of normal dermal microvascular endothelial cells (HMVEC‐d)‐NHDF stimulated or not with VEGF as pro‐angiogenic factor. Prior to these assays, preliminary cytotoxicity assays were performed using a standard WST‐8 reduction assay. The expressions of carboxymethyl‐lysine and glyoxalase‐1 were quantified on skin explants topically treated with 147 μg mL−1 GIE in basal and UVA‐irradiated conditions. A clinical study was conducted in 22 subjects using topical twice daily for 14 days on eye area (split‐face application: cream containing 147 μg mL−1 GIE versus placebo). 3D image acquisition and skin colour measurement were performed at D0 and D14. Results: Treatment of GIE upregulated the gene expression of NFE2L2 and downregulated the expression of CXCL8. GIE targeted AGEs pathways and reduced the formation of pseudotubes. A total of 147 μg mL−1 GIE gel cream significantly reduced significantly the average roughness and relief of the upper eyelid skin as well as the redness of dark circles after 14 days of application. Conclusion: By acting on the pathway of AGEs, VEGF‐A and VEFG‐C, GIE seems to allow a rejuvenation of the skin resulting, among others, in a decrease in redness. It now would be interesting to evaluate the efficacy of GIE on skin around eyes microbiota, antibacterial gentiopicroside property being well‐established. By acting on the pathway of AGEs, VEGF‐A and VEFG‐C, extract of Gentiana lutea seems to allow a rejuvenation of the skin resulting, among other things, in a decrease in redness. [ABSTRACT FROM AUTHOR]

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.

Background: Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. Methods: This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Results: Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE‐induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. Discussion: These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE‐induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double‐blind placebo‐controlled trial in abdominally obese individuals. Materials and methods: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m2) were randomized to an 8‐week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β‐cell function, insulin‐mediated microvascular recruitment, skin microvascular function, flow‐mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra‐performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one‐way ANCOVA. Results: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein‐bound Nδ‐(5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl)‐ornithine (MG‐H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule‐1 (sVCAM‐1) in the low and high PM dose group and of soluble intercellular adhesion molecule‐1 (sICAM‐1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. Conclusions: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM‐1 and sICAM‐1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract Background There are no studies that have assessed advanced glycation end products (AGEs) and interleukin 17A (IL-17A) levels in whole saliva (WS) of patients with dental implants. The aim was to compare levels of AGEs and IL-17A in WS and peri-implant clinical and radiographic status of patients with and without osteoporosis at 6-years’ follow-up. Methods Osteoporotic (Group-1) and systemically healthy controls (Group-2) having undergone dental implant therapy at least 5 years ago were included. A questionnaire was used to collect information about age, gender, duration and treatment of osteoporosis, number and duration of implants in function, and frequencies of toothbrushing, flossing and hygiene visits. Modified bleeding and plaque indies (mBI and mPI), peri-implant probing depth (PD) and crestal bone loss (CBL) were recorded. WS was collected and levels of AGEs and IL-17A were determined using enzyme linked immunosorbent assay. Sample-size estimation was done and statistical analyses were doing using the independent t- and Wilcoxon rank-sum tests. Statistical significance was marked for P-values that were below 0.01. Results In patients with (n = 24) and without (n = 27) osteoporosis, implants were in function for 6.3 ± 0.27 and 6.6 ± 0.5 years, respectively. There was no significant difference in peri-implant mBI, PD, mPI and CBL in both groups. Levels of AGE in patients with (119.6 ± 26.5 μg/ml) and without (91.5 ± 14.6 μg/ml) osteoporosis were comparable. Levels of whole salivary IL-17A in patients without and with osteoporosis were 4.6 ± 0.3 and 5.1 ± 0.8 pg/ml, respectively. Flossing of full mouth interproximal spaces once and twice daily toothbrushing daily was reported by 100% patients with osteoporosis. Among patients with osteoporosis 75% and 25% individuals were receiving professional dental prophylaxis every 4 and 6 months, respectively. Conclusion Within the limitations of the present study osteoporotic patients are not at an increased risk of peri-implant diseases and can demonstrate salivary AGE and IL-17A levels comparable to non-osteoporotic individuals as long as oral hygiene is stringently maintained.

Abstract Background Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. Methods This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Results Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE‐induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. Discussion These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE‐induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration.

Abstract Background The aim was to assess the association between levels of advanced glycation endproducts (AGEs) in the gingival crevicular fluid (GCF) and periodontal parameters among cigarette-smokers and waterpipe-users. Methods Self-reported cigarette-smokers; waterpipe-users and never-smokers were included. Demographic data was recorded using a questionnaire. Periodontal parameters (plaque index [PI], gingival index [GI], clinical attachment loss [AL], probing depth [PD], and marginal bone loss [MBL]) were assessed in all groups. The GCF samples were collected using standard techniques and assessed for AGEs levels using enzyme-linked immunosorbent assay. Sample-size estimation was done and group-comparisons were done. Correlation between levels of GCF AGEs levels and periodontal parameters was assessed using a logistic regression model. Level of significance was set at P

Abstract Background Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs. Methods In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway. Results Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage . Conclusions Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor.

