Concentrations Of Advanced Glycation End-products Research Articles

Effect of Anagliptin on Vascular Injury in the Femoral Artery of Type 2 Diabetic Rats.

Patients with diabetes mellitus (DM) often experience complications such as peripheral arterial disease (PAD), which is thought to be caused by vascular damage resulting from increased oxidative stress. Dipeptidyl peptidase-4 inhibitors have been reported to reduce oxidative stress, although the exact mechanism remains unclear. This study aimed to investigate the impact of long-term (6 weeks) anagliptin treatment at a dose of 200 mg/kg/d against oxidative stress in the femoral artery of Otsuka Long-Evans Tokushima Fatty (OLETF) rats using a well-established animal model for type 2 DM. Serum toxic advanced glycation end-products concentrations and blood glucose levels after glucose loading were significantly elevated in OLETF rats compared to Long-Evans Tokushima Otsuka (LETO) rats but were significantly suppressed by anagliptin administration. Plasma glucagon-like peptide-1 concentrations after glucose loading were significantly increased in anagliptin-treated rats. Superoxide production and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in femoral arteries were significantly increased in OLETF rats compared to LETO rats but were significantly decreased by anagliptin administration. The expressions of NADPH oxidase components (p22phox in the intima region and p22phox and gp91phox in the media region) in the femoral artery were significantly increased in OLETF rats compared to LETO rats but were significantly suppressed by anagliptin administration. Furthermore, the femoral artery showed increased wall thickness in OLETF rats compared to LETO rats, but anagliptin administration reduced the thickening. This study suggests that long-term anagliptin administration can reduce oxidative stress in femoral arteries and improve vascular injury.

Comparison of advanced glycation end products concentration in the skin among patients with rheumatic diseases, with and without comorbid depression: a case-control study.

Patients with rheumatic diseases suffer depression at a far greater rate than the general population. Aside from evident mental health degradation, in this group of patients depression can often lead to failures in the treatment of the basic disease. The aim of the study was to assess the concentration of advanced glycation end-products (AGE) in the skin autofluorescence (SAF) exam in patients with select rheumatic diseases depending on depression concomitance. 139 patients with rheumatic diseases were enrolled into the study-43 (39F/4M) patients with RA, 31 (24F/7M) patients with PsA, 27 (22F/5M) patients with SLE and 38 (33F/5M) patients with SSc. In all patients, the concentration of AGE was assessed using the AGE Reader device (DiagnOptics BV Groningen, The Netherlands). The Beck Depression Inventory II was used to assess depression in the patients. Patients who scored 14 points or more in the BDI-II were diagnosed with depression. In the studied group, depression was identified in 73 (53%) patients-25 with RA, 21 with PsA, 11 with SLE and 16 with SSc. Mean SAF in patients with depression was 2.8 ± 0.4, and in the group with no depression-2.2 ± 0.5 (p < 0.001). The study results indicate that in the course of rheumatic diseases, the presence of depression may influence the increase in AGE concentration in the skin. Therefore, evaluating AGE levels in the skin may be clinically relevant as it can help identify patients who may be at risk of developing depression.

Resveratrol Alleviates Advanced Glycation End-Products-Related Renal Dysfunction in D-Galactose-Induced Aging Mice.

The elderly have higher concentrations of advanced glycation end-products (AGEs). AGEs are considered risk factors that accelerate aging and cause diabetic nephropathy. The effects of AGEs on renal function in the elderly remain to be clarified. This study aimed to explore the role of AGEs in renal function decline in the elderly and the protective effect of resveratrol, a stilbenoid polyphenol, comparing it with aminoguanidine (an AGEs inhibitor). A D-galactose-induced aging mouse model was used to explore the role of AGEs in the process of renal aging. The mice were administered D-galactose subcutaneously for eight weeks in the presence or absence of orally administered aminoguanidine or resveratrol. The results showed that the serum levels of AGEs and renal function markers BUN, creatinine, and cystatin C in the mice significantly increased after the administration of D-galactose, and this outcome could be significantly reversed by treatment with aminoguanidine or resveratrol. The protein expression levels for apoptosis, fibrosis, and aging-related indicators in the kidneys were significantly increased, which could also be reversed by treatment with aminoguanidine or resveratrol. These findings suggest that resveratrol could alleviate AGEs-related renal dysfunction through the improvement of renal cellular senescence, apoptosis, and fibrosis in D-galactose-induced aging in mice.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present reviewwas to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Weak Association between Skin Autofluorescence Levels and Prediabetes with an ILERVAS Cross-Sectional Study.

