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Advanced glycation end-products: A review

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Advanced glycation end-products: A review

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Abstract

Advanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occurring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications.

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... [11,12] AGEs accumulate in various body tissues, including the dermis, amyloid plaques, coronary atheroma, renal cortex, basement membrane, cartilage, cardiac muscle, lungs and the liver. Therefore, increasing AGE levels in plasma has been associated with a broad range of diseases including diabetes, Alzheimer's disease, rheumatoid arthritis, atherosclerosis, etc. [13,14] Some exogenous causes have been identified as sources of AGEs including diet and smoking. Fried, baked or processed food can form AGEs during food processing which are then ingested into the human body. ...
... The formation of the reactive irreversible compounds and the stable AGEs occurs over a period of week(s); thus, it affects long-living proteins. [13] It was found that the rate of glycation end product formation and reactivity are depended upon the amount of sugar available in an openchain form. For example, both fructose and galactose are more available in open forms than glucose; therefore, the former two sugars have a greater glycation rate and reactivity than glucose. ...
... [25] 3-deoxyglucosone (3-DG) can also form during the polyol pathway. [13] The termination phase (Figure 2c) is the third and final phase of the Maillard reaction. In this phase, Amadori products can further react with amine groups in proteins to form intra-and inter-molecular crosslinks and protein-AGE adducts that build up inside and outside the cells and compromise protein normal function. ...
Article
Objectives Ageing is a major cause of multiple age-related diseases. Several mechanisms have been reported to contribute to these abnormalities including glycation, oxidative stress, the polyol pathway and osmotic stress. Glycation, unlike glycosylation, is an irregular biochemical reaction to the formation of active advanced glycation end-products (AGEs), which are considered to be one of the causes of these chronic diseases. This study provides a recent and comprehensive review on the possible causes, mechanisms, types, analytical techniques, diseases and treatments of the toxic glycation end products. Key findings Several mechanisms have been found to play a role in generating hyperglycaemia-induced oxidative stress including an increase in the levels of reactive oxygen species (ROS), increase in the levels of AGEs, binding of AGEs and their receptors (RAGE) and the polyol pathway and thus have been investigated as promising novel targets. Summary This review focuses on the key mechanisms attributed to cumulative increases of glycation and pathological RAGE expression as a significant cause of multiple age-related diseases, and reporting on different aspects of antiglycation therapy as a novel approach to managing/treating age-related diseases. Additionally, historical, current and possible future antiglycation approaches will be presented focussing on novel drug delivery methods.
... Interestingly, the pathogenesis and development of several NCDs have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs) [5,6]. AGEs are a heterogeneous group of compounds whose synthesis frequently begins with the non-enzymatic glycation of proteins [7]. The abnormal AGEs accumulation in human body tissues produces deleterious effects involving protein dysfunction, which arises from changes in their conformation (in some cases, AGEs may produce cross-links between proteins), function, and half-life. ...
... Endophytes comprise mainly fungi and bacteria, but it also includes archaea and protists that live in the internal tissues and organs of plants (leaves, stems, flowers, fruits, seeds, or roots). Some endophytes do not cause apparent signs of disease in their host plants [20]; other may even be beneficial to their host [7], while some could become opportunistic pathogens under particular circumstances [1]. The above depends on the plant and microbial genotype, quorum sensing, co-colonizing microbiota, and environmental conditions [1,21,22]. ...
... AGEs are a heterogeneous group of molecules whose formation usually involves non-enzymatic reactions of reducing sugars with proteins through the Maillard reaction [7]. The endogenous formation of AGEs is shown in Figure 1. ...
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Endophytes, microorganisms that live in the internal tissues and organs of the plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. For such reason, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest. Currently, many non-communicable diseases are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailment related to chronic inflammation and ageing. Intriguingly, the pathogenesis and development of these diseases have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs). AGEs are a heterogeneous group of compounds that can alter the conformation, function, and lifetime of proteins. Therefore, compounds that prevent the formation and consequent accumulation of AGEs (AntiAGEs compounds) could be useful to delay the progress of some chronic diseases, and/or harmful effects of undue AGEs accumulation. Despite the remarkable ability of endophytes to produce bioactive compounds, most of the natural antiAGEs compounds reported in the literature are derived from plants. Accordingly, this work covers 26 plant antiAGEs compounds and some derivatives that have been reported as endophytic metabolites, and discusses the importance, possible advantages, and challenges of using endophytes as a potential source of antiAGEs compounds.
... The heterogeneous group of advanced glycation end products (AGEs) are formed as a result of non-enzymatic attachment of glucose to proteins such as type I collagen, lipids, or nucleic acids through Maillard's reaction [1][2][3][4]. Tissues undergo unfavorable structural and functional modifications when AGEs accumulate, and subsequent binding to the receptor for advanced glycation end products (RAGE) occurs [3,5]. The accumulation of AGEs on tissue proteins has been implicated in playing a critical role in various settings such as aging, diabetes, cardiovascular diseases, Alzheimer's disease, and acute or chronic oxidative stress such as renal failure [6][7][8]. ...
... (1). ICC for intrarater reliability.(2). ...
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Background: Advanced glycation end products (AGEs) have been shown to accumulate in bone and are gaining interest in connective tissue research. Aims: To investigate the intrarater reliability, two-timepoint agreement and correlations within and between two commercially available skin autofluorescence (SAF) AGE devices. Methods: Healthy volunteers were enrolled in a prospective study at a single academic institution. Each participant underwent SAF analysis by two different, commercially available devices on two occasions, 14 days apart. Upon enrollment, a general survey about the participant's lifestyle and health status was completed and followed up on for any changes at timepoint two. Results: In total, 40 participants (F:M ratio 5:3) with an average age of 39.0 ± 12.5 years were analyzed. For the AGE reader (skin) and AGE sensor (fingertip), both intrarater reliability and two-timepoint agreement were excellent with an interclass correlation coefficient (ICC) > 0.90 and a strong correlation within both machines. However, there was no correlation between both machines for either timepoint. In total, 4 participants were identified as outliers above the +2SD. Additionally, 5 participants with dark-colored skin could not be measured with the AGE reader at timepoint one and 4 at timepoint two. In contrast, all participants were able to undergo SAF analysis with the AGE sensor, irrespective of their skin type. Conclusions: Both machines showed excellent intrarater reliability and two-timepoint agreement, but the skin AGE reader might have limited applicability in individuals with dark-colored skin. Future research on AGEs might take our findings into consideration.
... AGEs are the direct cause of various complications in diabetes patients. It is formed by the non-enzymatic catalytic reaction of -NH 2 in proteins, fatty acids or nucleic acids with -COin reducing sugars such as glucose, fructose and pentose to form compounds. 35 The accumulation of AGEs in the body will cause a range of pathologies. Therefore, the direct use of AGEs to construct a diabetic cell model is closer to the real human condition than a diabetic model constructed using a high glucose medium. ...
... The accumulation of AGEs in the body can lead to various complications of diabetes, and therefore AGEs are the key factor that affects the cells in the body. 35 Diabetes models constructed by incorporating AGEs are closer to the in vivo cytopathic conditions of diabetic patients than those constructed from cells cultured in high glucose. ...
Article
Drug-derived carbon dots (CDs) not only have excellent photoluminescence properties of CDs, but also maintain pharmacological effects of original drugs, so as to realize extended applications for both bioimaging and chemotherapy. In this work, metformin (Met)-derived CDs (Met-CDs) as multifunctional nanocarriers with tumor cell imaging and cancer therapy are synthesized using Met and citric acid as precursors. The created Met-CDs exhibit obvious resistance to photobleaching, significant pH sensitivity in acidic environments, good pH stability in alkaline environments, and high temperature sensitivity. In addition, we further investigate the biological activity of Met-CDs using the diabetic cell models, which demonstrate the ability of Met-CDs to treat diabetes and reduce the production of reactive oxygen species in diseased cells. Subsequently, human alveolar adenocarcinoma basal epithelial cells (A549) are cultured in both normal glucose and low glucose mediums, and different concentrations of Met and Met-CDs are added to investigate the effect of Met-CDs on A549 cells. Finally, we successfully utilize the prepared Met-CDs to image live A549 cells in vitro in normal glucose medium. The Met-CDs prepared in this work reveal high potential to be used as both fluorescent probes and drug agents for tumor therapy, realizing controllable integrated diagnosis and treatment of diseases.
... The protein, receptor for advanced glycation end-products (RAGE), was initially reported as the receptor for advanced glycation end-products (AGEs) [6], which are a broad and heterogeneous group of compounds derived from structural modifications of proteins, lipids, and nucleic acids, which become non-enzymatically glycated by reducing sugars [7]. Although these compounds were originally described in the well-known Maillard reaction, AGEs are also endogenously synthesized by a non-enzymatic reaction involving a glycation/condensation process between reducing sugars, such as glucose and fructose, and the free amino group of different biomolecules, such as proteins, lipids, and nucleic acids, to initially form Schiff bases, which are subsequently converted to intermediate glycation products, known as Amadori products [8]. ...
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The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.
... In diabetic condition, CML-modified proteins may exhibit structural alterations, thereby resulting in dysfunction of these proteins. Moreover, CML-modified protein also activates RAGE pathway, jointly accelerating the development of various vasculopathies (i.e., macrovascular and microvascular diseases) in diabetes [5,[9][10][11][12][13]. However, the relation of CML to coronary collateralization in diabetic patients with chronic total occlusion (CTO) remains unclear. ...
Article
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Background The formation of advanced glycation end-products (AGEs) is a crucial risk factor for the pathogenesis of cardiovascular diseases in diabetes. We investigated whether N-epsilon-carboxymethyllysine (CML), a major form of AGEs in vivo, was associated with poor coronary collateral vessel (CCV) formation in patients with type 2 diabetes mellitus (T2DM) and chronic total occlusion (CTO) of coronary artery. Methods This study consisted of 242 T2DM patients with coronary angiographically documented CTO. Blood samples were obtained and demographic/clinical characteristics were documented. The coronary collateralization of these patients was defined according to Rentrop or Werner classification. Serum CML levels were evaluated using ELISA assay. Receiver operating characteristic curve and multivariable regression analysis were performed. Results 242 patients were categorized into poor CCV group or good CCV group (107 vs. 135 by the Rentrop classification or 193 vs. 49 by the Werner classification, respectively). Serum CML levels were significantly higher in poor CCV group than in good CCV group (110.0 ± 83.35 vs. 62.95 ± 58.83 ng/ml by the Rentrop classification and 94.75 ± 78.29 ng/ml vs. 40.37 ± 28.69 ng/ml by Werner classification, both P < 0.001). Moreover, these CML levels were also significantly different across the Rentrop and Werner classification subgroups (P < 0.001). In multivariable logistic regression, CML levels (P < 0.001) remained independent determinants of poor CCV according to the Rentrop or Werner classification after adjustment of traditional risk factors. Conclusions This study suggests that higher serum CML level is associated with poor collateralization in T2DM patients with CTO.