Diabetes is associated with vascular injury and the onset of macrovascular complications. Advanced glycation endproducts (AGEs) and the AGE precursor methylglyoxal (MGO) have been identified as key players in establishing the relationship between diabetes and vascular injury. While most research has focused on the link between AGEs and vascular injury, less is known about the effects of MGO on vasculature. In this review, we focus on the mechanisms linking AGEs and MGO to the development of atherosclerosis. AGEs and MGO are involved in many stages of atherosclerosis progression. However, more research is needed to determine the exact mechanisms underlying these effects. Nevertheless, AGEs and MGO could represent valid therapeutic targets for the macrovascular complications of diabetes. The reactive dicarbonyl methylglyoxal (MGO) is the major precursor of endogenously formed advanced glycation endproducts (AGEs). MGO is an important factor contributing to endothelial dysfunction by inducing oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress. AGEs stimulate cholesterol accumulation in macrophages and phenotype switching of vascular smooth muscle cells (VSMCs) into macrophage-like cells, while the impact of MGO is less understood. AGEs and MGO can inhibit angiogenesis, but promote atherosclerosis-linked inflammation by inducing inflammatory polarization of macrophages and the induction of inflammatory pathways. AGEs promote calcification of VSMCs by increasing the expression of osteogenic proteins and transcription factors. The impact of MGO on calcification remains to be elucidated. [ABSTRACT FROM AUTHOR]

Background Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously and also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown. Objectives We sought to examine the associations of dietary dicarbonyl intake with low-grade inflammation and microvascular function. Methods In 2792 participants (mean ± SD age: 60 ± 8 y; 50% men; 26% type 2 diabetes) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking FFQ outcome data to our food composition database of the MGO, GO, and 3-DG content of >200 foods. Low-grade inflammation was assessed as six plasma biomarkers, which were compiled in a z score. Microvascular function was assessed as four plasma biomarkers, compiled in a z score; as diameters and flicker light–induced dilation in retinal microvessels; as heat-induced skin hyperemic response; and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and microvascular function were investigated using linear regression with adjustments for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle and dietary factors. Results Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z score for inflammation [standardized β coefficient (STD β): −0.05; 95% CI: −0.09 to −0.01, with strongest inverse associations for hsCRP and TNF-α: both −0.05; −0.10 to −0.01]. In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (STD β: −0.07; 95% CI: −0.12 to −0.01), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes. Conclusion Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation of an association between MGO intake and health outcomes in humans and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: There are no studies that have assessed advanced glycation end products (AGEs) and interleukin 17A (IL-17A) levels in whole saliva (WS) of patients with dental implants. The aim was to compare levels of AGEs and IL-17A in WS and peri-implant clinical and radiographic status of patients with and without osteoporosis at 6-years' follow-up. Methods: Osteoporotic (Group-1) and systemically healthy controls (Group-2) having undergone dental implant therapy at least 5 years ago were included. A questionnaire was used to collect information about age, gender, duration and treatment of osteoporosis, number and duration of implants in function, and frequencies of toothbrushing, flossing and hygiene visits. Modified bleeding and plaque indies (mBI and mPI), peri-implant probing depth (PD) and crestal bone loss (CBL) were recorded. WS was collected and levels of AGEs and IL-17A were determined using enzyme linked immunosorbent assay. Sample-size estimation was done and statistical analyses were doing using the independent t- and Wilcoxon rank-sum tests. Statistical significance was marked for P-values that were below 0.01. Results: In patients with (n = 24) and without (n = 27) osteoporosis, implants were in function for 6.3 ± 0.27 and 6.6 ± 0.5 years, respectively. There was no significant difference in peri-implant mBI, PD, mPI and CBL in both groups. Levels of AGE in patients with (119.6 ± 26.5 μg/ml) and without (91.5 ± 14.6 μg/ml) osteoporosis were comparable. Levels of whole salivary IL-17A in patients without and with osteoporosis were 4.6 ± 0.3 and 5.1 ± 0.8 pg/ml, respectively. Flossing of full mouth interproximal spaces once and twice daily toothbrushing daily was reported by 100% patients with osteoporosis. Among patients with osteoporosis 75% and 25% individuals were receiving professional dental prophylaxis every 4 and 6 months, respectively. Conclusion: Within the limitations of the present study osteoporotic patients are not at an increased risk of peri-implant diseases and can demonstrate salivary AGE and IL-17A levels comparable to non-osteoporotic individuals as long as oral hygiene is stringently maintained. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases. Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status. Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 ± 11.77 years, mean ± SD) and had significantly lower SAF (1.90 ± 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 ± 12.07 years; SAF: 2.27 ± 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (β = –0.002, 95% confidence interval (95%CI): –0.002 to –0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (β = 3.2 × 10–5, 95%CI: 0.000–0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (β = 4.2 × 10–4, 95%CI: 0.000–0.001, p < 0.001), but this association was not found in the chronic disease population (β = –3.2 × 10–4, 95%CI: –0.001 to 0.000, p = 0.347). Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