A large body of evidence demonstrates a relationship between hyperglycemia and increased concentrations of advanced glycation end-products (AGEs). However, there is little information about subcutaneous AGE accumulation in subjects with prediabetes, and whether or not this measurement could assist in the diagnosis of prediabetes is unclear. A cross-sectional study was conducted in 4181 middle-aged subjects without diabetes. Prediabetes (n = 1444) was defined as a glycosylated hemoglobin (HbA1c) level between 39 and 47 mmol/mol (5.7 to 6.4%), and skin autofluorescence (SAF) measurement was performed to assess AGEs. A multivariable logistic regression model and receiver operating characteristic curve were used. The cohort consisted of 50.1% women with an age of 57 [52;62] years, a BMI of 28.3 [25.4;31.6] kg/m2, and a prevalence of prediabetes of 34.5%. Participants with prediabetes showed higher SAF than control participants (2.0 [1.7;2.2] vs. 1.9 [1.7;2.2], p < 0.001). However, HbA1c was not significantly correlated with SAF levels (r = 0.026, p = 0.090). In addition, the SAF level was not independently associated with prediabetes (OR = 1.12 (0.96 to 1.30)). Finally, there was no good cutoff point for SAF to identify patients with prediabetes (AUC = 0.52 (0.50 to 0.54), sensitivity = 0.61, and 1-specificity = 0.56). Given all of this evidence, we can conclude that although there is an increase in SAF levels in participants with prediabetes, the applicability and clinical relevance of the results is low in this population.

Advanced Glycation End-Products (AGEs) and Their Soluble Receptor (sRAGE) in Women Suffering from Systemic Lupus Erythematosus (SLE).

Systemic lupus erythematosus (SLE) is characterized by abnormal action of the immune system and a state of chronic inflammation. The disease can cause life-threatening complications. Neoepitopes arising from interdependent glycation and oxidation processes might be an element of SLE pathology. The groups included in the study were 31 female SLE patients and 26 healthy female volunteers (the control group). Blood serum samples were obtained to evaluate concentrations of advanced glycation end-products (AGEs), carboxymethyllysine (CML), carboxyethyllysine (CEL), pentosidine, and a soluble form of the receptor for advanced glycation end-products (sRAGE). Compared to a healthy control group, the SLE patients exhibited a higher concentration of AGEs and a lower concentration of sRAGE in serum. There were no statistically significant differences in serum CML, CEL, and pentosidine concentrations between the groups. Therefore, SLE patients could be at risk of intensified glycation process and activation of the proinflammatory receptor for advanced glycation end-products (RAGE), which could potentially worsen the disease course; however, it is not clear which compounds contribute to the increased concentration of AGEs in the blood. Additionally, information about the cigarette smoking and alcohol consumption of the study participants was obtained.

Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

[Figure: see text].

Comparison of glucose degradation product and receptor levels in diabetic and normal pregnancy

Objective:The aim of this study was to assess the diagnostic values of new biochemical markers that may be an alternative to the oral glucose tolerance test (OGTT) and determine the differences in these markers among three groups of women with varying degrees of glucose homeostasis dysregulation.Material and Methods:This was a prospective study. All women were screened with 50 gram (g) oral glucose and a 100 g OGTT for gestational diabetes mellitus (GDM). The patients were divided into three groups depending on the result of the tests: no evidence of glucose metabolism abnormality (controls); impaired glucose tolerance (IGT); and GDM. All three groups were evaluated for serum human advanced glycation end-products (AGEs) concentrations, carboxymethyl lysine (CML) concentration and receptor for advanced glycation end-product concentrations (RAGE/AGER), body mass index (BMI), age, fasting glucose levels, obstetrical parameters and gestational age.Results:The study included 180 women divided into 59 (32.8%) GDM, 50 (27.8%) IGT and 71 (39.4%) controls. Age was similar among the three groups. Whereas fasting glucose levels and BMI in the three groups was significantly different, AGEs, CML, RAGE/AGER levels were found as significantly different between the groups (p<0.001).Conclusion:In this study the use of AGEs, CML, and RAGE/AGER concentrations for the diagnosis and screening of gestational diabetes was investigated. It was found that advanced glycation products were significantly elevated in pregnancies with both IGT and GDM. These biochemical markers of glucose homeostasis dysregulation may have potential for GDM screening in the future.