... The receptor for advanced glycation end products (RAGE) is a new member of the immunoglobulin superfamily, which is involved in the occurrence and development of chronic complications of diabetes. It is also associated with inflammation, tumor invasion and metastasis, and nerve regeneration (33,34). The calcium-dependent protein binding function may be related to cellular signal transduction and various biological processes ( Figures 5A, B) (35,36). ...
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Diabetes mellitus is a metabolic disorder that increases fracture risk and interferes with bone formation and impairs fracture healing. Genomic studies on diabetes and fracture healing are lacking. We used a weighted co-expression network analysis (WGCNA) method to identify susceptibility modules and hub genes associated with T2DM and fracture healing. First, we downloaded the GSE95849, GSE93213, GSE93215, and GSE142786 data from the Gene Expression Omnibus (GEO) website, analyzed differential expression genes and constructed a WGCNA network. Second, we screened out 30 hub genes, which were found to be enriched in neutrophil activation, translational initiation, RAGE receptor binding, propanoate metabolism, and other pathways through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses. Third, we searched for genes related to bone metabolism and fracture healing in the published genome-wide single nucleotide polymorphism (SNP) data, built a protein-protein interaction (PPI) network with hub genes, and found that they were associated with metabolic process, blood vessel development, and extracellular matrix organization. ANXA3 was identified as the biomarker based on gene expression and correlation analysis. And the AUC value of it was 0.947. Fourth, we explored that ANXA3 was associated with neutrophils in fracture healing process by single-cell RNA sequencing analysis. Finally, we collected clinical patient samples and verified the expression of ANXA3 by qRT-PCR in patents with T2DM and fracture non-union. In conclusion, this is the first genomics study on the effect of T2DM on fracture healing. Our study identified some characteristic modules and hub genes in the etiology of T2DM-associated fracture non-union, which may help to further investigate the molecular mechanisms. Up-regulated ANXA3 potentially contributed to fracture non-union in T2DM by mediating neutrophils. It can be a prognostic biomarker and potential therapeutic target.
... We previously identified a subpopulation of SCZ characterized by high plasma pentosidine (PEN-SCZ) [3]. Pentosidine, an advanced glycation end product, is a biological marker of glycation and oxidative stress [4]. Based on these findings, we conducted a 24-week, open-label design clinical trial of pyridoxal in patients with SCZ, partially confirming its efficacy (UMIN000006398) [5]. ...
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We previously identified a subtype of schizophrenia (SCZ) characterized by increased plasma pentosidine, a marker of glycation and oxidative stress (PEN-SCZ). However, the genetic factors associated with PEN-SCZ have not been fully clarified. We performed a genome-wide copy number variation (CNV) analysis to identify CNVs associated with PEN-SCZ to provide an insight into the novel therapeutic targets for PEN-SCZ. Plasma pentosidine was measured by high-performance liquid chromatography in 185 patients with SCZ harboring rare CNVs detected by array comparative genomic hybridization. In three patients with PEN-SCZ showing additional autistic features, we detected a novel deletion at 7q31.1 within exons 2 and 3 of IMMP2L , which encodes the inner mitochondrial membrane peptidase subunit 2. The deletion was neither observed in non-PEN-SCZ nor in public database of control subjects. IMMP2L is one of the SCZ risk loci genes identified in a previous SCZ genome-wide association study, and its trans-populational association was recently described. Interestingly, deletions in IMMP2L have been previously linked with autism spectrum disorder. Disrupted IMMP2L function has been shown to cause glycation/oxidative stress in neuronal cells in an age-dependent manner. To our knowledge, this is the first genome-wide CNV study to suggest the involvement of IMMP2L exons 2 and 3 in the etiology of PEN-SCZ. The combination of genomic information with plasma pentosidine levels may contribute to the classification of biological SCZ subtypes that show additional autistic features. Modifying IMMP2L functions may be useful for treating PEN-SCZ if the underlying biological mechanism can be clarified in further studies.
... AGEs can fuse with various tissues in the human body and damage these tissues, thereby damaging the human body. Experiments show that AGEs can accelerate the aging of the human body and cause various chronic degenerative diseases, such as atherosclerosis, Alzheimer's disease, and diabetes [1,10,11]. erefore, reducing AGEs can slow down the speed of aging and prevent many chronic degenerative diseases. e most crucial change in diabetic DR is the loss of pericytes and the disorder of endothelial cell function, which may cause blockage of capillaries and insufficient blood supply to the retina [12]. ...
Article
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Objective: We aimed to analyze the correlation between the level of skin advanced glycation end products (AGEs) in type 2 diabetes mellitus (T2DM) patients and the diabetic retinopathy (DR) staging in different traditional Chinese medicine (TCM) syndromes. Methods: 416 T2DM patients were divided into normal group, nonproliferative diabetic retinopathy (NPDR) group (mild, moderate, and severe), and proliferative diabetic retinopathy (PDR) group according to the DR grade. Patients' height, weight, fasting blood glucose (FBG), hemoglobin A1C (HbA1c), blood lipid, renal function, and skin AGEs were measured. According to TCM syndrome differentiation criteria, 230 patients with T2DM and DR were divided into I. qi and yin deficiency, collateral stasis group; II. liver and kidney deficiency, eye collaterals loss group; and III. yin and yang deficiency, blood stasis, and phlegm coagulation group. Results: The skin AGEs levels of different DR staging groups were statistically significant (P < 0.05), and the skin AGEs levels in the mild and moderate NPDR groups were significantly higher (P < 0.05) than those of the normal group. It was significantly higher (P < 0.05) in the severe NPDR group than in the normal group, mild and moderate NPDR groups. The skin AGEs levels of the PDR group were significantly higher (P < 0.05) than the normal group, mild and moderate NPDR groups. It was positively correlated with DR stage, HbA1c, total cholesterol (TC), low-density lipoprotein (LDL), and urine metal analysis (UMA) (r = 0.467, 0.411, 0.413, 0.503, 0.424, P < 0.05). The skin AGEs levels of the qi and yin deficiency and collaterals stasis syndrome group were significantly higher (P < 0.05) than in the liver and kidney deficiency and eye collaterals loss groups. It was also significantly higher (P < 0.05) in yin and yang deficiency, blood stasis, and phlegm coagulation syndrome groups than in qi and yin deficiency and collaterals stasis syndrome groups. Conclusion: There is a positive correlation between skin AGEs and DR staging in T2DM patients. Skin AGEs level is predictive for the risk of DR complications in T2DM patients and is vital in assessing DR degree per TCM syndrome type.
... Under physiological conditions, AGE formation is most common on long-lived proteins in the circulation and connective tissues [19], such as structural components of Nutrients 2022, 14, 2675 4 of 28 cellular basement membranes and proteins including globulin, immunoglobulins and albumin [30,41]. However, conditions such as chronic inflammation, hyperlipidaemia and oxidative stress further accelerate the process of glycation, increasing the likelihood of short-lived proteins also becoming AGE modified [42]. ...
Article
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Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a "western" diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, individuals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.
... It is unclear whether GA plays a causal role in the inflammatory process or is a mere consequence of the cascade. Advanced glycation end (AGE) products, including GA, which are mainly formed in a hyperglycaemic state, can be also found under inflammatory conditions [23,24]. The receptor for AGEs (RAGE) is a patternrecognition receptor, and once its ligands, and GA bind to RAGE, various intracellular signalling cascades are initiated [25,26]. ...
Article
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Background Glycated albumin (GA) is known to reflect the current inflammatory burden in non-diabetes mellitus (DM) patients. In this study, we investigated whether GA at diagnosis could reflect the cross-sectional activity and predict poor outcomes during follow-up in non-DM patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods The medical records of 118 immunosuppressive drug-naïve AAV patients were retrospectively reviewed, and 76 patients who had both GA and glycated haemoglobin (HbA1c) results but not DM were included in this study. Demographic, clinical, and laboratory data at diagnosis were assessed. Results The median age of AAV patients was 61 years, and 31 patients were male. GA was positively correlated with five-factor score ( r = 0.282), Birmingham vasculitis activity score (BVAS) assigned to renal manifestation ( r = 0.315), and blood urea nitrogen ( r = 0.382), whereas negatively correlated with haemoglobin ( r = -0.345). AAV patients with end-stage renal disease (ESRD) exhibited significantly higher GA than those without ESRD (15.8% vs. 13.6%). When the cut-off of GA at diagnosis for ESRD was set at GA ≥ 14.25%, AAV patients with GA ≥ 14.25% had a significantly higher risk for ESRD development than those without (relative risk 12.040). In addition, AAV patients with GA ≥ 14.25% exhibited significantly lower cumulative ESRD-free survival rates than those without ( P = 0.020). Conclusion In conclusion, GA at diagnosis can reflect the cross-sectional BVAS assigned to renal manifestation of AAV and predict ESRD development during follow-up better than HbA1c or GA/HbA1c in AAV patients.
... AGEs level was measured by fluorospectrometer at excitation/emission 335/385 nm compared to aminoguanidine (AMG, known AGEs inhibitor). Percent inhibition is calculated as 100 x (Intensitycontrol -Intensitysample)/ Intensitycontrol (Singh et al., 2001). ...
Conference Paper
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Introduction Honey has been used in Ayuravedic for thousand years such as wound healing, anti-inflammation, anti-oxidant and anti-bacterium. Stingless bees are widely used in Eastern Thailand for fertilizing in fruit orchards. Propolis from Tetragonula pagdeni Schwarz has been shown the highest bioactivities among variety stingless bee species. However, Bioactivities of honey from stingless bee are still limited. Therefore, this study aims to study anti-oxidant, anti-inflammatory activities and anti-advance glycation end products (AGEs) formation of honey from stingless bees-T. pagdeni Schwarz compared between fruit orchard and mangrove forest resources in Chanthaburi province, Eastern Thailand. Methods Honey from 2 resources: fruit orchard and mangrove forest were collected from Chanthaburi province in December 2015. Anti-oxidant activity was determined by FRAP and DPPH assay. Anti-inflammatory effect was evaluated by proteinase activity inhibitory assay. Anti-AGEs formation was investigated by inhibitory assay of in vitro Millard reaction. Results and Discussion The honey from mangrove forest (HM) showed the stronger anti-oxidant effect than the honey from fruit orchard (HF). TEAC of HM and HF by FRAP are 2.23±0.05 and 0.84±0.06 μM trolox/g, respectively and DPPH assay showed IC50 at 198.2±18.2 and 622.7±39.5 µg/ml, respectively. Inhibition of proteinase activity was found in honey from fruit orchard higher than honey from mangrove forest as IC50 less than 62.5 (minimum investigation) and 527.2±72.6 µg/ml, respectively. Anti-AGEs formation was not significant different between HM and HF with 77.98±21.48 and 95.79±23.55 µg/ml, respectively. Conclusion These results are basic information for bioactivities of honey of T. pagdeni Schwarz from Eastern Thailand showing the bioactivities differences based on their resources. Further identify the chemical compositions of each honey sample are required to find the relation of its specific activity and its identity.
