Plasma Levels Of AGEs Research Articles

Associations of Advanced Glycation End Products with Sleep Disorders in Chinese Adults.

Advanced glycation end products (AGEs), a group of food processing byproducts, have been implicated in the development of various diseases. However, the relationship between circulating AGEs and sleep disorders remains uncertain. This cross-sectional study elucidated the association of plasma AGEs with sleep disorders among 1732 Chinese adults who participated in the initial visit (2019-2020) of the Tongji-Shenzhen Cohort (TJSZC). Sleep behavior was assessed using self-reported questionnaires and precise accelerometers. Plasma levels of AGEs, including Nε-(Carboxymethyl)lysine (CML), Nε-(Carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine (MG-H1), were quantified by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In logistic regression, per IQR increment in individual AGEs was associated with an increased odds ratio of short sleep duration (CML: 1.11 [1.00, 1.23]; CEL: 1.16, [1.04, 1.30]), poor sleep quality (CML: 1.33 [1.10, 1.60]; CEL: 1.53, [1.17, 2.00]; MG-H1: 1.61 [1.25, 2.07]), excessive daytime sleepiness (CML: 1.33 [1.11, 1.60]; MG-H1: 1.39 [1.09, 1.77]), and insomnia (CML: 1.29 [1.05, 1.59]). Furthermore, in weighted quantile sum regression and Bayesian kernel machine regression analyses, elevated overall exposure levels of plasma AGEs were associated with an increased risk of sleep disorders, including short sleep duration, poor sleep quality, excessive daytime sleepiness, and insomnia, with CML being identified as the leading contributor. Insufficient vegetable intake and higher dietary fat intake was associated with an increase in plasma CEL. These findings support a significant association between plasma AGEs and sleep disorders, indicating that AGEs may adversely influence sleep health and reducing the intake of AGEs may facilitate preventing and ameliorating sleep disorders.

Accumulation of advanced glycation end products (AGEs) is associated with the severity of aortic stenosis in patients with concomitant type 2 diabetes

BackgroundAccumulation of advanced glycation end products (AGEs) leads to chronic glycation of proteins and tissue damage, particularly in patients with diabetes mellitus (DM). We aimed to evaluate whether increased accumulation of AGEs in patients with aortic stenosis (AS) and concomitant type 2 diabetes (DM) is associated with AS severity.MethodsWe prospectively enrolled 76 patients with severe AS (47.1% males; nonDM), aged 68 [66–72] years, and 50 age-matched DM patients with a median blood glucose level of 7.5 [5.9–9.1] mM and glycated hemoglobin (HbA1c) of 6.8 [6.3–7.8]%, scheduled for aortic valve replacement. Valvular expression of AGEs, AGEs receptor (RAGE), interleukin-6 (IL-6), and reactive oxygen species (ROS) induction were evaluated ex vivo by immunostaining and calculated as the extent of positive immunoreactive areas/total sample area. Plasma levels of AGEs and soluble RAGE (sRAGE) were assessed by ELISAs.ResultsSubjects with DM had increased valvular expression of both AGEs (6.6-fold higher, 15.53 [9.96–23.28]%) and RAGE (1.8-fold higher, 6.8 [4.9–8.45]%) compared to nonDM patients (2.05 [1.21–2.58]% and 2.4 [1.56–3.02]%, respectively; both p < 0.001). Plasma levels of AGEs (12-fold higher) and sRAGE (1.3-fold higher) were elevated in DM patients, compared to nonDM (both p < 0.0001). The percentage of valvular ROS-positive (2.28 [1.6–3.09] vs. 1.15 [0.94–1.4]%, p < 0.0001) but not IL-6-positive areas was higher within DM, compared to nonDM valves. In DM patients, the percentage of valvular AGEs- and RAGE-positive areas correlated with HbA1c (r = 0.77, p < 0.0001 and r = 0.30, p = 0.034). Similarly, plasma AGEs and sRAGE levels were associated with HbA1c in the DM group (r = 0.32, p = 0.024 and r = 0.33, p = 0.014, respectively). In all DM patients, we found an association between the amount of valvular AGEs and the disease severity measured as aortic valve area (AVA; r = 0.68, p < 0.0001). Additionally, in DM patients with HbA1c > 7% (n = 24, 48%) we found that valvular expression of AGEs correlated with mean transvalvular pressure gradient (PGmean; r = 0.45, p = 0.027). Plasma AGEs levels in the whole DM group correlated with AVA (r = − 0.32, p = 0.02), PGmean (r = 0.31, p = 0.023), and PGmax (r = 0.30, p = 0.03).ConclusionsOur study suggests that poorly-controlled diabetes leads to increased AGEs and RAGE valvular accumulation, which at least partially, might result in AS progression in DM patients.