A reducing sugar reacts with the protein, resulting in advanced glycation end-products (AGEs), which have been implicated in diabetes-related complications. Recently, it has been found that both type 1 and type 2 diabetic patients suffer from not only glucose but also ribose dysmetabolism. Here, we compared the effects of ribose and glucose glycation on epigenetics, such as histone methylation and demethylation. To prepare ribose-glycated (riboglycated) proteins, we incubated 150 μM bovine serum albumin (BSA) with 1 M ribose at different time periods, and we evaluated the samples by ELISAs, Western blot analysis, and cellular experiments. Riboglycated BSA, which was incubated with ribose for approximately 7 days, showed the strongest cytotoxicity, leading to a significant decrease in the viability of SH-SY5Y cells cultured for 24 h (IC50 = 1.5 μM). A global demethylation of histone 3 (H3K4) was observed in SH-SY5Y cells accompanied with significant increases in lysine-specific demethylase-1 (LSD1) and plant homeodomain finger protein 8 (PHF8) after treatment with riboglycated BSA (1.5 μM), but demethylation did not occur after treatment with glucose-glycated (glucoglycated) proteins or the ribose, glucose, BSA, and Tris--HCl controls. Moreover, a significant demethylation of H3K4, H3K4me3, and H3K4me2, but not H3K4me1, occurred in the presence of riboglycated proteins. A significant increase of formaldehyde was also detected in the medium of SH-SY5Y cells cultured with riboglycated BSA, further indicating the occurrence of histone demethylation. The present study provides a new insight into understanding an epigenetic mechanism of diabetes mellitus (DM) related to ribose metabolic disorders. [ABSTRACT FROM AUTHOR]

INTRODUCTION Chlorpyrifos is one of the most commonly used organophosphates in agriculture. Reports on animal models of chronically exposed chlorpyrifos showed significant histo-structural renal damage. Moreover, evidence of high incidence of diabetes mellitus was observed among agricultural workers exposed to organophosphates. Available evidence linking derangement of glucose metabolism pathway with renal damage in this chronically exposed chlorpyrifos is lacking. The aim of this study was to determine the involvement of advanced glycation end-products formation in the development of nephrotoxicity in animals with chronic subcutaneous exposure to chlorpyrifos. MATERIALS AND METHODS: Eighteen rats were divided into three groups, with six rats in each group. Group 1 served as a control group, while Groups 2 and 3 received subcutaneous 3% dimethyl sulfoxide and 97% volume per volume soy oil as a vehicle or chlorpyrifos, respectively, on alternate day for 180 days. Blood samples were taken for biochemical analysis. Kidney tissues were examined for immunohistochemistry and gene expression of pathways related to oxidative stress and advanced glycation end-products. RESULTS: Serum fasting glucose, creatinine, advanced glycation endproducts and malondialdehyde levels were significantly increased (p<0.05), whereas paraoxonase-1 level was decreased in chlorpyrifos-treated rats compared with the control groups (p<0.05). The proximal tubular cells and the glomeruli of chlorpyrifos-exposed kidney showed strong malondialdehyde and advanced glycation end-products expression respectively. Gene expression of catalase and glutathione reductase were downregulated in the chlorpyrifos-treated rats. CONCLUSION: Glucose derangement and oxidative stress are the possible mechanisms of organophosphate-induced kidney damage. [ABSTRACT FROM AUTHOR]

Advanced glycation endproducts (AGEs) have been confirmed to play a causative role in the development of diabetic nephropathy (DN). In this study, we revealed that AGE-induced kidney injury with characteristic patterns in different stages and moesin phosphorylation plays a role in these processes. In WT mice treated with AGE-modified bovine serum albumin (AGEBSA), distinct abnormal angiogenesis in Bowman’s capsule of the kidney emerged early after 1 m under AGE-BSA stimulation, while these neovessels became rare after 6 m. AGE-BSA also induced glomerular hypertrophy and mesangial expansion at 1 m but glomerular atrophy and fibrosis at 6 m. Electron microscopy imaging demonstrated the damage of foot process integrity in podocytes and the uneven thickening of the glomerular basement membrane in the AGE-BSA-treated group, which was more significant after 6 m of AGEBSA treatment than 1 m. The kidney dysfunction appeared along with these AGE-induced morphological changes. However, these AGE-BSA-induced pathological changes were significantly attenuated in RAGE-knockout mice. Moreover, moesin phosphorylation was accompanied by AGE-BSA-induced alterations and moesin deficiency in mice attenuated by AGE-BSA-induced fibrosis. The investigation on glomerular endothelial cells (GECs) also confirmed that the phosphorylation of moesin T558 is critical in AGE-induced tube formation. Overall, this study suggests that AGEs mediate kidney injury with characteristic patterns by binding with RAGE and inducing moesin phosphorylation. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon‐like peptide‐1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats. Methods: DM was induced in Sprague–Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post‐STZ injection, Liraglutide (200 μg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N‐ε‐(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM‐1 and VCAM‐1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo. Results: In the heart, Liraglutide treatment significantly reduced the DM‐increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p =.003) and atria (343 ± 29 to 122 ± 8; p =.0001) and for NOX2, ICAM‐1 and VCAM‐1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p =.0005) and 47 ± 13 (p =.02), respectively), and for NOX2 and NOX4. In the kidney, the DM‐induced expression of ICAM‐1 and VCAM‐1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight. Conclusions: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes‐induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model. [ABSTRACT FROM AUTHOR]

