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Aims/hypothesis The aim of this work was to assess the association of advanced glycation end-products (AGEs), measured by skin autofluorescence (SAF), with prevalent heart failure, and with systolic and diastolic cardiac function, in a large population-based cohort study. Methods We assessed the cross-sectional association between SAF and prevalent heart failure among 2426 participants from the population-based Rotterdam Study, using logistic regression. Next, among individuals free of heart failure ( N =2362), we examined the link between SAF (on a continuous scale) and echocardiographic parameters of left ventricular (LV) systolic and diastolic function using linear regressions. Analyses were adjusted for traditional cardiovascular risk factors. Results Higher levels of SAF were associated with higher odds of prevalent heart failure (multivariable adjusted OR 2.90 [95% CI 1.80, 4.62] for one unit higher SAF value). Among individuals without heart failure, one unit increase in SAF was associated with 0.98% lower LV ejection fraction (mean difference [β] −0.98% [95% CI −1.45%, −0.50%]). The association was stronger among participants with diabetes (β −1.84% [95% CI −3.10%, −0.58%] and β −0.78% [95% CI −1.29%, −0.27%] among participants with and without diabetes, respectively). Associations of SAF with diastolic function parameters were not apparent, except in men with diabetes. Conclusions/interpretation AGE accumulation was independently associated with prevalent heart failure. Among individuals free of heart failure, AGEs were associated with cardiac function, in particular systolic function. This association was present in participants with and without diabetes and was more prominent in those with diabetes. Graphical abstract

Background Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. Methods In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. Results 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. Conclusions Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. Trial registration : The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl ) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/ ) under shared catalogue number NTR6831.

Background Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear. Methods In the Rotterdam Study ( n  = 2577), AGEs (by skin autofluorescence (SAF)), FEV 1 and lung diffusing capacity (D LCO c and D LCO c /alveolar volume [V A ]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression. Results SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV 1 % predicted (β=-3.384 [-4.877, -1.892]), D LCO c (β=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p  = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV 1 %predicted was stronger in COPD (β=-6.362 [-9.055, -3.670]) than non-COPD (β=-1.712 [-3.306, -0.118]). Association of SAF with D LCO c and D LCO c/V A were confined to COPD (β=-0.550 [-0.909, -0.191]; β=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively). Conclusions Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD. Take-home message Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01–1.46]) and Alzheimer’s disease (1.19 [0.97–1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E ( APOE) ε4 carriers (1.34 [0.98–1.82]) and in participants with diabetes (1.35 [0.94–1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.

Williams–Beuren syndrome (WBS, OMIM-no.194050) is a rare congenital genetic disorder primarily marked by developmental delays and cardiovascular anomalies, with potential involvement of metabolic dysregulation. Despite this, the metabolic features of WBS have not been extensively studied. Thus, our objective was to examine the serum metabolome profile in children with WBS, elucidating metabolic changes and associated pathways in the disorder. We recruited 25 children with WBS (mean age 5.0 ± 2.6 years, 40% female) from the Children’s Hospital affiliated to Zhejiang University between 2020 and 2023. An age and sex matched healthy control group (N = 25) were recruited from the Health Management Center in the same hospital. Clinical information of WBS were extracted from the medical records. Blood samples were obtained for untargeted metabolomics analysis using UPLC-MS/MS. The metabolomic profiles of WBS patients were compared to those of healthy controls to identify metabolites with differential abundance. Enrichment analysis was conducted to identify potentially impacted KEGG pathways. Associations between metabolites and phenotypes were evaluated. Children with WBS exhibited a unique metabolic profile compared to healthy controls, as evidenced by the identification of 465 untargeted metabolites in serum. Of these metabolites, 169 showed differential abundance in WBS children. The top enriched KEGG pathways in WBS children included nicotine addiction, cholesterol metabolism, arginine biosynthesis, retrograde endocannabinoid signaling. Additionally, there were indications of potential metabolic alterations in the l -tryptophan pathway, with a shift from serotonin to l -kynurenine, as well as disruptions in bile acid metabolism. Metabolome data in children with WBS showed neurological and amino acid metabolism changes, indicating multisystem involvement and developmental delay. This data can help monitor and manage the disease, but further studies are needed to understand the underlying mechanisms and consequences.

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.

Gastric ulcer (GU), a prevalent digestive disease, has a high incidence and is seriously harmful to human health. Finding a natural drug with a gastroprotective effect is needed. Ocotillol, the derivate of ocotillol-type saponins in the Panax genus, possesses good anti-inflammatory activity. The study aimed to investigate the gastroprotective effect of ocotillol on acetic acid-induced GU rats. The serum levels of endothelin-1 (ET-1) and nitric oxide (NO), the gastric mucosa levels of epidermal growth factor, superoxide dismutase and NO were assessed. Hematoxylin and eosin staining of gastric mucosa for pathological changes and immunohistochemical staining of ET-1, epidermal growth factor receptors and inducible nitric oxide synthase were evaluated. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 21 potential metabolites involved in 7 metabolic pathways were identified. The study helps us to understand the pathogenesis of GU and to provide a potential natural anti-ulcer agent.

Advanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiological processes of dementia and potentially underlie the association of diabetes with neurodegeneration. However, longitudinal studies examining this association are lacking. To determine whether markers of the AGE-RAGE system are associated with prevalent and incident dementia and with cognition. In this population-based cohort study including participants from the prospective Rotterdam Study, extracellular newly identified RAGE binding protein (EN-RAGE) and soluble RAGE (S-RAGE) were measured in plasma collected between 1997 and 1999 in a random selection of participants, and additionally in participants with prevalent dementia. Participants without dementia were followed up for dementia until 2016. Skin AGEs, measured as skin autofluorescence, and cognition were measured between 2013 and 2016 in participants without dementia. Data analysis was performed from June 2019 to December 2019. EN-RAGE, S-RAGE, and skin autofluorescence. Prevalent and incident dementia and cognition, adjusted for potential confounders, including age, sex, diabetes, educational level, APOE ε4 carrier status, smoking, and estimated glomerular filtration rate. Of 3889 included participants (mean [SD] age, 72.5 [8.9] years; 2187 [56.2%] women), 1021 participants had data on plasma markers (mean [SD] age 73.6 [7.8] years; 564 [55.2%] women), 73 participants had dementia at baseline, and during 10 711 person-years of follow-up, 161 participants developed incident dementia. Compared with low levels, high EN-RAGE level was associated with a higher prevalence of dementia (odds ratio [OR], 3.68 [95% CI, 1.50-8.03]; P = .003), while high S-RAGE level was associated with a lower prevalence of dementia (OR, 0.37 [95% CI, 0.17-0.78]; P = .01). These associations attenuated in a longitudinal setting, with hazard ratios of 0.65 (95% CI, 0.42-1.01) for high EN-RAGE (P = .05) and 1.22 (95% CI, 0.82-1.81) for high S-RAGE (P = .33). Among 2890 participants without dementia (mean [SD] age, 72.5 [9.4] years; 1640 [57%] women), higher skin autofluorescence was associated with lower global cognitive function (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.07 [95% CI, -0.11 to -0.04]), especially among carriers of the APOE ε4 allele (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.15 [95% CI, -0.22 to -0.07]). These findings suggest that the AGE-RAGE system is associated with cognitive decline and dementia cross-sectionally but not longitudinally. This indicates either a short-term association or reverse causality. Findings of cross-sectional associations between higher skin autofluorescence and lower cognitive function and an association with APOE status also warrant replication and prospective studies.

Advanced glycation end products (AGEs) accumulate in tissues with aging and may influence age-related diseases. They can be estimated non-invasively by skin autofluorescence (SAF) using the AGE Reader™. Serum 25-hydroxyvitamin D (25(OH)D ) may inhibit AGEs accumulation through anti-oxidative and anti-inflammatory properties but evidence in humans is scarce. The objective was to investigate the association between serum 25(OH)D and SAF in the population-based cohort study. Serum 25(OH)D and other covariates were measured at baseline. SAF was measured on average 11.5 years later. Known risk factors for AGE accumulation such as higher age, BMI, and coffee intake, male sex, smoking, diabetes, and decreased renal function were measured at baseline. Linear regression models were adopted to explore the association between 25(OH)D and SAF with adjustment for confounders. Interaction terms were tested to identify effect modification. The study was conducted in the general community. 2746 community-dwelling participants (age ≥ 45 years) from the Rotterdam Study were included. Serum 25(OH)D inversely associated with SAF and explained 1.5% of the variance (unstandardized B = - 0.002 (95% CI[- 0.003, - 0.002]), standardized β = - 0.125), independently of known risk factors and medication intake. The association was present in both diabetics (B = - 0.004 (95% CI[- 0.008, - 0.001]), β = - 0.192) and non-diabetics (B = - 0.002 (95% CI[- 0.003, - 0.002]), β = - 0.122), both sexes, both smokers and non-smokers and in each RS subcohort. Serum 25(OH)D concentration was significantly and inversely associated with SAF measured prospectively, also after adjustment for known risk factors for high SAF and the number of medication used, but the causal chain is yet to be explored in future studies.Clinical Trial Registry (1) Netherlands National Trial Register: Trial ID: NTR6831 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 ). (2) WHO International Clinical Trials Registry Platform: under shared catalogue number NTR6831 ( www.who.int/ictrp/network/primary/en/ ).

Animal studies suggest a role for dietary advanced glycation end-products (dAGEs) in bone health, but human studies on dAGEs in relation to bone are lacking. We aimed to study whether dAGEs intake is associated with the parameters of bone strength namely, bone mineral density (BMD), prevalent vertebral (VFs), and major osteoporotic fractures (MOFs = hip, wrist, proximal humerus, and clinical VFs). 3949 participants (mean age 66.7 ± 10.5 years) were included from a Rotterdam study for whom Carboxymethyllysine (CML—a dietary AGE) was estimated from food frequency questionnaires combined with dAGEs databases. Multivariable linear and logistic regression models were performed adjusting for age, sex, energy intake, dietary quality, physical activity, diabetes, smoking, renal function, and cohort effect and for models on fractures, subsequently for BMD. We observed no association of CML with BMD at both femoral neck (β = −0.006; p = 0.70) and lumbar spine (β = −0.013; p = 0.38). A higher intake of CML was linearly associated with VFs (Odds ratio, OR = 1.16, 95% CI (1.02–1.32) and a similar but non-significant trend with MOFs (OR = 1.12 (0.98–1.27). Additional adjustment for BMD did not change the associations. Our results imply a positive association between dietary intake of CML and VFs independent of BMD. Future studies are needed in order to elucidate whether associations found are causal.