Advanced glycation end product levels were correlated with inflammation and carotid atherosclerosis in type 2 diabetes patients.

Diabetes mellitus with atherosclerosis (AS) adds to the social burden. This study aimed to investigate whether advanced glycation end product (AGE) levels were correlated with inflammation and carotid AS (CAS) in type 2 diabetes mellitus (T2DM) patients. A total of 50 elderly T2DM patients and 50 age-matched senior healthy subjects were recruited in this study. T2DM patients were classified into two groups based on the intima–media thickness (IMT) of the carotid artery from color Doppler ultrasonography. Patients with IMT > 1 mm were classified into the T2DM + CAS group (n = 28), and patients with IMT < 1 mm were assigned as the T2DM + non-atherosclerosis (NAS) group (n = 22). The plasma levels of AGEs, receptor for AGE (RAGE), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) of all subjects were measured by enzyme-linked immunosorbent assay. The T-lymphocyte subsets were analyzed by a flow detector. T2DM + CAS patients showed significantly higher concentrations of AGEs, RAGE, TNF-α, and IFN-γ in the peripheral blood. The highest levels of CD4+ T cells were observed in the T2DM + CAS group. The AGE level was positively correlated with the concentrations of RAGE, TNF-α, IFN-γ, and CD4+. In summary, the results showed that the levels of AGEs may be correlated with the inflammatory status in T2DM patients with CAS.

P0152EFFECT OF LOSARTAN ON AMBULATORY SHORT-TERM BLOOD PRESSURE VARIABILITY AND CARDIOVASCULAR REMODELING IN HYPERTENSIVE PATIENTS ON HEMODIALYSIS

Abstract Background and Aims Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. Method 40 hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. Results After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. Conclusion These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.

High Plasmatic Levels of Advanced Glycation End Products are Associated with Metabolic Alterations and Insulin Resistance in Preeclamptic Women.

The purpose of this study was to investigate the association between plasmatic levels of advanced end glycation products (AGEs) and the metabolic profile in subjects diagnosed with preeclampsia, due to the known relation of these molecules with oxidative stress and inflammation, which in turn are related with PE pathogenesis. It has been reported that increased levels of AGEs are observed in patients with preeclampsia as compared with healthy pregnant subjects, which was mainly associated with oxidative stress and inflammation. Besides, in women with preeclampsia, there are metabolic changes such as hyperinsulinemia, glucose intolerance, dyslipidemia, among others, that are associated with an exacerbated insulin resistance. Additionally, some parameters indicate the alteration of hepatic function, such as increased levels of liver enzymes. However, the relationship of levels of AGEs with altered lipidic, hepatic, and glucose metabolism parameters in preeclampsia has not been evaluated. To investigate the association between plasmatic levels of AGEs and hepatic, lipid, and metabolic profiles in women diagnosed with preeclampsia. Plasma levels of AGEs were determined by a competitive enzyme-linked immunosorbent assay (ELISA) in 15 patients diagnosed with preeclampsia and 28 normoevolutive pregnant subjects (control group). Hepatic (serum creatinine, gammaglutamyl transpeptidase, aspartate transaminase, alanine transaminase, uric acid, and lactate dehydrogenase), lipid (apolipoprotein A, apolipoprotein B, total cholesterol, triglycerides, low-density lipoproteins, and high-density lipoproteins), and metabolic variables (glucose, insulin, and insulin resistance) were assessed. Plasmatic levels of AGEs were significantly higher in patients with preeclampsia as compared with the control. A positive correlation between circulating levels of AGEs and gamma-glutamyl transpeptidase, uric acid, glucose, insulin, and HOMA-IR levels was found in patients with preeclampsia. In conclusion, circulating levels of AGEs were higher in patients with preeclampsia than those observed in healthy pregnant subjects. Besides, variables of hepatic and metabolic profile, particularly those related to insulin resistance, were higher in preeclampsia as compared with healthy pregnant subjects. Interestingly, there is a positive correlation between AGEs levels and insulin resistance. Circulating levels of AGEs were higher in patients with preeclampsia than those observed in healthy pregnant subjects. Besides, hepatic and metabolic profiles, particularly those related to insulin resistance, were higher in preeclampsia as compared with healthy pregnant subjects. Interestingly, there is a positive correlation between AGEs levels and insulin resistance, suggesting that excessive glycation and an impaired metabolic profile contribute to the physiopathology of preeclampsia.