... Advanced glycation end-products (AGEs), generated through a non-enzymatic reaction between sugar residues and proteins or lipids [24], are increased in patients with DM and are correlated with diabetic vascular complications [25,26]. AGEs activate ECs by binding to RAGE, the receptor for AGEs, which then induces the generation of reactive oxygen species [27], impairing ECs and eventually leading to EC apoptosis [25,26]. ...
Article
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The pathogenesis of vascular calcification in diabetic patients remains elusive. As an effective information transmitter, small extracellular vesicles (sEVs) carry abundant microRNAs (miRNAs) that regulate the physiological and pathological states of recipient cells. In the present study, significant up-regulation of miR-126-5p was observed in sEVs isolated from human umbilical vein endothelial cells (HUVECs) stimulated with advanced glycation end-products (A-EC/sEVs). Intriguingly, these sEVs suppressed the osteogenic differentiation of vascular smooth muscle cells (VSMCs) by targeting BMPR1B, which encodes the receptor for BMP, thereby blocking the smad1/5/9 signalling pathway. In addition, knocking down miR-126-5p in HUVECs significantly diminished the anti-calcification effect of A-EC/sEVs in a mouse model of type 2 diabetes. Overall, miR-126-5p is highly enriched in sEVs derived from AGEs stimulated HUVECs and can target BMPR1B to negatively regulate the trans-differentiation of VSMCs both in vitro and in vivo. Graphical Abstract
... AGEs on microvessels limit neuronal blood flow by increasing vascular permeability, inhibiting vasodilation via nitric oxide (NO) interference, inducing cytokine release and increasing oxidative stress [72,[75][76][77][78]. AGEs also interact with receptors for advanced glycation end products (RAGEs), which signal to nuclear factor kappa B (NF-kB), a protein that controls several inflammatory markers, resulting in neurodegeneration and the inability to auto-repair [76]. The inconsistent approaches employed across studies to detect AGEs on cells, however, impact the quality of research on the glycation pathway [79]. ...
Article
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Distal symmetrical polyneuropathy (DSPN) is a serious complication of diabetes associated with significant disability and mortality. Although more than 50% of people with diabetes develop DSPN, its pathogenesis is still relatively unknown. This lack of understanding has limited the development of novel disease-modifying therapies and left the reasons for failed therapies uncertain, which is critical given that current management strategies often fail to achieve long-term efficacy. In this article, the pathogenesis of DSPN is reviewed, covering pathogenic changes in the peripheral nervous system, microvasculature and central nervous system (CNS). Furthermore, the successes and limitations of current therapies are discussed, and potential therapeutic targets are proposed. Recent findings on its pathogenesis have called the definition of DSPN into question and transformed the disease model, paving the way for new research prospects.
... Elevated circulating protein carbonyls were detected in T2DM [148,152], in hypercholesterolemia [151], and in CAD patients [149] (Table 3). Advanced glycation end products (AGEs) are protein carbonyls generated in the "secondary protein carbonylation" process through glycoxidation, and N ε -(carboxymethyl)lysine is the most abundant AGE [172], which is measurable in organic fluids and tissues [173]. AGEs cause cell damage by binding its receptor (RAGE), which activates nuclear factor-kappa B (NF-κB) [174], and seem to be involved in T2DM-related CV complications [147,150,153,155]. ...
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Oxidative stress is generated by the imbalance between reactive oxygen species (ROS) formation and antioxidant scavenger system’s activity. Increased ROS, such as superoxide anion, hydrogen peroxide, hydroxyl radical and peroxynitrite, likely contribute to the development and complications of atherosclerotic cardiovascular diseases (ASCVD). In genetically modified mouse models of atherosclerosis, the overexpression of ROS-generating enzymes and uncontrolled ROS formation appear to be associated with accelerated atherosclerosis. Conversely, the overexpression of ROS scavenger systems reduces or stabilizes atherosclerotic lesions, depending on the genetic background of the mouse model. In humans, higher levels of circulating biomarkers derived from the oxidation of lipids (8-epi-prostaglandin F2α, and malondialdehyde), as well as proteins (oxidized low-density lipoprotein, nitrotyrosine, protein carbonyls, advanced glycation end-products), are increased in conditions of high cardiovascular risk or overt ASCVD, and some oxidation biomarkers have been reported as independent predictors of ASCVD in large observational cohorts. In animal models, antioxidant supplementation with melatonin, resveratrol, Vitamin E, stevioside, acacetin and n-polyunsaturated fatty acids reduced ROS and attenuated atherosclerotic lesions. However, in humans, evidence from large, placebo-controlled, randomized trials or prospective studies failed to show any athero-protective effect of antioxidant supplementation with different compounds in different CV settings. However, the chronic consumption of diets known to be rich in antioxidant compounds (e.g., Mediterranean and high-fish diet), has shown to reduce ASCVD over decades. Future studies are needed to fill the gap between the data and targets derived from studies in animals and their pathogenetic and therapeutic significance in human ASCVD.
... It is most likely that diabetic vascular damage is the result of an overlap of these interlinked theories (17). The hallmarks of diabetic microvascular disease include thickening of the basement membrane, increased vascular permeability and prothrombotic state (18). ...
... We concluded that the pathological classifications, the extent of mesangial expansion, the incidence of K-W nodules, and capillary microaneurysms of the low-zinc group were more serious and evident than those of the normal-zinc group. In diabetes, nonenzymatic glycation reactions occur between the amino group of proteins, fatty acids, or nucleic acids and the aldehyde group of reducing sugars, resulting in an increase of advanced glycation end products (AGEs) [29,30]. Mesangial cells can synthesize and secrete matrix components simultaneously with uptake and degradation of AGEs, resulting in an increase of mesangial matrix components. ...
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Objective We investigated the correlation between zinc levels and Nrf2 expression and potential effects on the clinicopathology of patients with diabetic nephropathy (DN). Methods We selected 30 patients with DN, diagnosed via renal biopsy at our hospital from March 2018 to November 2019, and enrolled 30 healthy individuals from a medical examination center as the control group. Patients with DN were divided into normal-zinc and low-zinc groups. We detected the levels of zinc, copper, and Nrf2 mRNA in their serum, and collected the clinical and pathological data of DN patients. Results Serum zinc level and Nrf2 mRNA expression were significantly decreased in patients with DN compared to those of healthy people ( P < 0.05). Of the 30 patients, 16 had low zinc (53.3%) and 14 had normal zinc levels (46.7%). There was no significant difference in the blood Nrf2 mRNA expression between the two groups ( P > 0.05). However, the expression of Nrf2 in the kidney tissue of the low-zinc group was significantly lower compared to the normal-zinc group ( P < 0.05). Diastolic blood pressure and copper levels were significantly higher in the low-zinc group ( P < 0.05). In contrast, body mass index, red blood cell count, Hb level, and the ratio of zinc to copper were significantly lower in the low-zinc group ( P < 0.05). The pathological classifications of the low-zinc group were more severe ( P < 0.05). Conclusion Patients with DN were more likely to have zinc deficiency and lower expression of Nrf2. Additionally, DN patients with zinc deficiency were prone to have more severe clinical and pathological manifestations.
... The formation and accumulation of AGE products in various cells and tissues leads to damage to extracellular and intracellular structures, disruption of their functions and is one of the causes for the development of diabetic complications. Increased accumulation of AGE products has been revealed in aging, diabetes [68], arthritis, atherosclerosis, chronic renal failure, nephropathy, neuropathy, Alzheimer's disease, and other pathologies [69]. The ability of squid skin ommochromes to suppress the process of nonenzymatic glycation may be associated with their antioxidant activity [8,10]. ...
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Ommochromes are pigments of invertebrates that exhibit oxidative stress protection. The aim of this study was to investigate ommochromes extracted from cephalopod’s skin for their ability to inhibit age-related-macular degeneration (AMD)-related factors such as H2O2-induced and iron-dependent oxidative stress (ferroptosis and erastin), accumulation of advanced glycation end-products (AGEs), as well as vascular endothelial growth factor (VEGF), and inflammatory cytokines (interleukin 6 and interleukin 8) secretion. As cell systems, we used primary porcine retinal pigment epithelium (RPE), human retinal pigment epithelium cell line ARPE-19 and uveal melanoma cell line OMM-1. In vitro, ommochromes produced an antiglycation effect by the inhibition of fructosylation reaction. The ommochromes showed protective effects against erastin- induced cell death in ARPE-19. In addition, in long-term stimulation (7 days) ommochromes decreased constitutively secreted VEGF, as well as interleukin 6 and interleukin 8 induced by Poly I:C in primary RPE. No relevant effects were detected in OMM-1 cells. The effects are dependent on the cell system, time of exposition, and concentration. This substance is of interest for further research concerning age-related macular degeneration.
... Consequently, high consumption of thermally processed foods increases Advanced Glycation End Products (AGEs) (32). AGEs are a complex and heterogeneous group of compounds whose accumulation contributes to increased oxidative stress inflammation and are related to numerous chronic non-communicable diseases (NCDs) and the aging process (31,33). OLEU has important reported properties such as antioxidant, anti-inflammatory, antimicrobial, and hypolipidemic activity (30,(34)(35)(36)(37). ...
Article
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Olive oil consumption has increased in the last two decades and consequently, its wastes have increased, which generates a tremendous environmental impact. Among by-products, are the olive mill leaves, which are easier and inexpensive to treat than other olive by-products. However, little research has been done on their chemical composition and potential bioactivity. Hence, in this study, olive mill leaves were used to obtain Oleuropein-Enriched Extracts (OLEU-EE) using Conventional Extraction, Ultrasound-Assisted Extraction, and Homogenization-Assisted Extraction. These three techniques were evaluated using a Factorial Design to determine the parameters to obtain an OLEU-EE with high content of Total Phenolic Compounds (TPC), Antioxidant Activity (AA), and Oleuropein concentration (OLEU). From the results, Homogenizer-Assisted Extraction (HAE) technique was selected at 18,000 rpm, solid: liquid ratio 1:10, and 30 seconds of homogenization with 70% ethanol, due to its high TPC (5,196 mg GA/100 g), AA (57,867 µmol of TE/100 g), and OLEU (4,345 mg of OLEU/100 g). In addition, antiglycating effect of OLEU-EE on the levels of 1) fluorescent Advanced Glycation End Products (AGEs) were IC50 of 0.1899 and 0.1697 mg/mL for 1λEXC 325/λEM 440; 2λEXC 389/λEM 443, respectively; 2) protein oxidative damage markers such as dityrosine (DiTyr), N-formylkynurenine (N-Formyl Kyn), and kynurenine (Kyn) were IC50 of 0.1852, 0.2044 and 0.1720 mg/mL, respectively. In conclusion, OLEU-EE from olive mill leaves has different capacities to inhibit AGEs evidenced by the IC50 of fluorescent AGEs and protein oxidation products, together with the scavenging free radical evidenced by the concentration of Trolox Equivalent. Therefore, OLEU-EE could be potential functional ingredients that prevent oxidative damage caused by free radicals and AGEs accumulation.