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 versus Q1 = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.

Advanced glycation end products predict long-term outcome of catheter ablation in paroxysmal atrial fibrillation.

Oxidative stress is an important contributor to the etiology of atrial fibrillation (AF). Our aim was to study oxidative stress biomarkers in patients undergoing pulmonary vein isolation (PVI) for paroxysmal AF with radiofrequency catheter ablation and to assess its prognostic value in predicting long-term PVI outcome. In this prospective cohort study, we included 62 patients (mean age 55±8 years, 12 females and 50 males) with paroxysmal AF and implanted ECG loop recorders who underwent PVI. Plasmatic concentrations of advanced glycation end-products (AGEs), fructosamine, advanced oxidation protein products, and thiobarbituric-acid reacting substances were measured before PVI. AF burden (percentage of time spent in AF) was continually assessed during the follow-up period (1063±271 days). Nineteen patients (31%) were defined as optimal responders (oR) with AF burden < 0.5% after PVI. Remaining 43 patients (69%) were defined as sub-optimal responders. Concentration of AGEs was significantly lower in oR by 3.7 g/g (CI: -6.5 to -1.7; P=0.0003). After adjustment for age, sex, BMI, left atrial size, arterial hypertension, and AF burden before PVI, only low concentration of AGEs remained significantly associated with oR (odds ratio: 1.3; P=0.04). AGEs concentration achieved area under the curve of 0.78 for predicting optimal long-term PVI response. AGEs concentration before PVI was associated with long-term PVI outcome in patients with paroxysmal AF. Further research will show if this biomarker could contribute to optimal patient selection for catheter ablation.

Plasma Concentration of Advanced Glycation End-Products From Wild Canids and Domestic Dogs Does Not Change With Age or Across Body Masses.

Dogs provide a physiological paradox: In domestic dogs, small breeds live longer lives than large breed dogs. Comparatively, a wild canid can be a similar size than many large breed dogs and outlive their domestic cousin. We have previously shown that oxidative stress patterns between domestic and wild canids differ, so that wild canids invest in a robust antioxidant system across their lives; whereas domestic dogs tend to accumulate lipid damage with age. There is a close association between oxidative stress and the production of a carbohydrate based-damage, Advanced Glycation End-products (AGEs). AGEs can bind to their receptor (RAGE), which can lead to increases in reactive oxygen species (ROS) production, and decreases in antioxidant capacity. Here, I used plasma from wild and domestic canids to address whether blood plasma AGE-BSA concentration associated with body mass and age in domestic dogs; And whether AGE-BSA concentration patterns in blood plasma from wild canids are similar to those found in domestic dogs. I found no correlation between circulating AGE-BSA concentration and body size or age in either domestic dogs and wild canids. These data suggest that AGEs formation may be a conserved trait across the evolution of domesticated dogs from wild ancestors, in opposition to oxidative stress patterns between these two groups. And, that, in domestic dogs, lipid metabolism, rather than carbohydrate metabolism, may be upregulated to yield the previously found differences in circulating lipid damage across lifespan and body sizes.