Bradykinin and oxidative stress in patients with hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema (HAE) is a rare autosomal dominant disease caused by genetic dysfunction of C1 inhibitor (C1-INH) due to mutations in the SERPING1 gene. The disorder is mediated mainly by bradykinin. The clinical course of the disease is varied and not related to genetic changes. We aimed to evaluate redox homeostasis of peripheral blood mononuclear cells (PBMCs) in patients with HAE due to C1-INH deficiency (C1 INH HAE) by measuring the levels of reactive oxygen species (ROS) of PBMCs as well as plasma advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). We also aimed to assess the effect of bradykinin on ROS levels. We enrolled 30 adults with C1-INH-HAE and 15 healthy individuals. The levels of ROS were measured by flow cytometry, while the plasma levels of AGEs and AOPPs were determined spectrophotometrically by enzyme‑ linked immunosorbent assays. Basal and hydrogen peroxide (H2O2)-induced ROS levels were higher in patients with HAE when compared with controls (P = 0.002 and P = 0.001, respectively), indicating abnormalities in redox homeostasis. Plasma AOPP and AGE levels were similar in both groups. Bradykinin reduced basal and H2O2-induced ROS generation in PBMCs only in patients with HAE (P = 0.03). The higher basal and H2O2-induced ROS levels in patients with C1 INH HAE indicate redox imbalance. However, by reducing basal and H2O2-induced ROS levels, bradykinin shows antioxidant action in this disorder.

Characterization of advanced glycation end products and their receptor (RAGE) in an animal model of myocardial infarction.

Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.

Relationship between advanced glycation end products and gestational diabetes mellitus

Objective: To investigate the levels of and dynamic changes of advanced glycation end products (AGEs) in maternal plasma during pregnancy and explore the association between these levels and gestational diabetes mellitus (GDM).Methods: This study recruited 90 GDM women and 90 healthy pregnant controls. The women received prenatal care and were hospitalized for delivery in Peking University First Hospital in China between October 2015 and April 2016. The patients were recruited and provided blood samples during gestational weeks 24–29. The levels of AGEs, TNF-α, hs-CRP, plasma glucose, and FINS and lipid profiles were measured, and HOMA-IR was calculated. New blood samples were collected and AGE was measured again in the two groups at 33–41 weeks of gestation to identify its dynamic changes.Results: The levels of AGEs were significantly higher in the GDM group than in the NGT group at both 24–29 weeks (473.65 ± 105.32 versus 324.36 ± 57.86 ng/L; p < .001) and 33–41 weeks (533.47 ± 146.95 versus 315.50 ± 77.79 ng/L; p < .001), and plasma levels of TNF-α and hs-CRP were significantly higher in the GDM group than in the NGT group (282.58 ± 45.85 versus 177.54 ± 35.14 pg/mL; 1.11 ± 0.25 versus 0.6 ± 0.19 µg/mL; p < .001), even after adjusting for other confounding factors, AGE levels were positively correlated with the levels of 2hPG (p = .003), TNF-α (p = .005), and hs-CRP (p < .001). A logistic regression analysis showed that AGE (OR = 1.037, 95%CI: 1.017 ∼ 1.058) and TNF-α (OR = 1.115, 95%CI: 1.048 ∼ 1.186) levels were independent risk factors for GDM. In the GDM group, the concentration of AGEs was significantly higher at 33–41 weeks than at 24–29 weeks (p = .001). In the NGT group, there was no significant change in the concentration of AGEs between the two gestational periods (p = .388).Conclusions: Plasma levels of AGEs are associated with GDM. During pregnancy, the changes observed in the levels of AGEs were different between GDM and normal pregnancies.

Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension?

There is a close relationship between arterial stiffness and blood pressure. The studies suggest that the advanced glycation end products (AGEs) and its cell receptor (RAGE) are involved in the arterial stiffness in two ways: changes in arterial structure and vascular function. Plasma levels of AGEs and expression of RAGE are elevated, while the levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are lowered in patients with hypertension (HTN). There is a positive correlation between plasma levels of AGEs and arterial stiffness, and an inverse association between arterial stiffness/HTN, and serum levels of sRAGE and esRAGE. Various measures can reduce the levels of AGEs and expression of RAGE, and elevate sRAGE. Arterial stiffness and blood pressure could be reduced by lowering the serum levels of AGEs, and increasing the levels of sRAGE. Levels of AGEs can be lowered by reducing the consumption of AGE-rich diet, short duration of cooking in moist heat at low temperature, and cessation of cigarette smoking. Drugs such as aminoguanidine, vitamins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin inhibit AGE formation. Alagebrium, an AGE breakers reduces levels of AGEs. Clinical trials with some drugs tend to reduce stiffness. Systemic administration of sRAGE has beneficial effect in animal studies. In conclusion, AGE-RAGE axis is involved in arterial stiffness and HTN. The studies suggest that inhibition of AGEs formation, reduction of AGE consumption, blockade of AGE-RAGE interaction, suppression of RAGE expression, and exogenous administration of sRAGE may be novel therapeutic strategies for treatment of arterial stiffness and HTN.

Association between Advanced Glycation End Products and Impaired Fasting Glucose: Results from the SALIA Study.

Advanced glycation end products (AGEs) may contribute to the development of type 2 diabetes and related complications, whereas their role in the early deterioration of glycaemia is unknown. While previous studies used antibody-based methods to quantify AGEs, data from tandem mass spectrometry coupled liquid chromatography (LC-MS/MS)-based measurements are limited to patients with known diabetes. Here, we used the LC-MS/MS method to test the hypothesis that plasma AGE levels are higher in individuals with impaired fasting glucose (IFG) than in those with normal fasting glucose (NFG). Secondary aims were to assess correlations of plasma AGEs with quantitative markers of glucose metabolism and biomarkers of subclinical inflammation. This study included on 60 women with NFG or IFG (n = 30 each, mean age 74 years) from the German SALIA cohort. Plasma levels of free metabolites (3-deoxyfructose, 3-deoxypentosone, 3-deoxypentulose), two hydroimidazolones, oxidised adducts (carboxymethyllysine, carboxyethyllysine, methionine sulfoxide) and Nε-fructosyllysine were measured using LC-MS/MS. Plasma concentrations of all tested AGEs did not differ between the NFG and IFG groups (all p>0.05). Associations between plasma levels of AGEs and fasting glucose, insulin and HOMA-IR as a measure of insulin resistance were weak (r between -0.2 and 0.2, all p>0.05). The association between 3-deoxyglucosone-derived hydroimidazolone with several proinflammatory biomarkers disappeared upon adjustment for multiple testing. In conclusion, plasma AGEs assessed by LC-MS/MS were neither increased in IFG nor associated with parameters of glucose metabolism and subclinical inflammation in our study. Thus, these data argue against strong effects of AGEs in the early stages of deterioration of glucose metabolism.