... However, autophagy has also been found to induce macrophage polarization to the M1 phenotype and inhibit M2 polarization. Advanced glycation end-products (AGEs) are a group of modified molecular products formed by nonenzymatic glycation reactions between carbonyl group of reducing sugars and the free amino group of proteins, lipids or nucleic acids, the formation and aggregation of AGEs can accelerate the progression of diabetic macroangiopathy by increasing intracellular oxidative stress (111,112). Macrophage autophagy induced by AGEs promoted M1 macrophage polarization and hindered the healing of skin wounds (113). Adipose stem cell-derived exosomes promoted M2 macrophage polarization by inhibiting autophagy and significantly decreased the cerebral injury area of infarction (114). ...
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Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high morbidity and mortality that poses a major challenge in critical care medicine. The development of ALI/ARDS involves excessive inflammatory response, and macrophage autophagy plays an important role in regulating the inflammatory response in ALI/ARDS. In this paper, we review the effects of autophagy in regulating macrophage function, discuss the roles of macrophage autophagy in ALI/ARDS, and highlight drugs and other interventions that can modulate macrophage autophagy in ALI/ARDS to improve the understanding of the mechanism of macrophage autophagy in ALI/ARDS and provide new ideas and further research directions for the treatment of ALI/ARDS.
... It is vital to notice that glycation including glucose is a lengthy process, although fructose, glucose-6 phosphate and intracellular glucose may create AGE relatively quickly [19]. Glycation is a non-enzymatic process; thus, its speed is expressed by the serum level of glucose (fructose, galactose) [20,21]. ...
Article
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The formation of advanced glycation end-products (AGE) in tissues is a physiological process; however, excessive production and storage are pathological and lead to inflammation. A sedentary lifestyle, hypercaloric and high-fructose diet and increased intake of processed food elements contribute to excessive production of compounds, which are created in the non-enzymatic multi-stage glycation process. The AGE’s sources can be endogenous and exogenous, mainly due to processing food at high temperatures and low moisture, including grilling, roasting, and frying. Accumulation of AGE increases oxidative stress and initiates various disorders, leading to the progression of atherosclerosis, cardiovascular disease, diabetes and their complications. Inborn defensive mechanisms, recovery systems, and exogenous antioxidants (including polyphenols) protect from excessive AGE accumulation. Additionally, numerous products have anti-glycation properties, occurring mainly in fruits, vegetables, herbs, and spices. It confirms the role of diet in the prevention of civilization diseases.
... The formation and accumulation of AGE products in various cells and tissues leads to damage to extracellular and intracellular structures, disruption of their functions and is one of the causes for the development of diabetic complications. Increased accumulation of AGE products has been revealed in aging, diabetes [68], arthritis, atherosclerosis, chronic renal failure, nephropathy, neuropathy, Alzheimer's disease, and other pathologies [69]. The ability of squid skin ommochromes to suppress the process of nonenzymatic glycation may be associated with their antioxidant activity [8,10]. ...
Article
Full-text available
Ommochromes are pigments of invertebrates that exhibit oxidative stress protection. The aim of this study was to investigate ommochromes extracted from cephalopod’s skin for their ability to inhibit age-related-macular degeneration (AMD)-related factors such as H2O2-induced and iron-dependent oxidative stress (ferroptosis and erastin), accumulation of advanced glycation end-products (AGEs), as well as vascular endothelial growth factor (VEGF), and inflammatory cytokines (interleukin 6 and interleukin 8) secretion. As cell systems, we used primary porcine retinal pigment epithelium (RPE), human retinal pigment epithelium cell line ARPE-19 and uveal melanoma cell line OMM-1. In vitro, ommochromes produced an antiglycation effect by the inhibition of fructosylation reaction. The ommochromes showed protective effects against erastin- induced cell death in ARPE-19. In addition, in long-term stimulation (7 days) ommochromes decreased constitutively secreted VEGF, as well as interleukin 6 and interleukin 8 induced by Poly I:C in primary RPE. No relevant effects were detected in OMM-1 cells. The effects are dependent on the cell system, time of exposition, and concentration. This substance is of interest for further research concerning age-related macular degeneration.
... AGEs can promote the production of reactive oxygen species (ROS), activate the NF-κB signaling pathway, and stimulate the expression of VCAM-1 (Qin et al. 2017;Ticala et al. 2020). These effects of AGEs can lead to a range of diabetes-related microvascular diseases, including AS (Singh et al. 2001). One study found that Lf could bind to AGEs and interact with AGE ligands, affecting subsequent intracellular signal transduction (Schmidt et al. 1994). ...
Article
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Atherosclerosis (AS) is a common pathological basis for many cardiovascular diseases (CVDs) and result in high mortality and immense health and economic burdens worldwide. Early prevention, diagnosis, and treatment are promising approaches for stemming the development and progression of AS. Lactoferrin (Lf) is an iron-binding glycoprotein belonging to the transferrin family. It is widely found in body fluids such as digestive tract fluids, tears, and milk. Lf possesses anti-inflammatory, antibacterial, immunoregulatory, antioxidant and many other physiological functions. The serum Lf level is reportedly associated with the risk of AS and AS-related CVDs. Lf administration is closely involved in several mechanisms, including cholesterol metabolism, foam cell formation, ICAM-1 expression, homocysteine and leptin levels, anti-inflammatory and antioxidant function. Moreover, Lf has also been applied in the sythesis of magnetic resonance imaging (MRI) contrast agents to detect AS. Lf plays an important role in AS and may therefore be used in its diagnosis and treatment. Thus, this article aims to review the association between Lf and the risk of AS and AS-related CVDs, the mechanisms of Lf administration on AS, and its potential application in AS diagnosis.
... 3 Genistein can decrease arterial pressure through the inhibition of ACE, PKC-βII, NO/NOS, and vasoconstriction. 4 AGEs are formed through the non-enzymatic glycosylation of amino groups on proteins by reducing sugars or dicarbonyl [217], which is related to the pathogenesis of complications (e.g., kidney) of type 2 diabetes mellitus [218], and can be inhibited by genistein via the upregulation of glyoxalase I/II, AR, and FBG. 5 It reduces fibrosis by increasing ALKBH5 and Klotho and decreasing α-SMA and CTGF. 6 It inhibits apoptosis and promotes cell apoptosis through the inhibition of SIRT1 expression in common kidney diseases. ...
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Genistein is a naturally occurring phytoestrogen (soy or soybean products) that is classified as an isoflavone, and its structure is similar to that of endogenous estrogens; therefore, genistein can exert an estrogen-like effect via estrogen receptors. Additionally, genistein is a tyrosine kinase inhibitor, which enables it to block abnormal cell growth and proliferation signals through the inhibition of tyrosine kinase. Genistein is also an angiogenesis inhibitor and an antioxidant. Genistein has effects on kidney cells, some of the kidney’s physiological functions, and a variety of kidney diseases. First, genistein exerts a protective effect on normal cells by reducing the inflammatory response, inhibiting apoptosis, inhibiting oxidative stress, inhibiting remodeling, etc., but after cell injury, the protective effect of genistein decreases or even has the opposite effect. Second, genistein can regulate renin intake to maintain blood pressure balance, regulate calcium uptake to regulate Ca2+ and Pi balances, and reduce vasodilation to promote diuresis. Third, genistein has beneficial effects on a variety of kidney diseases (including acute kidney disease, kidney cancer, and different chronic kidney diseases), such as reducing symptoms, delaying disease progression, and improving prognosis. Therefore, this paper reviews animal and human studies on the protective effects of genistein on the kidney in vivo and in vitro to provide a reference for clinical research in the future.
... Approximately 80% of diabetic patients experience DR 20 years following onset, and its incidence is increasing worldwide (1,2). It has become one of the most important causes of blindness and visual impairment in working-age individuals (3,4). The initial stage of DR does not present with apparent symptoms; however, as the disease progresses, patients may experience blurred vision or even blindness (5,6). ...
... AGEs are produced through a non-enzymatic reaction between protein and lipids in the presence of reducing sugars and are found at high levels in the plasma of diabetic patients. They adversely affect cellular processes by directly trapping and cross-linking proteins or by binding to receptors for signalling pathways [13,14]. Advanced glycation end-product generation leads to the formation of reactive oxygen species (ROS), oxidative stress and altered gene expression. ...
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Diabetes is a global epidemic, with cardiovascular disease being the leading cause of death in diabetic patients. There is a pressing need for an in vitro model to aid understanding of the mechanisms driving diabetic heart disease, and to provide an accurate, reliable tool for drug testing. Human induced-pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have potential as a disease modelling tool. There are several factors that drive molecular changes inside cardiomyocytes contributing to diabetic cardiomyopathy, including hyperglycaemia, lipotoxicity and hyperinsulinemia. Here we discuss these factors and how they can be seen in animal models and utilised in cell culture to mimic the diabetic heart. The use of human iPSC-CMs will allow for a greater understanding of disease pathogenesis and open up new avenues for drug testing.
... glycation end products (AGEs) are the final products formed from the non-enzymatic glycation and oxidation of proteins, lipids, and nucleic acids in the Maillard reaction(Maietta, Colombo, Corana, & Papetti, 2018;Singh, Barden, Mori, & Beilin, 2001). The formation and accumulation of AGE are associated with hyperglycemia and diabetes(Carvajal-Carvajal, 2015). ...
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Oregano is the name given to a great variety of herbs belonging mainly to the Lamiaceae and Verbenaceae botanical families. Oregano species are rich sources of phytochemicals such as phenolic compounds like rosmarinic acid, salvianolic acid, and luteolin, among others. A few articles have previously accessed some potential pharmacological bioactivities of oregano plants; however, none has focused on the antidiabetic studies. This review aims to summarize recent studies about the potential effect of phenolic compounds from oregano plant species. The reports were retrieved from electronic databases such as PubMed, Web of Science, National Center for Biotechnology Information (NCBI), and Scopus. In addition, articles related to the mentioned topics and published between 2004–2022 were selected. The results from this study show that the antidiabetic pharmacological reports of oregano phenolic compounds are mainly in vitro reports. Therefore, the diversity of oregano species yields a broad variety of phenolic constituents, where preclinical and clinical studies are strongly recommended. Phenolics from oregano: potential adjuvants against diabetes mellitus.
... AGEs contribute to diabetes mellitus macro-and microvascular complications through adduct formation. Adducts form in basement membranes and cause changes in extracellular matrix proteins like elastin and collagen [28]. Moreover, it is suggested that AGEs, through interaction with RAGE, may result in the inflammatory process, oxidative stress, as well as development of clots and calcification in the arteries. ...