Context: Type 2 diabetes (T2D) patients have reduced bone turnover and increased fractures. Advanced glycation endproducts (AGEs) impair osteoblasts and are implicated in diabetic fractures. Pyridoxamine (PM) is a vitamin B6 metabolite which inhibits formation of AGEs., Objective: We hypothesized that PM treatment in older T2D patients, by inhibiting AGEs, would increase bone formation., Design: Double-blind RCT., Setting: Academic center., Participants: Older T2D women (n=55)., Intervention: Oral PM 200 mg twice daily for one year., Main Outcomes: The primary outcome was the change in the bone formation marker P1NP. Other outcomes were changes in bone resorption, bone mineral density (BMD), HbA1c and skin autofluorescence (SAF), and in a bone biopsy sub-group, the correlation between bone fluorescent AGEs (fAGEs) and SAF., Results: P1NP increased 23.0% with PM (95% CI: 9, 37; within-group p=0.028) vs. 4.1% with placebo (-9, 17; within-group p=0.576; between-groups p=0.056). BMD increased at the femoral neck (PM: 2.6±5% vs. placebo: -0.9±4%; between-groups p=0.007). Bone resorption markers and SAF did not change. HbA1c decreased (PM: -0.38 ± 0.7% vs. placebo: 0.05 ± 1.7%; between-groups p =0.04). Within the PM group, the HbA1c change correlated inversely with the % P1NP change (r =-0.50, p=0.034). Cortical bone biopsy fAGEs correlated with SAF (r=0.86, p=0.001). Adverse events were similar between groups., Conclusion: PM tended to increase P1NP in older T2D women, as well as increasing bone density and reducing HbA1c. Further studies are needed to investigate the potential of PM as a disease mechanism-directed approach to reduce fractures in T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α‐dicarbonyl‐derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new‐onset CVD in 2 population‐based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case‐cohort sample (n=1631) from the Multi‐Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi‐Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow‐up of 11 years, 439 participants in the Multi‐Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl‐lysine, 3‐deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi‐Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α‐dicarbonyl‐derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle‐aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α‐dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high‐risk older populations.

• SAF is a validated marker of AGE accumulation in the skin. • SAF may be influenced by several factors which should be addressed when used as a systemic biomarker of AGEs. • Studies focusing on eliminating confounding factors of the AGE Reader measurement should be encouraged. Advanced glycation endproducts (AGEs) are sugar-modified adducts which arise during non-enzymatic glycoxidative stress. These compounds may become systemically elevated in disease states, and accumulate in tissue, especially on long-lived proteins. AGEs have been implicated in various acute, and chronic diseases, stressing the need for reliable and comprehensive measuring techniques. Measurement of AGEs in tissue such as skin requires invasive skin biopsies. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively using the fluorescent properties of several AGEs. Various studies have shown that SAF is a useful marker of disease processes associated with oxidative stress. It is prospectively associated with the development of cardiovascular events in patients with diabetes, renal or cardiovascular disease, and it predicts diabetes, cardiovascular disease, and mortality in the general population. However, when measuring SAF in individual subjects, several factors may limit the reliability of the measurement. These include endogenous factors present in the skin that absorb emission light such as melanin in dark-skinned subjects, but also factors that lead to temporal changes in SAF such as acute diseases and strenuous physical exercise associated with glycoxidative stress. Also, exogenous factors could potentially influence SAF levels inadvertently such as nutrition, and for example the application of skin care products. This review will address the AGE Reader functionality and the endogenous, and exogenous factors which potentially influence the SAF assessment in individual subjects. [ABSTRACT FROM AUTHOR]

Background: The aim was to assess the association between levels of advanced glycation endproducts (AGEs) in the gingival crevicular fluid (GCF) and periodontal parameters among cigarette-smokers and waterpipe-users. Methods: Self-reported cigarette-smokers; waterpipe-users and never-smokers were included. Demographic data was recorded using a questionnaire. Periodontal parameters (plaque index [PI], gingival index [GI], clinical attachment loss [AL], probing depth [PD], and marginal bone loss [MBL]) were assessed in all groups. The GCF samples were collected using standard techniques and assessed for AGEs levels using enzyme-linked immunosorbent assay. Sample-size estimation was done and group-comparisons were done. Correlation between levels of GCF AGEs levels and periodontal parameters was assessed using a logistic regression model. Level of significance was set at P < 0.01. Results: Eighty-two individuals (28 cigarette-smokers, 28 waterpipe-users and 26 never-smokers) were included. There was no difference in mean ages of all patients. Cigarette-smokers had a smoking history of 5.1 ± 0.2 pack years and waterpipe-users were using waterpipe for 4.4 ± 0.6 years. There was no statistically significant difference in PI, GI, clinical AL, PD and MBL in all groups. Levels of AGEs were significantly higher among cigarette-smokers (P < 0.001) and waterpipe-users (P < 0.001) than never-smokers. There was no significant correlation between levels of GCF AGEs levels and periodontal parameters in all groups. Conclusion: Clinical periodontal status of individuals with a short history of cigarette-smoking and waterpipe-usage may appear similar to never-smokers. On a molecular level, cigarette-smoking and waterpipe-users express raised levels of AGEs than never-smokers that sirens about the ongoing yet latent periodontal inflammatory process. [ABSTRACT FROM AUTHOR]