The potential role of advanced glycation end products (AGEs) and soluble receptors for AGEs (sRAGE) in the pathogenesis of adult-onset still's disease.

BackgroundAccumulating evidence has demonstrated a pathogenic role of advanced glycation end products (AGEs) and receptors for AGEs (RAGE) in inflammation. Soluble RAGE (sRAGE), with the same ligands-binding capacity as full-length RAGE, acts as a “decoy” receptor. However, there has been scanty data regarding AGEs and sRAGE in adult-onset Still’s disease (AOSD). This study aimed to investigate AGEs and sRAGE levels in AOSD patients and examine their association with clinical characteristics.MethodsUsing ELISA, plasma levels of AGEs and sRAGE were determined in 52 AOSD patients, 36 systemic lupus erythematosus(SLE) patients and 16 healthy controls(HC). Their associations with activity parameters and disease courses were evaluated.ResultsSignificantly higher median levels of AGEs were observed in active AOSD patients (16.75 pg/ml) and active SLE patients (14.80 pg/ml) than those in HC (9.80 pg/ml, both p < 0.001). AGEs levels were positively correlated with activity scores (r = 0.836, p < 0.001), ferritin levels (r = 0.372, p < 0.05) and CRP levels (r = 0.396, p < 0.005) in AOSD patients. Conversely, significantly lower median levels of sRAGE were observed in active AOSD patients (632.2 pg/ml) and active SLE patients (771.6 pg/ml) compared with HC (1051.7 pg/ml, both p < 0.001). Plasma sRAGE levels were negatively correlated with AOSD activity scores (r = −0.320, p < 0.05). In comparison to AOSD patients with monocyclic pattern, significantly higher AGEs levels were observed in those with polycyclic or chronic articular pattern. With treatment, AGEs levels declined while sRAGE levels increased in parallel with the decrease in disease activity.ConclusionThe elevation of AGEs levels with concomitant decreased sRAGE levels in active AOSD patients, suggests their pathogenic role in AOSD.

Plasma Levels of Advanced Glycation End Products Are Related to the Clinical Presentation and Angiographic Severity of Symptomatic Lower Extremity Peripheral Arterial Disease.

Evidence implicates a role of advanced glycation end products (AGEs) in the development of atherosclerosis. The present study examined the relationship between plasma levels of AGEs and the clinical and angiographic characteristics of patients with symptomatic peripheral arterial disease (PAD). A total of 40 consecutive patients with symptomatic lower extremity PAD undergoing invasive evaluation were enrolled. Clinical history, angiographic data, and plasma levels of total AGE (tAGE), N'-carboxymethyllysine (CML), and high-sensitivity C-reactive protein were obtained. In multivariate analyses, there were independent relationships noted between tAGE levels and the presence of critical limb ischemia (CLI) (r (2) = 0.195, p = 0.003), Rutherford stage (r (2) = 0.351, p < 0.001), and the average below the knee (BTK) score (r (2) = 0.119, p = 0.006). Presence of CLI (r (2) = 0.154, p = 0.012) and the Rutherford stage (r (2) = 0.194, p = 0.003) were associated with CML levels. We demonstrate a relationship between tAGE and the symptom profile of patients with PAD and an association between tAGE and infrapopliteal angiographic disease severity. Both tAGE and CML levels were related to the presence of CLI. These data suggest that AGE levels may reflect the severity of PAD and may be of importance in CLI.

Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular remodeling in hypertensive patients on hemodialysis

Objective Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. Methods Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group ( n = 20) or the control treatment group ( n = 20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. Results After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. Conclusion These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.