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Background Diabetes-induced chronic hyperglycemia results in the formation and aggregation of advanced glycation end-products (AGEs), which are products of non-enzymatic glycosylation of lipids or proteins. The development of diabetic complications can be accelerated by AGEs. In the current study, we aimed to explore the relationship between AGEs levels and ABC goals of diabetes control (A: Hemoglobin A1C < 7.0%, B: Blood pressure < 140/90 mmHg, and C: low-density lipoprotein cholesterol [LDL] < 100 mg/dL). Methods In the current cross-sectional study, 293 patients with type 2 diabetes mellitus (T2D), were enrolled. Demographic and clinical characteristics of the individuals were collected. AGEs levels were measured using quantitative fluorescence spectroscopy. Finally, the association of AGEs levels with patients' characteristics and ABC goals was assessed. Results Higher serum AGEs concentration was detected in older age, smoking patients and those with higher diastolic blood pressure, lower high-density lipoprotein (HDL) level, lower body mass index (BMI) and retinopathy. Moreover, the T2D patients who achieved higher numbers of ABC goals of diabetes were younger age (P-value = 0.003), with lower hemoglobin A1C (P-value = 0.001), fasting blood sugar (P-value = 0.002) diastolic blood pressure (P-value = 0.001), systolic blood pressure (P-value = 0.001), cholesterol (P-value = 0.001), LDL (P-value = 0.001), and AGEs (P-value = 0.023) levels. Diabetic patients with AGEs levels above 73.9% were about 2.2 times more likely to achieve none of ABC treatment goals (95% CI 1.107–3.616). Conclusion Our results revealed the relationship between AGEs and ABC goal achievement, and microvascular diabetic complications, and imply that AGEs measurement may be valuable in the monitoring of diabetic patients' complications and treatment adjustment.
... can also induce peripheral vascular disease, which leads to nerve ischemia and damage (Malavige and Levy, 2009). The mechanism of diabetic vasculopathy is associated with endothelial dysfunction, since AGE accumulation results in vascular thickening and atherosclerosis (Singh et al., 2001). ...
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Diabetic erectile dysfunction (DED) is one of the most common complications of diabetes mellitus. However, current therapeutics have no satisfactory effect on DED. In recent years, traditional Chinese medicine (TCM) has shown good effects against DED. By now, several clinical trials have been conducted to study the effect of TCM in treating DED; yet, the underlying mechanism is not fully investigated. Therefore, in this review, we briefly summarized the pathophysiological mechanism of DED and reviewed the published clinical trials on the treatment of DED by TCM. Then, the therapeutic potential of TCM and the underlying mechanisms whereby TCM exerts protective effects were summarized. We concluded that TCM is more effective than chemical drugs in treating DED by targeting multiple signaling pathways, including those involved in oxidation, apoptosis, atherosclerosis, and endothelial function. However, the major limitation in the application of TCM against DED is the lack of a large-scale, multicenter, randomized, and controlled clinical trial on the therapeutic effect, and the underlying pharmaceutical mechanisms also need further investigation. Despite these limitations, clinical trials and further experimental studies will enhance our understanding of the mechanisms modulated by TCM and promote the widespread application of TCM to treat DED.
... During the thermal processing of food, the generation of color, taste, and aroma is also accompanied by the generation of advanced glycation end products (AGEs), which are a group of complex heterogeneous compounds formed by amino acids and reducing sugars (Singh, Barden, Mori, & Beilin, 2001). The two predominant sources of AGEs in the body are endogenous and exogenous formation, and exogenous AGEs from the diet are the major source in vivo (Brownlee, Vlassara, & Cerami, 1984;Goldberg et al., 2004). ...
Article
Nɛ-Carboxymethyl-lysine (CML) is a primary advanced glycation end product that exists in the body and food as free and bound forms with different bioavailability and physiological effects. To compare the uptake, tissue distribution, and fecal excretion of dietary free and bound CML, free or bound CML were administered to healthy mice at 10 mg CML kg⁻¹ body weight per day for 12 weeks. The results demonstrated that free CML was significantly absorbed in serum and accumulated in the colon, ileum, lung, kidneys, heart, spleen, brain, and liver after intake of free and bound CML, whereas no statistical increase was found in the accumulation of bound CML in the serum, lung, spleen, kidneys, and liver. The colon was the main tissue for the accumulation of free and total CML. Moreover, the accumulation of free CML in tissues and organs was significantly correlated with free CML levels in serum. In conclusion, consumption of bound CML caused a higher uptake, accumulation, and fecal excretion of CML in the body than intake of free CML.
... GO, a kind of α-dicarbonyl compound, is a crucial precursor substance during the formation of AGEs [40], which is produced primarily through cleavage of the Schiff base, glucose oxidation, and lipid oxidation [41]. As shown in Figure 3, the GO content of control samples increased by 42.74% when increasing the frozen time from 0 months to 6 months, while the GO content of samples treated with GLP and TP decreased by 8.27% and 10.78% compared with control samples after freezing for 6 months. ...
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The inhibitory effect of guava leaf polyphenols (GLP) on advanced glycation end products (AGEs) of frozen chicken meatballs (−18 °C) and its possible inhibitory mechanism was investigated. Compared with control samples after freezing for 6 months, acidic value (AV), lipid peroxides, thiobarbituric acid reactive substance (TBARS), A294, A420, glyoxal (GO), Nε-carboxymethyl-lysine (CML), pentosidine, and fluorescent AGEs of chicken meatballs with GLP decreased by 11.1%, 22.3%, 19.5%, 4.30%, 8.66%, 8.27%, 4.80%, 20.5%, and 7.68%, respectively; while free sulfhydryl groups the content increased by 4.90%. Meanwhile, there was no significant difference between meatballs with GLP and TP in AV, A294, GO, and CML (p > 0.05). Correlation analysis indicated that GO, CML, pentosidine, and fluorescent AGEs positively correlated with AV, TBARS, A294, and A420, while GO, CML, pentosidine, and fluorescent AGEs negatively correlated with free sulfhydryl groups. These results manifested GLP could inhibit AGEs formation by inhibiting lipid oxidation, protein oxidation, and Maillard reaction. The possible inhibitory mechanism of GLP on the AGEs included scavenging free radicals, capturing dicarbonyl compounds, forming polyphenol–protein compounds, and reducing the formation of glucose. Therefore, the work demonstrated that the addition of plant polyphenols may be a promising method to inhibit AGEs formation in food.
Article
Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent. We investigated the relationship between dietary intake of carboxymethyllysine (dCML) – an AGE prototype – and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study. Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia. 2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01–1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86–1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91–1.07)] or frailty [OR = 1.01 (0.83–1.22)] when non-frail subjects were used as reference. Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.
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Diabetic patients are prone to developing chronic inflammation after trauma and have persistent nonhealing wounds. Reactive oxygen species (ROS) and recurrent bacterial infections at the site of long‐term wounds also further delay skin wound healing and tissue regeneration. In this study, a granular gel (which exhibits ROS scavenging and antibacterial properties) is fabricated based on hyaluronic acid‐g‐lipoic acid (HA‐LA). Briefly, HA‐LA is synthesized to fabricate HA‐LA microgels, which are further assembled by Ag+ via its coordination effect with disulfide in dithiolane to form a granular gel. The extrudable bulk granular gel possesses a shear‐thinning feature and is immediately restored to a solid state after extrusion, and this can be easily applied to the whole wound area. Therefore, the grafted LA not only allows for the construction of the granular gel but also removes excess ROS from the microenvironment. Additionally, the presence of Ag+ realizes the assembly of microgels and has antibacterial effects. In vivo experiments show that the HA‐LA granular gel eliminates excessive ROS at the wound site and up‐regulates the secretion of reparative growth factors, thus, accelerating common and diabetic wound healing significantly. Therefore, the ROS‐scavenging granular gel that can be applied to the wound surface with chronic inflammation demonstrates strong clinical utility.
Article
Introduction Erectile dysfunction (ED) is very common in diabetic males, especially type 2 diabetes mellitus (T2DM). Many factors and complications of diabetes such as macro- and micro-angiopathy are associated with risks leading to ED in male patients. Aim Analysis of factors associated with ED in T2DM. The purpose of this study is to shed light on potential associations between ED, type 2 diabetes, and some risks factors. Material and methods This was a prospective analytic study of T2DM over 18. The study population consisted of diabetic patients seen at the endocrinology and urology departments of the University Hospital during the study period. Evaluation of ED was made by IIEF 5 score. Outcomes A total of 333 patients were selected for the study. The mean age was 56.6 ± 9.8 and the prevalence of ED was 82.6% (n = 275). Results In univariate analysis, several associated factors were identified such as micro-angiopathic type complications including diabetic retinopathy (OR 4.88 [2.31–10.33], P < .001), diabetic nephropathy (OR 12.67 [1.71–93.66], P = .002) and macro-angiopathic type including arterial hypertension (OR 3.12 [1.69–5.75], P < .001). In multivariate analysis, duration of diabetes, micro and macroangiopathic complications, and hyperuricemia were independent risk factors for the occurrence of ED (P < .05). Clinical Implications The presence of certain complications of diabetes such as micro or macro angiopathy or hyperuricemia should lead to a search for a ED. The presence of these associated factors identified in type 2 diabetic patients should systematically prompt an ED diagnosis which is often moderate or severe. That diagnosis would help design a protocol for the management and improvement of the life quality of these patients. Strengths and Limitations The strength of this work is that it was conducted in the biggest hospital in the country which gives us a good idea of the trend of this ailment in the country. But the limitation of the study is that it only included patients who visited the hospital. This is monocentric hospital study was also transversal which does allow to establish a causal link. Conclusion ED has a significant prevalence in T2DM. Several associated factors identified in uni and multivariate analyses, including duration of diabetes, micro and macro angiopathic complications, and hyperuricemia, increase ED risk. Therefore, it is essential to investigate the existence of these factors to improve the management of ED, which may allow the patient to regain a better overall health status. SNN Milama, A Mougougou, S G Olagui, et al. Analysis of the Factors Associated With ED in Type 2 Diabetics at the University Hospital of Libreville. Sex Med 2022;10:100564.
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In recent years, the risk, such as hypertension, obesity and diabetes mellitus, of cardiovascular diseases has been increasing explosively with the development of living conditions and the expansion of social psychological pressure. The disturbance of glucose and lipid metabolism contributes to both collapse of myocardial structure and cardiac dysfunction, which ultimately leads to diabetic cardiomyopathy. The pathogenesis of diabetic cardiomyopathy is multifactorial, including inflammatory cascade activation, oxidative/nitrative stress, and the following impaired Ca2+ handling induced by insulin resistance/hyperinsulinemia, hyperglycemia, hyperlipidemia in diabetes. Some key alterations of cellular signaling network, such as translocation of CD36 to sarcolemma, activation of NLRP3 inflammasome, up-regulation of AGE/RAGE system, and disequilibrium of micro-RNA, mediate diabetic oxidative stress/inflammation related myocardial remodeling and ventricular dysfunction in the context of glucose and lipid metabolic disturbance. Here, we summarized the detailed oxidative stress/inflammation network by which the abnormality of glucose and lipid metabolism facilitates diabetic cardiomyopathy.