Dietary protein intake and circulating advanced glycation end product/receptor for advanced glycation end product concentrations in the Health, Aging, and Body Composition Study

Advanced glycation end products (AGEs) promote adverse health effects and may contribute to the multi-system functional decline observed in aging. Diet is a major source of AGEs, and foods high in protein may increase circulating AGE concentrations. However, epidemiological evidence that high-protein diets increase AGEs is lacking. We examined whether dietary protein intake was associated with serum concentrations of the major AGE carboxymethyl-lysine (CML) and the soluble receptor for AGEs (sRAGE) in 2439 participants from the Health, Aging, and Body Composition study (mean age, 73.6±2.9 y; 52% female; 37% black). CML and sRAGE were measured by ELISA, and the CML/sRAGE ratio was calculated. Protein intake was estimated using an interviewer-administered FFQ and categorized based on current recommendations for older adults: <0.8 g/kg/d (n=1077), 0.8 to <1.2 g/kg/d (n=922), and ≥1.2 g/kg/d (n=440). Associations between protein intake and AGE-RAGE biomarkers were examined using linear regression models adjusted for demographics, height, lifestyle behaviors, prevalent disease, cognitive function, inflammation, and other dietary factors. CML concentrations were higher in individuals with higher total protein intake (adjusted least squares mean±SE: <0.8 g/kg/d, 829±17 ng/ml; 0.8 to <1.2 g/kg/d, 860±15 ng/ml; ≥1.2 g/kg/d, 919±23 ng/ml; P for trend=0.001), as were sRAGE concentrations (<0.8 g/kg/d, 1412±34 pg/ml; 0.8 to <1.2 g/kg/d, 1479±31 pg/ml; ≥1.2 g/kg/d, 1574±47 pg/ml; P for trend<0.0001). Every 0.1 g/kg/d increment in total protein intake was associated with a 13.3±3.0 ng/ml increment in CML and a 22.1±6.0 pg/ml increment in sRAGE (P<0.0001 for both). Higher CML and sRAGE concentrations were also associated with higher intakes of both animal and vegetable protein (all P values ≤0.01). There were no significant associations with the CML/sRAGE ratio. Higher dietary protein intake was associated with higher CML and sRAGE concentrations in older adults; however, the CML/sRAGE ratio remained similar across groups.

Long Term Dietary Restriction of Advanced Glycation End-Products (AGEs) in Older Adults with Type 2 Diabetes Is Feasible and Efficacious-Results from a Pilot RCT.

Introduction: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. Methods: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article (ClinicalTrials.gov Identifier: NCT02739971). Results: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. Conclusions: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.

Data on advanced glycation end-products concentrations and haemodynamic parameters following caffeine and nicotine consumption in nursing students.

This work presents data from a non-invasive interventional trial investigating the early effects of caffeine and nicotine on both the concentrations of advanced glycation end-products (AGEs) and haemodynamic parameters in 178 healthy nursing students aged between 18 and 40. These students were allocated into four groups (A, B, C and D) and the concentrations of AGEs as well as haemodynamic parameters were measured non-invasively using the AgeReader and the Finometer devices, respectively. The haemodynamic parameters that were measured included systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, inter-beat interval, stroke volume, cardiac output, ventricular ejection time, total peripheral resistance, ascending aorta impedance and total arterial compliance. According to our protocol, each beverage contained 100 mg of caffeine each cigarette contained 1.5 mg of nicotine. The present data reveal the combined effect of smoke and caffeine consumption to several hemodynamic parameters that may be related to the onset of elevated blood pressure during smoking and following caffeine consumption.

Comparison of glucose degradation product and receptor levels in dıabetic and normal pregnancy

The aim of this study was to assess the diagnostic values of new biochemical markers that may be an alternative to the oral glucose tolerance test (OGTT) and determine the differences in these markers among three groups of women with varying degrees of glucose homeostasis dysregulation. This was a prospective study. All women were screened with 50 gram (g) oral glucose and a 100 g OGTT for gestational diabetes mellitus (GDM). The patients were divided into three groups depending on the result of the tests: no evidence of glucose metabolism abnormality (controls); impaired glucose tolerance (IGT); and GDM. All three groups were evaluated for serum human advanced glycation end-products (AGEs) concentrations, carboxymethyl lysine (CML) concentration and receptor for advanced glycation end-product concentrations (RAGE/AGER), body mass index (BMI), age, fasting glucose levels, obstetrical parameters and gestational age. The study included 180 women divided into 59 (32.8%) GDM, 50 (27.8%) IGT and 71 (39.4%) controls. Age was similar among the three groups. Whereas fasting glucose levels and BMI in the three groups was significantly different, AGEs, CML, RAGE/AGER levels were found as significantly different between the groups (p<0.001). In this study the use of AGEs, CML, and RAGE/AGER concentrations for the diagnosis and screening of gestational diabetes was investigated. It was found that advanced glycation products were significantly elevated in pregnancies with both IGT and GDM. These biochemical markers of glucose homeostasis dysregulation may have potential for GDM screening in the future.

Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin

The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5–10 mM), moderate (50–100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-ε-carboxymethyl lysine (CML), N-ε-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit β5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding.

Maternal corticosterone in the mouse alters oxidative stress markers, antioxidant function and mitochondrial content in placentas of female fetuses.

Maternal exposure to the stress hormone corticosterone is known to programme a range of sex specific disease outcomes in offspring. Sex differences in placental adaptations are thought to mediate these processes. Placental oxidative stress is implicated in a range of pregnancy disorders but the role of placental oxidative stress in sex specific disease outcomes following prenatal corticosterone exposure is unknown. This study demonstrates that maternal corticosterone reduced placental hydrogen peroxide and 8-hydroxy-2'-deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. These results highlight that placentas of female fetuses respond differently to maternal corticosterone exposure, with oxidative stress a major finding in placentas of female fetuses. Maternal exposure to glucocorticoids during pregnancy increases offspring risk of developing a range of sex specific disease phenotypes. These sex specific disease outcomes are thought to be in part mediated by different placental adaptations in males and females. The placenta is a highly metabolic organ which is vulnerable to the effects of oxidative stress. In other tissues, males and females have been shown to respond differently to the pro-oxidant effects of glucocorticoids. This study therefore used a well characterized animal model of maternal corticosterone exposure to investigate sex specific alterations in reactive oxygen species production, antioxidant concentrations and mitochondrial properties that might contribute to sex differences in placental outcomes. C57BL/6 mice were implanted with osmotic minipumps containing corticosterone (33μgkg-1 h-1 ) at embryonic day (E) 12.5 and placentas collected at E14.5 for analysis. Corticosterone exposure reduced placental hydrogen peroxide (H2 O2 ) and 8-hydroxy-2'-deoxyguanosine concentrations but increased protein carbonyl content and advanced glycation end product concentrations in placentas of female fetuses but not male fetuses. This dysregulation of different markers of oxidative stress may be due to increased placental activity of thioredoxin reductase in female but not male fetuses. Corticosterone reduced placental mitochondrial content but increased protein expression of the autophagosome cargo protein p62. This study demonstrates that placentas of female fetuses respond differently to maternal corticosterone exposure and highlights an important role of reactive oxygen species, mitochondrial adaptations and antioxidant responses in glucocorticoid induced programmed disease.

Altered Tissue Composition, Microarchitecture, and Mechanical Performance in Cancellous Bone From Men With Type 2 Diabetes Mellitus

People with type 2 diabetes mellitus (T2DM) have normal-to-high BMDs, but, counterintuitively, have greater fracture risks than people without T2DM, even after accounting for potential confounders like BMI and falls. Therefore, T2DM may alter aspects of bone quality, including material properties or microarchitecture, that increase fragility independently of bone mass. Our objective was to elucidate the factors that influence fragility in T2DM by comparing the material properties, microarchitecture, and mechanical performance of cancellous bone in a clinical population of men with and without T2DM. Cancellous specimens from the femoral neck were collected during total hip arthroplasty (T2DM: n = 31, age = 65 ± 8 years, HbA1c = 7.1 ± 0.9%; non-DM: n = 34, age = 62 ± 9 years, HbA1c = 5.5 ± 0.4%). The T2DM specimens had greater concentrations of the advanced glycation endproduct pentosidine (+ 36%, P < 0.05) and sugars bound to the collagen matrix (+ 42%, P < 0.05) than the non-DM specimens. The T2DM specimens trended toward a greater bone volume fraction (BV/TV) (+ 24%, NS, P = 0.13) and had greater mineral content (+ 7%, P < 0.05) than the non-DM specimens. Regression modeling of the mechanical outcomes revealed competing effects of T2DM on bone mechanical behavior. The trend of higher BV/TV values and the greater mineral content observed in the T2DM specimens increased strength, whereas the greater values of pentosidine in the T2DM group decreased postyield strain and toughness. The long-term medical management and presence of osteoarthritis in these patients may influence these outcomes. Nevertheless, our data indicate a beneficial effect of T2DM on cancellous microarchitecture, but a deleterious effect of T2DM on the collagen matrix. These data suggest that high concentrations of advanced glycation endproducts can increase fragility by reducing the ability of bone to absorb energy before failure, especially for the subset of T2DM patients with low BV/TV. © 2019 American Society for Bone and Mineral Research.