Effects of Astragalous Injection on oxidative stress status in maintenance hemodialysis patients

To analyze the effects of Astragalous Injection on oxidative stress and micro-inflammatory status in patients undergoing maintenance hemodialysis (MHD). Sixty MHD patients were included and randomized into treatment group and control group, with another 10 healthy volunteers as normal control. The patients in the treatment group were treated with Astragalous Injection and the patients in the control group were treated with normal saline for 12 weeks. A spectrophotometric method was used for the measurement of plasma concentrations of oxidative parameters including advanced glycation end products (AGEs), advanced oxidation protein product (AOPP), malondialdehyde (MDA) and vitamin E (Vit E). The content of C-reactive protein (CRP) was evaluated by enzyme-linked immunosorbent assay. Compared with the normal control group, the plasma levels of AGEs, AOPP, MDA and CRP were significantly increased, while plasma level of Vit E was significantly decreased in MHD patients ( P<0.01). After Astragalous Injection treatment, the plasma levels of AGEs, AOPP, MDA and CRP were decreased as compared with the control group ( P<0.01), while there was no significant difference in plasma Vit E level between the treatment group and control group. There exist oxidative stress and micro-inflammation in MHD patients. Astragalous Injection can ameliorate the accumulation of oxidative products and micro-inflammatory status, but it has no significant effect on plasma Vit E level.

Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient

Advanced glycation of proteins and their attendant advanced glycation end products (AGEs) contribute to the complications associated with diabetes mellitus or uremia. Regulatory mechanisms of AGE formation in vivo remain an issue of particular interest. We investigated a role of the glyoxalase detoxification system of precursor reactive carbonyl compounds (RCOs) in the in vivo AGE formation. Plasma levels of AGEs [pentosidine and Nepsilon-carboxymethyllysine (CML)], their RCO precursors, d-lactate (the final product resulting from the glyoxalase detoxification pathway), as well as of various compounds known to generate AGE precursors and surrogate markers for oxidative stress (antioxidant enzymes and glutathione), were measured in both hemodialysis (HD) patients and normal subjects. The activity and protein expression of glyoxalase I, an enzyme essential for the detoxification of alpha-oxoaldehydes, in red blood cells (RBC) were also examined. In one 69-year-old lady who had been on hemodialysis (HD) for three years and had suffered from recurrent cardiovascular complications despite the absence of significant risk factors, plasma levels of pentosidine (77.3 +/- 2.4 pmol/mg protein) and CML (330.8 +/- 8.2 pmol/mg protein) were markedly elevated as compared to other HD patients (N = 20: 26.6 +/- 11.8 pmol/mg protein for pentosidine and 224.4 +/- 51.7 pmol/mg protein for CML). The plasma level of RCO precursors for pentosidine and CML was also higher in this patient than in other HD patients. Further investigation disclosed a very low activity in RBC of glyoxalase I (1.5 +/- 0.4 mU/106 RBC), as compared to other HD patients (3.9 +/- 0.6 mU/106 RBC) or normal subjects (4.0 +/- 0.6 mU/106 RBC). The glyoxalase I protein level, assessed in RBC by immunoblot analysis with a specific antibody, was markedly lower than that observed in HD patients and normal subjects. The causes of this deficiency remain unknown. Nucleotide sequencing of the products of reverse transcription-polymerase chain reaction from the patient's mononuclear cells revealed no genetic mutation within the coding region of the glyoxalase I gene. Plasma d-lactate level was also in the lower range (0.18 +/- 0.03 mg/dL) of the values measured in the other HD patients (0.27 +/- 0.09 mg/dL) and normal subjects (0.35 +/- 0.12 mg/dL). The plasma levels of various compounds known to generate AGE precursors (glucose, lipids and ascorbic acid) were either normal or low. The surrogate markers for oxidative stress such as antioxidant enzymes (glutathione peroxidases and superoxide dismutase) and glutathione were all within the range observed in the other HD patients. The unusually high levels of AGEs in this patient implicate a deficient glyoxalase detoxification of RCO precursors. The present clinical observation implicates, to our knowledge for the first time, the glyoxalase detoxification system and, in particular, glyoxalase in the actual level of AGEs in a uremic patient.