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Objective: Cardio-metabolic risk assessment in the general population is of paramount importance to reduce diseases burdened by high morbility and mortality. The present paper defines a strategy for out-of-hospital cardio-metabolic risk assessment, based on data acquired from contact-less sensors. Methods: We employ Structural Equation Modeling to identify latent clinical variables of cardio-metabolic risk, related to anthropometric, glycolipidic and vascular function factors. Then, we define a set of sensor-based measurements that correlate with the clinical latent variables. Results: Our measurements identify subjects with one or more risk factors in a population of 68 healthy volunteers from the EU-funded SEMEOTICONS project with accuracy 82.4%, sensitivity 82.5%, and specificity 82.1%. Conclusions: Our preliminary results strengthen the role of self-monitoring systems for cardio-metabolic risk prevention.
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Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.
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Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU’s antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8–100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.
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A nonenzymatic reaction between reducing sugars and amino groups of proteins results in the formation of advanced glycation end products, which are linked to a number of chronic progressive diseases with macro- and microvascular complications. In this research, we sought to ascertain the immunological response to d-ibose-glycated fibrinogen. New Zealand White female rabbits were immunized with native and d-ribose-glycated (Rb-gly-Fb) fibrinogen and used for studying the immunological response. Serum from these rabbits analyzed using direct binding and competitive inhibition ELISA was found to contain a high titer of antibodies against Rb-gly-Fb; Rb-gly-Fb was much more immunogenic than its native form. The IgG against Rb-gly-Fb (Rb-gly-Fb-IgG) was highly specific against the immunogenic protein. Moreover, histopathology and immunofluorescence studies revealed the deposition of the Rb-gly-Fb-IgG immune complex in the glomerular basement membrane of the kidneys of immunized rabbits. Furthermore, immunization with Rb-gly-Fb increased the expression of genes encoding proinflammatory cytokines, tumour necrosis factor α, interleukin-6, interleukin-1β, and interferon-gamma, which is indicative of increased inflammation and the antigenic role of Rb-gly-Fb in provoking an immune response.
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Methylglyoxal (MGO) is a reactive dicarbonyl compound formed as a byproduct of glycolysis. MGO is a major cell-permeant precursor of advanced glycation end products (AGEs), since it readily reacts with basic phospholipids and nucleotides, as well as amino acid residues of proteins, such as arginine, cysteine, and lysine. The AGEs production induced by MGO are widely associated with several pathologies, including neurodegenerative diseases. However, the impact of MGO metabolism and AGEs formation in the central nervous system (particularly in neurons, astrocytes and oligodendrocytes) on behavior and psychiatric diseases is not fully understood. Here, we briefly present background information on the biological activity of MGO in the central nervous system. It was gathered the available information on the role of MGO metabolism at the physiological processes, as well as at the neurobiology of psychiatry diseases, especially pain-related experiences, anxiety, depression, and cognition impairment-associated diseases. To clarify the role of MGO on behavior and associated diseases, we reviewed primarily the main findings at preclinical studies focusing on genetic and pharmacological approaches. Since monoamine neurotransmitter systems are implicated as pivotal targets on the pathophysiology and treatment of psychiatry and cognitive-related diseases, we also reviewed how MGO affects these neurotransmission systems and the implications of this phenomenon for nociception and pain; learning and cognition; and mood. In summary, this review highlights the pivotal role of glyoxalase 1 (Glo1) and MGO levels in modulating behavioral phenotypes, as well as related cellular and molecular signaling. Conclusively, this review signals dopamine as a new neurochemical MGO target, as well as highlights how MGO metabolism can modulate the pathophysiology and treatment of pain, psychiatric and cognitive-related diseases.
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A major precursor of advanced glycation end-products (AGEs) - methylglyoxal (MG) - is a reactive carbonyl metabolite that originates from glycolytic pathways. MG formation and accumulation has been implicated in the pathogenesis of diabetes and age-related chronic musculoskeletal disorders. Human bone marrow-derived stromal cells (BMSCs) are multipotent cells that have the potential to differentiate into cells of mesenchymal origin including osteoblasts, but the role of MG on their differentiation is unclear. We therefore evaluated the effect of MG on proliferation and differentiation of BMSC-derived osteoblasts. Cells were treated with different concentrations of MG (600, 800 and 1000 μM). Cell viability was assessed using a Cell Counting Kit-8 assay. Alkaline phosphatase (ALP) activity and calcium deposition assays were performed to evaluate osteoblast differentiation and mineralization. Gene expression was measured using qRT-PCR, whereas AGE specific receptor (RAGE) and collagen 1 were examined by immunocytochemistry and Western blotting. RAGE knockdown was performed by transducing RAGE specific short hairpin RNAs (shRNAs) using lentivirus. During osteogenic differentiation, MG treatment resulted in reduction of cell viability (27.7 %), ALP activity (45.5 %) and mineralization (82.3 %) compared to untreated cells. MG significantly decreased expression of genes involved in osteogenic differentiation - RUNX2 (2.8 fold), ALPL (3.2 fold), MG detoxification through glyoxalase - GLO1 (3 fold) and collagen metabolism - COL1A1 (4.9 fold), COL1A2 (6.8 fold), LOX (5.4 fold) and PLOD1 (1.7 fold). MG significantly reduced expression of collagen 1 (53.3 %) and RAGE (43.1 %) at protein levels. Co-treatment with a MG scavenger - aminoguanidine – prevented all negative effects of MG. RAGE-specific knockdown during MG treatment did not reverse the effects on cell viability, osteogenic differentiation or collagen metabolism. In conclusion, MG treatment can negatively influence the collagen metabolism and differentiation of BMSCs-derived osteoblasts through a RAGE independent mechanism.
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Objectives Accumulation of advanced glycation end products (AGEs) in articular cartilage during aging has been proposed as a mechanism involved in the development of osteoarthritis (OA). Therefore, we investigated a cross-sectional relationship between skin AGEs, a biomarker for systemic AGEs accumulation, and OA. Methods Skin AGEs were estimated with the AGE ReaderTM as skin autofluorescence (SAF). Knee and hip X-rays were scored according to Kellgren and Lawrence (KL) system. KL-sum score of all four joints was calculated per participant to assess severity of overall radiographic OA (ROA) including or excluding those with prosthesis. Knee MRI of tibiofemoral joint (TFMRI) was assessed for cartilage loss. Sex-stratified regression models were performed after testing interaction with SAF. Results 2153 participants were included for this cross-sectional analysis. In women (n=1206) for one unit increase in SAF, the KL-sum score increased by 1.15 (95% confidence interval = 1.00-1.33) but excluding women with prosthesis, there was no KL-sum score increase [0.96 (0.83-1.11)]. SAF was associated with higher prevalence of prosthesis [Odds ratio, OR = 1.67 (1.10-2.54)] but not with ROA [OR = 0.83 (0.61-1.14)] when compared to women with no ROA. In men (n=947), there was inconclusive association between SAF and KL sum score or prosthesis. For TFMRI (n=103 women), SAF was associated with higher prevalence of cartilage loss, full-thickness [OR = 5.44 (1.27-23.38)] and partial-thickness [OR = 1.45 (0.38-5.54)], when compared to participants with no cartilage loss. Conclusion Higher SAF in women was associated with higher prosthesis prevalence and a trend towards higher cartilage loss on MRI. Our data presents inconclusive results between SAF and ROA in both sexes.
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Bioprosthetic heart valves (BHV) fabricated from heterograft tissue, such as glutaraldehyde pretreated bovine pericardium (BP), are the most frequently used heart valve replacements. BHV durability is limited by structural valve degeneration (SVD), mechanistically associated with calcification, advanced glycation end products (AGE), and serum protein infiltration. We investigated the hypothesis that anti-AGE agents, Aminoguanidine, Pyridoxamine [PYR], and N-Acetylcysteine could mitigate AGE-serum protein SVD mechanisms in vitro and in vivo, and that these agents could mitigate calcification or demonstrate anti-calcification interactions with BP pretreatment with ethanol. In vitro, each of these agents significantly inhibited AGE-serum protein infiltration in BP. However, in 28-day rat subdermal BP implants only orally administered PYR demonstrated significant inhibition of AGE and serum protein uptake. Furthermore, BP PYR preincubation of BP mitigated AGE-serum protein SVD mechanisms in vitro, and demonstrated mitigation of both AGE-serum protein uptake and reduced calcification in vivo in 28-day rat subdermal BP explants. Inhibition of BP calcification as well as inhibition of AGE-serum protein infiltration was observed in 28-day rat subdermal BP explants pretreated with ethanol followed by PYR preincubation. In conclusion, AGE-serum protein and calcification SVD pathophysiology are significantly mitigated by both PYR oral therapy and PYR and ethanol pretreatment of BP.
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Introduction: Diabetes is the most common cause of end stage kidney disease. Therapies such as sodium-glucose co-transporter-2 inhibitors have been identified over the last decade as effective oral hypoglycemic agents that also confer additional cardio and kidney protection. Knowledge of their mechanism of action and impact on patients with diabetes and albuminuria is vital in galvanizing prescriber confidence and increasing clinical uptake. Areas covered: This manuscript discusses the pathophysiology of diabetic kidney disease, patho-physiological mechanisms for sodium-glucose co-transporter-2 inhibitors, and their impact on patients with Type 2 diabetes mellitus and albuminuric kidney disease. Expert opinion: Sodium-glucose co-transporter-2 inhibitors reduce albuminuria with consequent benefits on cardiovascular and kidney outcomes in patients with diabetes and severe albuminuria. Whilst they have been incorporated into guidelines, the uptake of these agents into clinical practice has been slow. Increasing the uptake of these agents into clinical practice is necessary to improve outcomes for the large number of patients with diabetic kidney disease globally.
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Crataegus pinnatifida Bge. is a worthwhile industrial crop for its extensive application in Chinese herbal pharmaceuticals, food, and other industries. In this study, proanthocyanidins were extracted from the pulp of Crataegus pinnatifida Bge., and the structure, antityrosinase, antimelanogenesis, anti-α-glucosidase, and anti-glycation activities of these compounds were systematically elucidated. The combined utilization of high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS), matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), and nuclear magnetic resonance (NMR) demonstrated that the proanthocyanidins were B-type procyanidin polymers consisting of epicatechin. These polymers were efficient, reversible, and competitive inhibitors of both tyrosinase and α-glucosidase with IC50 values of 0.10 ± 0.01 mg/mL (for monophenolase), 0.16 ± 0.02 mg/mL (for diphenolase), and 0.50 ± 0.02 µg/mL, respectively. Moreover, the process of nonenzymatic glycation was also delayed by proanthocyanidins. Further cell assays suggested that these polymers strongly inhibited intracellular tyrosinase activity and melanogenesis and induced apoptosis in mouse melanoma cells. The results of circular dichroism (CD), molecular docking, and molecular dynamics (MD) consistently revealed that the inhibition of procyanidins on the two enzymes was primarily driven by hydrogen bonding and hydrophobic interactions, and the binding of epicatechin caused structural stretching and conformational modification of tyrosinase. Consequently, this study confirms novel tyrosinase, melanogenesis, α-glucosidase, and nonenzymatic glycation inhibitors, which might offer scientific evidence for potential applications in the cosmetics and pharmaceutical industries.