Background: Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs.Methods: In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway.Results: Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage .Conclusions: Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor. [ABSTRACT FROM AUTHOR]

• The study involved a large cohort of 63,425 participants with and without diabets mellitus, renal disease, and/or cardiovascular disease. • Increased skin autofluorescence is a marker of increased advanced glycation end-products and has already been shown to be associated with increased morbidity and mortality. • More hours of moderate to vigorous activity were associated with lower skin autofluorescence in the group with chronic disease. • More physical activity is associated with lower skin autofluorescence and could help to promote health and prolong longevity. Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases. This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status. Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 ± 11.77 years, mean ± SD) and had significantly lower SAF (1.90 ± 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 ± 12.07 years; SAF: 2.27 ± 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (β = –0.002, 95% confidence interval (95%CI): –0.002 to –0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (β = 3.2 × 10–5, 95%CI: 0.000–0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (β = 4.2 × 10–4, 95%CI: 0.000–0.001, p < 0.001), but this association was not found in the chronic disease population (β = –3.2 × 10–4, 95%CI: –0.001 to 0.000, p = 0.347). Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: This study aims to investigate the relationship of serum and dietary advanced glycation endproducts (AGEs) with cardiac function and structure after eight years of follow-up.Methods and Results: We included 370 Hoorn Study participants (aged 66.4 ± 6.1, 47% women). Serum protein-bound AGEs [Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine], as well as echocardiography to assess left atrium volume index (LAVI), left ventricle ejection fraction (LVEF), and left ventricle mass index (LVMI), were measured at baseline and after 8 years of follow-up. Dietary AGEs [Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine] were estimated at baseline with a validated food-frequency questionnaire and an AGEs database. Increased pentosidine [-1.4% (-2.6;-0.2)] and overall serum AGEs Z-scores over time [-2.1% (-3.8;-0.5)] were associated with decreased LVEF at follow-up, adjusted for confounders. Glucose metabolism status was an effect modifier (P-for-interaction = 0.04). In participants with impaired glucose metabolism, but not type 2 diabetes, increased pentosidine was associated with decreased LVEF [-4.2 (-8.0;-0.3)%]. Higher dietary Nε-(carboxyethyl)lysine [1.9 (0.1; 3.7)%] and overall dietary AGEs Z-scores [2.1 (0.1; 4.2)%] were associated with higher LVEF at follow-up. However, prior cardiovascular disease (CVD) was an effect modifier (P = 0.02). We found a stronger, non-significant, association of higher dietary (carboxyethyl)lysine with higher LVEF at follow-up in participants without CVD [2.3 (-0.1; 4.7)%] compared to participants with CVD [0.6 (-2.1; 3.4)%].Conclusion: Overall serum AGEs were longitudinally associated with impaired systolic function. Future research should focus on including changes in dietary AGEs intake over time and the relation of dietary AGEs with cardiac measures needs to be established in intervention studies using low AGEs diets. [ABSTRACT FROM AUTHOR]

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine (MG‐H1), was estimated using country‐specific dietary questionnaires linked to an AGEs database. Cause‐specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow‐up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR‐CML = 0.87, 95% CI: 0.76‐0.99, HR‐CEL = 0.84, 95% CI: 0.74‐0.96 and HR‐MH‐G1 = 0.84, 95% CI: 0.74‐0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR‐CML = 1.28, 95% CI: 1.05‐1.56, HR‐CEL = 1.17; 95% CI: 0.96‐1.40, HR‐MH‐G1 = 1.27, 95% CI: 1.06‐1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer. What's new? Advanced glycation endproducts (AGEs) are proteins or lipids with sugars added to them, and they can form in foods during cooking. They have pro‐inflammatory and pro‐oxidative properties in the body. These authors investigated whether dietary consumption of AGEs affect risk of liver cancer, using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants filled out food questionnaires to determine AGE consumption. Higher intakes of AGEs were associated with reduced risk of hepatocellular carcinoma (HCC) and increased risk of gallbladder cancer. However, it's still not entirely clear how much AGEs in the diet contribute to circulating AGE levels. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) excessive accumulation in the body either by exogenous intake or endogenous formation makes individuals prone to oxidative stress and inflammation damage. In this study, DCFH-DA fluorescence test and qPCR experiment were carried out to study the effect of some dietary flavonoids on AGEs induced toxicity. Among four tested flavonoids, it was found that hesperetin could significantly inhibit both AGEs-induced ROS production and gene expressions of TNF-α, IL-1β, IL-6, MCP-1, COX-2 and iNOS. High-throughput transcriptome analysis showed that the protective effect of hesperetin against AGEs-induced toxicity might be attributed to inhibit the activation of MAPK, JAK, NF-κB-related pathways. Furthermore, gene set enrichment analysis was performed using the MSigDB database and twenty-three key genes related were screened. This study might provide new ideas for the prevention of AGEs-related diseases and lay a theoretical foundation for the application of dietary flavonoids.

