scholarly journals Development and Application of Mass Spectroscopy Assays for Nε-(1-Carboxymethyl)-L-Lysine and Pentosidine in Renal Failure and Diabetes

2020 ◽  
Vol 5 (3) ◽  
pp. 558-568
Author(s):  
Katherine L O’Grady ◽  
Sundeep Khosla ◽  
Joshua N Farr ◽  
Olga P Bondar ◽  
Elizabeth J Atkinson ◽  
...  
Keyword(s):  
Renal Failure ◽  
Mass Spectroscopy ◽  
Disease States ◽  
Glycation End Products ◽  
Control Versus ◽  
Development And Validation ◽  
Lower Limits ◽  
Circulating Levels ◽  
Separate Cohort

Abstract Background Advanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging. Methods We describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine. Results Serum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P < 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P < 0.001). Conclusions These mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

Development and validation of a tool for predicting type 2 diabetes in Mexican women of reproductive age

2020 ◽  
Vol 67 (9) ◽  
pp. 578-585
Author(s):  
Fabiola Mabel Del Razo-Olvera ◽  
Enrique Reyes-Muñoz ◽  
Rosalba Rojas-Martínez ◽  
Fernando Guerrero-Romero ◽  
Roopa Mehta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Reproductive Age ◽  
Mexican Women ◽  
Women Of Reproductive Age ◽  
Development And Validation

scholarly journals Role of Glucose-Lowering Medications in Erectile Dysfunction

2021 ◽  
Vol 10 (11) ◽  
pp. 2501
Author(s):  
Angelo Cignarelli ◽  
Valentina Annamaria Genchi ◽  
Rossella D’Oria ◽  
Fiorella Giordano ◽  
Irene Caruso ◽  
...  
Keyword(s):  
Erectile Dysfunction ◽  
Current Knowledge ◽  
Smooth Muscle Contractility ◽  
Glucose Lowering ◽  
Glycation End Products ◽  
Altered Metabolism

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

Development and Validation of a Chronic Kidney Disease Prediction Model for Type 2 Diabetes Mellitus in Thailand

2021 ◽  
Vol 24 ◽  
pp. 157-166
Author(s):  
Wilailuck Tuntayothin ◽  
Stephen John Kerr ◽  
Chanchana Boonyakrai ◽  
Suwasin Udomkarnjananun ◽  
Sumitra Chukaew ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Disease ◽  
Prediction Model ◽  
Disease Prediction ◽  
Development And Validation

scholarly journals PAR-4/Ca2+-calpain pathway activation stimulates platelet-derived microparticles in hyperglycemic type 2 diabetes

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Alessandra Giannella ◽  
Giulio Ceolotto ◽  
Claudia Maria Radu ◽  
Arianna Cattelan ◽  
Elisabetta Iori ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Normal Glucose Tolerance ◽  
Calpain Inhibitor ◽  
Pathway Activation ◽  
Normal Glucose ◽  
Circulating Levels ◽  
Dependent Mechanism

Abstract Background Patients with type 2 diabetes (T2DM) have a prothrombotic state that needs to be fully clarified; microparticles (MPs) have emerged as mediators and markers of this condition. Thus, we investigate, in vivo, in T2DM either with good (HbA1c ≤ 7.0%; GGC) or poor (HbA1c > 7.0%; PGC) glycemic control, the circulating levels of MPs, and in vitro, the molecular pathways involved in the release of MPs from platelets (PMP) and tested their pro-inflammatory effects on THP-1 transformed macrophages. Methods In 59 T2DM, and 23 control subjects with normal glucose tolerance (NGT), circulating levels of CD62E+, CD62P+, CD142+, CD45+ MPs were determined by flow cytometry, while plasma levels of ICAM-1, VCAM-1, IL-6 by ELISA. In vitro, PMP release and activation of isolated platelets from GGC and PGC were investigated, along with their effect on IL-6 secretion in THP-1 transformed macrophages. Results We found that MPs CD62P+ (PMP) and CD142+ (tissue factor-bearing MP) were significantly higher in PGC T2DM than GGC T2DM and NGT. Among MPs, PMP were also correlated with HbA1c and IL-6. In vitro, we showed that acute thrombin exposure stimulated a significantly higher PMP release in PGC T2DM than GGC T2DM through a more robust activation of PAR-4 receptor than PAR-1 receptor. Treatment with PAR-4 agonist induced an increased release of PMP in PGC with a Ca2+-calpain dependent mechanism since this effect was blunted by calpain inhibitor. Finally, the uptake of PMP derived from PAR-4 treated PGC platelets into THP-1 transformed macrophages promoted a marked increase of IL-6 release compared to PMP derived from GGC through the activation of the NF-kB pathway. Conclusions These results identify PAR-4 as a mediator of platelet activation, microparticle release, and inflammation, in poorly controlled T2DM.

Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells

2008 ◽  
Vol 294 (3) ◽  
pp. H1119-H1129 ◽  
Author(s):  
Susann Patschan ◽  
Jun Chen ◽  
Alla Polotskaia ◽  
Natalja Mendelev ◽  
Jennifer Cheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Umbilical Vein ◽  
Acid Sphingomyelinase ◽  
Premature Senescence ◽  
Human Umbilical Vein ◽  
Glycation End Products ◽  
Umbilical Vein Endothelial Cells ◽  
Stress Induced Premature Senescence

Our group (Patschan S, Chen J, Gealekman O, Krupincza K, Wang M, Shu L, Shayman JA, Goligorsky MS; Am J Physiol Renal Physiol 294: F100–F109, 2008) previously observed an accumulation of gangliosides coincident with development of cell senescence and demonstrated lysosomal permeabilization in human umbilical vein endothelial cells exposed to glycated collagen I (GC). Therefore, we investigated whether the lysosome-dependent, caspase-independent or type 2-programmed cell death (autophagy) is involved in development of premature senescence of endothelial cells. The cleaved microtubule-associated protein 1 light-chain 3 (LC3), a marker of autophagosome formation, was overexpressed within 24 h of GC treatment; however, by 4–5 days, it was nearly undetectable. Early induction of autophagosomes was associated with their fusion with lysosomes, a phenomenon that later became subverted. Autophagic cell death can be triggered by the products of damaged plasma membrane, sphingolipids, and ceramide. We observed a clustering of membrane rafts shortly after exposure to GC; later, after 24 h, we observed an internalization, accompanied by an increased acid sphingomyelinase activity and accumulation of ceramide. Pharmacological inhibition of autophagy prevented development of premature senescence but did lead to the enhanced rate of apoptosis in human umbilical vein endothelial cells exposed to GC. Pharmacological induction of autophagy resulted in reciprocal changes. These observations appear to represent a mechanistic molecular cascade whereby advanced glycation end products like GC induce sphingomyelinase activity, accumulation of ceramide, clustering, and later internalization of lipid rafts.

Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness

2015 ◽  
Vol 309 (8) ◽  
pp. L789-L800 ◽  
Author(s):  
Akihiko Taniguchi ◽  
Nobuaki Miyahara ◽  
Koichi Waseda ◽  
Etsuko Kurimoto ◽  
Utako Fujii ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Allergic Airway Inflammation ◽  
T Helper ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Group 2 ◽  
Airway Responses

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE−/− mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

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