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Objective: The liver protection of blood coral polysaccharide (BCP) was investigated. Materials and methods: We evaluated the effect of BCP on liver pathology, liver function, oxidation and inflammation-related indicators of D-Gal/LPS-induced acute liver failure (ALF) mice in vivo. Results: Liver index and liver pathology observation in mice showed that BCP could inhibit liver tissue swelling and hemorrhage, hepatocyte damage, and inflammatory infiltration in ALF. Serum liver function results showed that BCP effectively inhibits the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total bilirubin (TBil), alkaline phosphatase (AKP), myeloperoxidase (MPO). High dose-blood coral polysaccharide (H-BCP) was better than silymarin. Serum antioxidant and immune results showed that BCP increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px), and inhibited the levels of malondialdehyde (MDA) and nitric oxide (NO). Also, BCP increased immunoglobulins G (IgG) and A (IgA) levels, thereby enhancing humoral immunity. Liver anti-inflammatory ELISA results showed that BCP reduced the levels of interleukin (IL)-6, IL-1β, IL-17, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, and enhanced the level of anti-inflammatory factor IL-10. H-BCP was the most effective treatment. Real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) of liver tissues confirmed that BCP increases the relative expression levels of antioxidant and anti-inflammatory-related cuprozinc superoxide dismutase (Cu/Zn-SOD, SOD1), manganese superoxide dismutase (Mn-SOD, SOD2), CAT, GSH, GSH-Px, and IL-10. In contrast, it inhibits inflammation-related genes IL-6, IL-1β, IL-17, TNF-α, IFN-γ, inducible nitric oxide synthase (iNOS, NOS2), and cyclooxygenase (COX)-2. In addition, BCP also inhibits the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and enhance B-cell inhibitor-α (IκB-α) gene relative expression in the liver, which may be related to NF-κB pathway inhibition. Conclusion: BCP prevents D-Gal/LPS-induced ALF in mice, and its effect is concentration dependent.
Chapter
Fundamental aging processes appear to be the root cause contributors to the chronic diseases that account for the bulk of morbidity, hospital admissions, mortality, and health costs. They may also contribute to causing aging phenotypes, geriatric syndromes (e.g., frailty, sarcopenia, cognitive impairment, falling, and incontinence), and loss of physical resilience (e.g., delayed or prolonged recovery and increased mortality from injury, infection, or surgery, inadequate response to vaccination, and adverse drug reactions), which is the geroscience hypothesis. In this review, we discuss these fundamental aging processes or “hallmarks of aging,” their interconnectedness (the Unitary Theory of Fundamental Aging Mechanisms), and interventions targeting these hallmarks that have been reported, are being tested, or may be developed. Next, we propose ideas about how to intervene at points that would impact different hallmarks of aging simultaneously or sequentially, potentially to achieve additive or synergistic benefits in enhancing health span by delaying, preventing, or alleviating chronic diseases, the geriatric syndromes, aging phenotypes, and/or enhancing physical resilience.
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This pilot study tested the effects of the supplements containing water chestnut extract and carotenoids on antiglycation and carotenoid levels. Twenty Japanese subjects (mean age, 67 ± 7 years; 13 men) ingested 200 mg of Tarpa bispinosa Roxb. extract (containing >50 mg of polyphenols), 20 mg of lutein, and 3 mg of zeaxanthin daily for 3 months. Advanced glycation end product (AGEs) levels were estimated by fingertip skin autofluorescence using the AGEs Sensor; carotenoid levels were estimated by pressure-mediated reflection spectroscopy of the fingertips using the Veggie Meter. Compared to baseline, the mean AGEs score decreased significantly (0.55 ± 0.04 arbitrary units (AU) vs. 0.52 ± 0.07 AU, p = 0.03); the mean carotenoid score increased significantly (256 ± 68 optical density (OD) vs. 302 ± 109 OD, p = 0.02) at 3 months. Blood pressure, body weight, visual acuity, refractive error, and intraocular pressure were equivalent between baseline and 3 months. Compared to baseline, 13 (65%) patients had decreased AGEs scores, and 14 (70%) had increased carotenoid scores at 3 months; 9 (45%) subjects had both decreased AGEs scores and increased carotenoid scores, and two (10%) subjects had an inverse response. Co-administration of water chestnut extract and lutein for 3 months decreased the AGEs and increased the carotenoids estimated in the fingertip skin of humans.
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Attack by reactive oxygen intermediates, common to many kinds of cell/tissue injury, has been implicated in the development of diabetic and other vascular diseases. Such oxygen-free radicals can be generated by advanced glycation end products (AGEs), which are nonenzymatically glycated and oxidized proteins. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGE (RAGE) and the lactoferrin-like polypeptide (LF-L), we tested the hypothesis that AGE ligands tethered to the complex of RAGE and LF-L could induce oxidant stress. AGE albumin or AGEs immunoisolated from diabetic plasma resulted in induction of endothelial cell (EC) oxidant stress, including the generation of thiobarbituric acid reactive substances (TBARS) and resulted in the activation of NF-kappaB, each of which was blocked by antibodies to AGE receptor polypeptides and by antioxidants. Infusion of AGE albumin into normal animals led to the appearance of malondialdehyde determinants in the vessel wall and increased TBARS in the tissues, activation of NF-kappaB, and induction of heme oxygenase mRNA. AGE-induced oxidant stress was inhibited by pretreatment of animals with either antibodies to the AGE receptor/binding proteins or antioxidants. These data indicate that interaction of AGEs with cellular targets, such as ECs, leads to oxidant stress resulting in changes in gene expression and other cellular properties, potentially contributing to the development of vascular lesions. Further studies will be required to dissect whether oxidant stress occurs on the cell surface or at an intracellular locus.
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Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
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Advanced glycation end products (AGEs) have been identified as relevant mediators of late diabetic complications such as atherosclerotic disease. The endothelial migration of monocytes is one of the first steps in atherogenesis and monocyte-endothelial interaction itself is linked to the express ion of adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1). Recently, stimulation of VCAM-1 by AG Es has been demonstrated. Since endothelial stimulation by AGEs is followed by generation of oxygen free radicals with subsequent activation of nuclear transcription factor kappa B, we investigated the influence of alpha-lipoic acid on the expression of VCAM-1 and monocyte adherence to endothelial cells in vitro by means of cell-associated chemiluminescence assays and quantitative reverse transcriptase polymerase chain reaction using a constructed recombinant RNA standard. We found that alpha-lipoic acid was able to decrease the number of VCAM-1 transcripts from 41.0+/-11.2 to 9.5+/-4.7 RNA copies per cell in AGE-stimulated cell cultures. Furthermore, expression of VCAM-1 was suppressed in a time- and dose-dependent manner by alpha-lipoic acid as shown by chemiluminescence endothelial cell assay. Pretreatment of endothelial cells with 0.5 mM or 5 mM alpha-lipoic acid reduced AGE-induced endothelial binding of monocytes from 22.5+/-2.9% to 18.3+/-1.9% and 13.8+/-1.8% respectively. Thus, we suggest that extracellularly administered alpha-lipoic acid reduces AGE-albumin-induced endothelial expression of VCAM-1and monocyte binding to endothelium in vitro. These in vitro results may contribute to the understanding of a potential antioxidative treatment of atherosclerosis.
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Hyperglycemia accelerates the formation and accumulation of advanced glycation end products (AGE) in plasma and tissue, which may cause diabetic vascular complications. We recently reported that scavenger receptors expressed by liver endothelial cells (LECs) dominantly mediate the endocytic uptake of AGE proteins from plasma, suggesting its potential role as an eliminating system for AGE proteins in vivo (Smedsrod, B., Melkko, J., Araki, N., Sano, H., and Horiuchi, S. (1997) Biochem. J. 322, 567-573). In the present study we examined the effects of insulin on macrophage scavenger receptor (MSR)-mediated endocytic uptake of AGE proteins. LECs expressing MSR showed an insulin-sensitive increase of endocytic uptake of AGE-bovine serum albumin (AGE-BSA). Next, RAW 264.7 cells expressing a high amount of MSR were overexpressed with human insulin receptor (HIR). Insulin caused a 3.7-fold increase in endocytic uptake of 125I-AGE-BSA by these cells. The effect of insulin was inhibited by wortmannin, a phosphatidylinositol-3-OH kinase (PI3 kinase) inhibitor. To examine at a molecular level the relationship between insulin signal and MSR function, Chinese hamster ovary (CHO) cells expressing a negligible level of MSR were cotransfected with both MSR and HIR. Insulin caused a 1.7-fold increase in the endocytic degradation of 125I-AGE-BSA by these cells, the effect of which was also inhibited by wortmannin and LY294002, another PI3 kinase inhibitor. Transfection of CHO cells overexpressing MSR with two HIR mutants, a kinase-deficient mutant, and another lacking the binding site for insulin receptor substrates (IRS) resulted in disappearance of the stimulatory effect of insulin on endocytic uptake of AGE proteins. The present results indicate that insulin may accelerate MSR-mediated endocytic uptake of AGE proteins through an IRS/PI3 kinase pathway.
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Reactive aldehydes derived from reducing sugars and peroxidation of lipids covalently modify proteins and may contribute to oxidative tissue damage. We recently described another mechanism for generating reactive aldehydes from free α-amino acids. The pathway begins with myeloperoxidase, a heme enzyme secreted by activated neutrophils. Conversion of α-amino acids to aldehydes requires hypochlorous acid (HOCl), formed from H2O2 and chloride by myeloperoxidase. When L-serine is the substrate, HOCl generates high yields of glycolaldehyde. We now demonstrate that a model protein, ribonuclease A (RNase A), exposed to free L-serine and HOCl exhibits the biochemical hallmarks of advanced glycation end (AGE) products — browning, increased fluorescence, and cross-linking. Furthermore, Nε-(carboxymethyl)lysine (CML), a chemically well-characterized AGE product, was generated on RNase A when it was exposed to reagent HOCl-serine, the myeloperoxidase-H2O2-chloride system plus L-serine, or activated human neutrophils plus L-serine. CML production by neutrophils was inhibited by the H2O2 scavenger catalase and the heme poison azide, implicating myeloperoxidase in the cell-mediated reaction. CML was also generated on RNase A by a myeloperoxidase-dependent pathway when neutrophils were activated in a mixture of amino acids. Under these conditions, we observed both L-serine–dependent and L-serine–independent pathways of CML formation. The in vivo production of glycolaldehyde and other reactive aldehydes by myeloperoxidase may thus play an important pathogenic role by generating AGE products and damaging tissues at sites of inflammation.