The objective of this study was to establish and validate an UHPLC-MS/MS method for simultaneous determination of advanced glycation endproducts (AGEs) in either free or bound form in milk powder. The target analytes in free form in milk powder were extracted by 1% trichloroacetic acid, while target analytes in bound form were hydrolyzed by hydrochloric acid to cleave the protein amide bond and consequently dissociated. After extraction and purification, Nε-(carboxymethyl)lysine (CML) and Nε-(1-carboxyethyl)lysine (CEL) were quantified by internal standard method and pyrraline (Pyr) was by external standard method. Results revealed that three target analytes displayed excellent linearity in their corresponding concentration ranges. Limits of quantifications (LOQs) were in the range of 20–95 μg/kg. The average recoveries of three target analytes spiked at three concentration levels were in the ranges of 81.8–107.2% with relative standard deviations (RSDs) of 3.5–8.1%. Finally, the described method was proved to be suitable for the quantification of these AGEs in milk powder products. [ABSTRACT FROM AUTHOR]

Posttranslational protein modification by lysine acylation is an emerging mechanism of cellular regulation and fine-tunes metabolic processes to environmental changes. In this review we focus on recently discovered pathways of non-enzymatic lysine acylation by reactive acyl-CoA species, acyl phosphates, and α-dicarbonyls. We summarize the metabolic sources of these highly reactive intermediates, demonstrate their reaction mechanisms, give an overview of the resulting acyl lysine modifications, and evaluate the consequences for cellular regulatory processes. Finally, we discuss interferences between lysine acylation and lysine ubiquitylation as a potential molecular mechanism of dysregulated protein homeostasis in aging and related diseases.

Aims: Non-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation in dark skin. Methods: Skin biopsies were obtained in 12 dark-skinned subjects (6 healthy subjects, median age 22 years; 6 diabetes mellitus (DM) subjects, 65 years). SAF was measured with the AGE Reader, IF using confocal microscopy, and AGE distribution with specific antibodies. CML and MG-H1 were quantified with UPLC-MS/MS and pentosidine with HPLC and fluorescent detection. Results: SAF correlated with IF from the dermis (405nm, r = 0.58, p < 0.05), but not with CML (r = 0.54, p = 0.07). CML correlated with IF from the dermis (405nm, r = 0.90, p < 0.01). UV reflectance and the coefficient of variation of SAF were negatively correlated (r = -0.80, p < 0.01). CML and MG-H1 were predominantly present around blood vessels, in collagen and fibroblasts in the dermis. Conclusion: This proof of concept study is the first to compare non-invasive SAF with AGE levels measured in skin biopsies in dark-skinned subjects. SAF did not correlate with individual AGEs from biopsies, but was associated with IF. However, the intra-individual variance was high, limiting its application in dark-skinned subjects on an individual basis.

Proliferative diabetic retinopathy (PDR) involves persistent, uncontrolled formation of premature blood vessels with reduced number of pericytes. Our previous work showed that advanced glycation endproducts (AGEs) induced angiogenesis in human umbilical vein endothelial cells, mouse retina, and aortic ring, which was associated with moesin phosphorylation. Here we investigated whether moesin phosphorylation may contribute to pericyte detachment and the development of PDR. Primary retinal microvascular pericytes (RMPs) were isolated, purified from weanling rats, and identified by cellular markers α-SMA, PDGFR-β, NG2, and desmin using immunofluorescence microscopy. Effects of AGE-BSA on proliferation and migration of RMPs were examined using CCK-8, wound healing, and transwell assays. Effects on moesin phosphorylation were examined using western blotting. The RMP response to AGE-BSA was also examined when cells expressed the non-phosphorylatable Thr558Ala mutant or phospho-mimicking Thr558Asp mutant of moesin or were treated with ROCK inhibitor Y27632. Colocalization and interaction between CD44, phospho-moesin, and F-actin were observed. Experiments with cultured primary RMPs showed that AGE-BSA inhibited the proliferation, enhanced the migration, and increased moesin phosphorylation in a dose- and time-dependent manner. AGE-BSA also triggered the rearrangement of F-actin and promoted the interaction of CD44 with phospho-moesin in RMPs. These effects were abrogated in cells expressing the non-phosphorylatable moesin mutant and the application of ROCK inhibitor Y27632 attenuated AGE-induced alteration in cultured RMPs by abolishing the phosphorylation of moesin. However, those AGE-induced pathological process occurred in RMPs expressed the phospho-mimicking moesin without AGE-BSA treatment. It is concluded that AGEs could activate ROCK to mediate moesin phosphorylation at Thr558, and resulting phospho-moesin interacts with CD44 to form CD44 cluster, which might stimulate the migration of RMPs and subsequent RMP detachment in microvessel. This pathway may provide new drug targets against immature neovessel formation in PDR.