Fangchinoline Ameliorates Diabetic Retinopathy by Inhibiting Receptor for Advanced Glycation End-Products (RAGE)-Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) Pathway in Streptozotocin (STZ)-Induced Diabetic Rats.

BackgroundDiabetic retinopathy (DR) is a macrovascular complication that occurs in diabetic patients. Conventional treatments for the management of DR have many limitations. Thus, the present investigation evaluated the protective effect of fangchinoline against diabetic retinopathy (DR).Material/MethodsDR was induced by streptozotocin (STZ; 60 mg/kg; i.p.) and rats were treated with fangchinoline 1, 3, and 10 mg/kg for 16 weeks. DR was confirmed by determining the concentration of advanced glycation end-products (AGEs) and morphology of retinal tissues. Parameters of oxidative stress and expression of inflammatory cytokines and receptor for advanced glycation end-products (RAGE) in the retinal tissue were determined by Western blot assay and reverse transcription polymerase chain reaction (RT-PCR). Moreover enzyme-linked immunosorbent assay (ELISA) was used to determine the apoptosis index and activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the retinal tissues.ResultsOur study reveals that the concentration of glycosylated hemoglobin (HbA1c) and glucose in the plasma and AGEs in the retinal tissue were significantly reduced in the fangchinoline group compared to the DR group. Moreover, treatment with fangchinoline attenuated the altered retinal morphology and expression of inflammatory mediators and RAGE in the retinal tissues of DR rats. There was a significant (p<0.01) decrease in oxidative stress, activity of NF-κB, and apoptosis index in the fangchinoline group compared to the DR group of rats.ConclusionsOur investigation shows that fangchinoline attenuates the apoptosis of retinal cells in STZ-induced diabetic retinopathy rats by inhibiting the RAGE/NF-κB pathway.

Glycation of Lys-16 and Arg-5 in amyloid-β and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer's disease.

Extensive research has linked the amyloid-beta (Aβ) peptide to neurological dysfunction in Alzheimer's disease (AD). Insoluble Aβ plaques in the AD patient brain contain high concentrations of advanced glycation end-products (AGEs) as well as transition metal ions. This research elucidated the roles of Aβ, sugars, and Cu2+ in the oxidative stress mechanism of AD at the molecular level. Mass spectral (MS) analysis of the reactions of Aβ with two representative sugars, ribose-5-phosphate (R5P) and methylglyoxal (MG), revealed Lys-16 and Arg-5 as the primary glycation sites. Quantitative analysis of superoxide [Formula: see text] production by a cyt c assay showed that Lys-16 generated four times as much [Formula: see text] as Arg-5. Lys-16 and Arg-5 in Aβ1-40 are both adjacent to histidine residues, which are suggested to catalyze glycation. Additionally, Lys-16 is close to the central hydrophobic core (Leu-17-Ala-21) and to His-13, both of which are known to lower the pKa of the residue, leading to increased deprotonation of the amine and an enhanced glycation reactivity compared to Arg-5. Gel electrophoresis results indicated that all three components of AD plaques-Aβ1-40, sugars, and Cu2+-are necessary for DNA damage. It is concluded that the glycation of Aβ1-40 with sugars generates significant amounts of [Formula: see text], owing to the rapid glycation of Lys-16 and Arg-5. In the presence of Cu2+, [Formula: see text] converts to hydroxyl radical (HO·), the source of oxidative stress in AD.