There is increasing evidence for the role of intestinal permeability as a contributing factor in the pathogenesis of diabetes; however, the molecular mechanisms are poorly understood. Advanced glycation endproducts, of both exogenous and endogenous origin, have been shown to play a role in diabetes pathophysiology, in part by their ligation to the receptor for advanced glycation endproducts (RAGE), leading to a proinflammatory signalling cascade. RAGE signalling has been demonstrated to play a role in the development of intestinal inflammation and permeability in Crohn’s disease and ulcerative colitis. In this review, we explore the role of AGE-RAGE signalling and intestinal permeability and explore whether activation of RAGE on the intestinal epithelium may be a downstream event contributing to the pathogenesis of diabetes complications.

This article examines the importance of advanced glycation endproducts (AGEs) and summarizes the structure of AGEs, pathological changes associated with AGEs, the contribution of AGEs to metabolic memory, and the value of AGEs as a predictor of diabetic complications and cardiovascular disease in people with and without diabetes. As a practical focus, skin autofluorescence (SAF) is examined as an attractive approach for estimating AGE burden. The measurement of AGEs may be of significant value to specific individuals and groups, including Black and Hispanic/Latino Americans, as they appear to have higher concentrations of hemoglobin A 1c (HbA 1c ) than would be predicted by other metrics of mean glycemia. We hypothesize that if the amount of glycation of HbA 1c is greater than expected from measured glucose levels, and if AGEs are accumulating, then this accumulation of AGEs might account for the increased rate of complications of diabetes in populations with high rates of vascular disease and other complications. Thus, identifying and modifying the burden of AGEs based on measurement of AGEs by SAF may turn out to be a worthwhile metric to determine individuals who are at high risk for the complications of diabetes as well as others without diabetes at risk of vascular disease. We conclude that available evidence supports SAF as both a clinical measurement and as a means of evaluating interventions aimed at reducing the risks of vascular disease and diabetic complications., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DCK is a consultant for Afon, Better Therapeutics, Integrity, Lifecare, Nevro, Novo, Samsung, and Thirdwayv. AP has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies, and has received nonfinancial support from Pfizer and Merck. AP is also a consultant for Palomarin Inc with stocks compensation and has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), and the National Institute of Heart, Lung, and Blood Institute (R21HL169708). CR has received honoraria and/or grant support from AstraZeneca, Dexcom, Fresenius, and Vifor. GAF is an advisor for 180 Life Sciences, 89bio, Adocia, Abbott, AdipoPharma, Aerami, Amolyt, Carthera, Catalyst, Cohen Global, CMC Magnetics, Diasome, Eleos, Entera Bio, Enterin, Glyscend, Hagar, Hogan Lovells, IM Therapeutics, Innoneo, Intarcia, Levicure, Lilly Asia Ventures, Lumos, Mars Symbioscience, Melior, metaLead Therapeutics, Microbiotix, MMD, Modular Medical, New Amsterdam, Northwestern, NuSirt, NuVox, Oramed, Pano, Pasithea, PhylloPharma, Pleiogenix, Recordati, Regor, Remodeless, Renaissance, RenovoRx, Rivus, RxMP, Sera Biopharma, Seraxis, Serpin, SFC Fluidics, Skinject, SROne, Stalicla, Surf Bio, TIXiMED, Veroscience, Verthermia, WaveBreak, Zealand Pharma, and Zucara. DBS receives research support from the Intramural Research Program of the National Institutes of Health. RP-B receives grant support from Novo Nordisk, Lexicon Pharmaceuticals, and Medtronic and received consulting fee from Bayer, Lexicon Pharmaceuticals, Novo Nordisk, and Roche. DK has received research support from Abbott Diabetes Care and has been a Consultant to Sanofi, Better Therapeutics, and Abbott Diagnostics.

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine.Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome.Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002).Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD. [ABSTRACT FROM AUTHOR]

Proliferative diabetic retinopathy (PDR) involves persistent, uncontrolled formation of premature blood vessels with reduced number of pericytes. Our previous work showed that advanced glycation endproducts (AGEs) induced angiogenesis in human umbilical vein endothelial cells, mouse retina, and aortic ring, which was associated with moesin phosphorylation. Here we investigated whether moesin phosphorylation may contribute to pericyte detachment and the development of PDR. Primary retinal microvascular pericytes (RMPs) were isolated, purified from weanling rats, and identified by cellular markers α-SMA, PDGFR-β, NG2, and desmin using immunofluorescence microscopy. Effects of AGE-BSA on proliferation and migration of RMPs were examined using CCK-8, wound healing, and transwell assays. Effects on moesin phosphorylation were examined using western blotting. The RMP response to AGE-BSA was also examined when cells expressed the non-phosphorylatable Thr558Ala mutant or phospho-mimicking Thr558Asp mutant of moesin or were treated with ROCK inhibitor Y27632. Colocalization and interaction between CD44, phospho-moesin, and F-actin were observed. Experiments with cultured primary RMPs showed that AGE-BSA inhibited the proliferation, enhanced the migration, and increased moesin phosphorylation in a dose- and time-dependent manner. AGE-BSA also triggered the rearrangement of F-actin and promoted the interaction of CD44 with phospho-moesin in RMPs. These effects were abrogated in cells expressing the non-phosphorylatable moesin mutant and the application of ROCK inhibitor Y27632 attenuated AGE-induced alteration in cultured RMPs by abolishing the phosphorylation of moesin. However, those AGE-induced pathological process occurred in RMPs expressed the phospho-mimicking moesin without AGE-BSA treatment. It is concluded that AGEs could activate ROCK to mediate moesin phosphorylation at Thr558, and resulting phospho-moesin interacts with CD44 to form CD44 cluster, which might stimulate the migration of RMPs and subsequent RMP detachment in microvessel. This pathway may provide new drug targets against immature neovessel formation in PDR. [ABSTRACT FROM AUTHOR]

Background: The association between coronary artery disease (CAD) and diabetes mellitus (DM) is strong but the physiologic mechanisms responsible for this association remain unclear. Patients with DM exhibit high circulating levels of glycated proteins and lipoproteins called advanced glycation end products (AGEs) which have been implicated in the development of oxidative damage to vascular endothelium. We examined the relationships between the presence and extent of CAD and AGEs in patients undergoing elective coronary artery catheterization in an urban teaching hospital. Methods: Patients with possible CAD (n = 364) were recruited prior to elective cardiac catheterization (52% male, 48% diabetic). Regression and correlation analyses were used to examine the relationship between serum AGE concentrations, soluble AGE receptor (sRAGE) concentration, HbA1c, LDL and the presence of obstructive CAD along with the burden of CAD measured by SYNTAX and SYNTAX II scores. Results: AGE and sRAGE levels did not significantly correlate with any of the studied coronary artery disease parameters. HbA1c showed positive correlation with both SYNTAX and SYNTAX II scores in patients with and without diabetes. Conclusion: In this cross-sectional study of patients with possible CAD, serum AGEs and sRAGE concentrations did not correlate with SYNTAX or SYNTAX II scores regardless of diabetic status. HbA1C correlated positively with the SYNTAX and SYNTAX II scores in both diabetic and non-diabetic populations.

In this study, cookies were incorporated with three polyphenols (rosmarinic acid, resveratrol, and epicatechin) at two concentrations (0.02% and 0.2%), and baked under three temperatures (150, 170, and 190 °C) to observe their interaction. They didn’t significantly change the cookie texture, but influence the color and pH. Temperature was a significant determinant to affect polyphenols’ stability and accordingly influenced cookies’ antioxidant capacity. 73.4%, 26.7% and 9.9% of rosmarinic acid, resveratrol, and epicatechin remained after baking at 190 °C for 10 min. Two addition levels of polyphenols decreased fluorescent advanced glycation endproducts (AGEs) by 18.58% to 40.29% and 28.60% to 62.05% respectively, while only resveratrol and epiatechin could reduce the level of glyoxal and methylglyoxal in cookies. In addition, we discovered that thermal processing could enhance the cytotoxicity of rosmarinic acid against cancer cells. Thus polyphenols were suggested as beneficial additives for enhancing antioxidant intake and lowering total fluorescent AGEs.

Hyperglycemia, when sustained over a long time in diabetes mellitus (DM), leads to biochemical and cellular abnormalities, primarily through the formation of advanced glycation end-products (AGEs). In the treatment of diabetes, beside blood-sugar-lowering medications, a consumption of herbal products that can inhibit the AGEs’ formation is recommended. This study investigated the in vitro antiglycoxidative potential of extracts and fractions from the rhizomes of Japanese, Giant, and Bohemian knotweeds (Reynoutria japonica (Houtt.), R. sachalinensis (F. Schmidt) Nakai, and R.× bohemica Chrtek et Chrtkova). Their effects on glycooxidation of bovine and human serum albumin were evaluated by incubation of the proteins with a mixture of glucose and fructose (0.5 M) and 150 µg/mL of extract for 28 days at 37 °C, followed by measuring early and late glycation products, albumin oxidation (carbonyl and free thiol groups), and amyloid-β aggregation (thioflavin T and Congo red assays). The highest antiglycoxidative activity, comparable or stronger than the reference drug (aminoguanidine), was observed for ethyl acetate and diethyl ether fractions, enriched in polyphenols (stilbenes, phenylpropanoid disaccharide esters, and free and oligomeric flavan-3-ols). In conclusion, the antiglycoxidative compounds from these three species should be further studied for potential use in the prevention and complementary treatment of DM.