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Smokers have a significantly higher risk for developing coronary and cerebrovascular disease than nonsmokers. Advanced glycation end products (AGEs) are reactive, cross-linking moieties that form from the reaction of reducing sugars and the amino groups of proteins, lipids, and nucleic acids. AGEs circulate in high concentrations in the plasma of patients with diabetes or renal insufficiency and have been linked to the accelerated vasculopathy seen in patients with these diseases. Because the curing of tobacco takes place under conditions that could lead to the formation of glycation products, we examined whether tobacco and tobacco smoke could generate these reactive species that would increase AGE formation in vivo. Our findings show that reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke in a form that can rapidly react with proteins to form AGEs. This reaction can be inhibited by aminoguanidine, a known inhibitor of AGE formation. We have named these glycation products “glycotoxins.” Like other known reducing sugars and reactive glycation products, glycotoxins form smoke, react with protein, exhibit a specific fluorescence when cross-linked to proteins, and are mutagenic. Glycotoxins are transferred to the serum proteins of human smokers. AGE-apolipoprotein B and serum AGE levels in cigarette smokers were significantly higher than those in nonsmokers. These results suggest that increased glycotoxin exposure may contribute to the increased incidence of atherosclerosis and high prevalence of cancer in smokers.
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Pyrraline is one of the major Maillard compounds resulting from the reaction of glucose with amino compounds at slightly acidic pH. For in vivo studies, monoclonal pyrraline antibodies were raised after immunization of Balb/c mice with keyhole limpet hemocyamin-caproyl pyrraline conjugate. Of 660 hybridoma clones from one donor, 260 produced an antibody to the free hapten, two of which named Pyr-A and Pyr-B also cross-reacted with L-lysyl pyrraline. Using Pyr-B antibody and an ELISA, a gradual increase in pyrraline immunoreactivity was observed in serum albumin incubated with glucose or 3-deoxyglucosone. Plasma pyrraline levels increased fourfold (P less than 0.001) in Sprague-Dawley rats upon induction of diabetes with streptozotocin and were twofold increased in randomly selected plasmas from diabetic humans. Highly specific pyrraline immunoreactivity was detected in sclerosed glomeruli from diabetic and old normal kidneys as well as in renal arteries with arteriolosclerosis and in perivascular and peritubular sclerosed extracellular matrix and basement membranes. The preferential localization of pyrraline immunoreactivity in the extracellular matrix strengthens the notion that the advanced glycosylation reaction may contribute to decreased turnover and thickening of the extracellular matrix in diabetes and aging.
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Oxidized (ox-) low density lipoproteins (LDL) is characterized by the formation of lipid peroxides and their decomposition to reactive aldehydes which covalently link to apoB in LDL. These chemical changes are believed to be responsible for the enhanced recognition of ox-LDL by receptors on macrophages in culture. When oxidation is extensive, particle aggregation also occurs. The aim of this study was to characterize aggregation formation and how this influences the interaction of ox-LDL with macrophages in culture. When LDL was oxidized by incubating at 500 micrograms of protein/ml with 10 microM Cu2+ at 20 degrees C for up to 25 h, time-dependent increases in thiobarbituric acid reactive substances, conjugated diene content, electrophoretic mobility, and fluorescence at 360 excitation/430 emission were found. Particle aggregation increased in parallel with several parameters of oxidation and increased with increasing incubation temperatures and LDL concentrations used. When evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, apoB fragments of reproducible sizes and higher molecular weight species appeared after mild oxidation of LDL. The percent of total apoB remaining aggregated in sodium dodecyl sulfate was 50-80% at high degrees of oxidation, whereas it was far less in LDL that had been aggregated without chemical modification. This suggested that intermolecular cross-linking of apoB had occurred during oxidation of LDL at high concentrations. Degradation of ox-LDL in mouse peritoneal macrophages (MPM) increased in parallel with the degree of oxidation and with particle aggregation but reached a plateau after 12 h. Results from cross-competition studies in MPM with soluble and insoluble portions of extensively ox-LDL and with acetyl-LDL were consistent with uptake of soluble ox-LDL via both the scavenger receptor and another receptor on MPM, and uptake of the insoluble ox-LDL by an alternative mechanism.
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Structure elucidation of a specific fluorophore from the aging extracellular matrix revealed the presence of a protein crosslink formed through nonenzymatic glycosylation of lysine and arginine residues. The unexpected finding that a pentose instead of a hexose is involved in the crosslinking process suggested that the crosslink, named pentosidine, might provide insight into abnormalities of pentose metabolism in aging and disease. This hypothesis was investigated by quantitating pentosidine in hydrolysates of 103 human skin specimens obtained randomly at autopsy. Pentosidine level was found to increase exponentially from 5 to 75 pmol/mg collagen over lifespan (r = 0.86, P less than 0.001). A three- to tenfold increase was noted in insulin-dependent diabetic and nondiabetic subjects with severe end-stage renal disease requiring hemodialysis (P less than 0.001). Moderately elevated levels were also noted in some very old subjects, some subjects with non-insulin dependent diabetes, and two subjects with cystic fibrosis and diabetes. The cause of the abnormal pentose metabolism in these conditions is unknown but may relate to hemolysis, impaired pentose excretion, cellular stress, and accelerated breakdown of ribonucleotides. Thus, pentosidine emerges as a useful tool for assessment of previously unrecognized disorders of pentose metabolism in aging and disease. Its presence in red blood cells and plasma proteins suggests that it might be used as a measure of integrated pentosemia in analogy to glycohemoglobin for the assessment of cumulative glycemia.
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A new affinity chromatography system that selectively retains glycosylated amino acids has been utilized to determine the amount of nonenzymatic glycosylation present in peripheral nerve from diabetic and control rats and dogs. The mean value for glycosylated amino acids in diabetic rats was 2.8 times greater than the mean value in normal rats (P less than 0.001). In diabetic dogs, mean values were 2.15 times greater than normal values (P less than 0.05). Amino acid analysis of reduced, glycosylated amino acids previously isolated by affinity chromatography showed that glycosylated lysine and its hydrolysis rearrangement products were the major borohydride-reducible adduct present. In addition, another glycosylated product was noted to be present in major proportions. This radioactive product did not chromatograph with any of the available glycosylated amino acid standards. The finding that diabetes results in a nearly 3-fold increase of peripheral nerve glycosylation is consistent with a number of previous investigations in which glycosylation was measured in hemoglobin, serum albumin, and urinary amino acids and peptides from diabetics and normals. The results reported here provide evidence that increased nonenzymatic glycosylation is occurring in a tissue where physiological, morphological, and clinical degeneration characteristically develop as a result of diabetes mellitus.
Article
This study was undertaken to determine whether and how advanced glycation end products (AGE), senescent macroproteins accumulated in various tissues under hyperglycemic states, cause angiogenesis, the principal vascular derangement in diabetic microangiopathy. We first prepared AGE-bovine serum albumin (BSA) and anti-AGE antiserum using AGE-RNase A. Then AGE-BSA was administered to human skin microvascular endothelial cells in culture, and their growth was examined. The AGE-BSA, but not nonglycated BSA, was found to induce a statistically significant increase in the number of viable endothelial cells as well as their synthesis of DNA. The increase in DNA synthesis by AGE-BSA was abolished by anti-AGE antibodies. AGE-BSA also stimulated the tube formation of endothelial cells on Matrigel. We obtained the following evidence that it is vascular endothelial growth factor (VEGF) that mainly mediates the angiogenic activities of AGE. (1) Quantitative reverse transcription-polymerase chain reaction analysis of poly(A)(+) RNA from microvascular endothelial cells revealed that AGE-BSA up-regulated the levels of mRNAs for the secretory forms of VEGF in time- and dose-dependent manners, while endothelial cell expression of the genes encoding the two VEGF receptors, kinase insert domain-containing receptor and fms-like tyrosine kinase 1, remained unchanged by the AGE treatment. Immunoprecipitation analysis revealed that AGE-BSA did increase de novo synthesis of VEGF. (2) Monoclonal antibody against human VEGF completely neutralized both the AGE-induced DNA synthesis and tube formation of the endothelial cells. The results suggest that AGE can elicit angiogenesis through the induction of autocrine vascular VEGF, thereby playing an active part in the development and progression of diabetic microangiopathies.
Article
Advanced glycation end products (AGEs), formed from the nonenzymatic glycation of proteins and lipids with reducing sugars, have been implicated in many diabetic complications; however, their role in diabetic retinopathy remains largely unknown. Recent studies suggest that the cellular actions of AGEs may be mediated by AGE-specific receptors (AGE-R). We have examined the immunolocalization of AGEs and AGE-R components R1 and R2 in the retinal vasculature at 2, 4, and 8 months after STZ-induced diabetes as well as in nondiabetic rats infused with AGE bovine serum albumin for 2 weeks. Using polyclonal or monoclonal anti-AGE antibodies and polyclonal antibodies to recombinant AGE-R1 and AGE-R2, immunoreactivity (IR) was examined in the complete retinal vascular tree after isolation by trypsin digestion. After 2, 4, and 8 months of diabetes, there was a gradual increase in AGE IR in basement membrane. At 8 months, pericytes, smooth muscle cells, and endothelial cells of the retinal vessels showed dense intracellular AGE IR. AGE epitopes stained most intensely within pericytes and smooth muscle cells but less in basement membrane of AGE-infused rats compared with the diabetic group. Retinas from normal or bovine-serum-albumin-infused rats were largely negative for AGE IR. AGE-R1 and -R2 co-localized strongly with AGEs of vascular endothelial cells, pericytes, and smooth muscle cells of either normal, diabetic, or AGE-infused rat retinas, and this distribution did not vary with each condition. The data indicate that AGEs accumulate as a function of diabetes duration first within the basement membrane and then intracellularly, co-localizing with cellular AGE-Rs. Significant AGE deposits appear within the pericytes after long-term diabetes or acute challenge with AGE infusion conditions associated with pericyte damage. Co-localization of AGEs and AGE-Rs in retinal cells points to possible interactions of pathogenic significance.
Article
Nerve regeneration in diabetic animals is delayed and qualitatively impaired, but the mechanisms responsible for these defects have not been elucidated. The extracellular matrix protein laminin promotes the extension of neuronal processes, and recent studies have localized neurite-promoting activity to a lysine-containing sequence (IKVAV) within the laminin molecule. Because long-lived molecules such as laminin are likely to accumulate excessive amounts of nonenzymatic glycosylation products in diabetic subjects, we have investigated whether such adduct formation on laminin or the IKVAV peptide affects their neurite-promoting properties. These studies used the murine neuroblastoma cell line NB2a, which extends neurites on laminin when differentiated by cAMP. Neurite outgrowth in NB2a cells plated on glycosylated laminin was significantly decreased from that occurring on unmodified laminin. Similarly, neurite outgrowth in NB2a cells plated on glycosylated IKVAV peptide was inhibited compared with that observed on native IKVAV. These data suggest that nonenzymatic glycosylation of a biologically active domain within laminin may contribute to impaired nerve regeneration in diabetes.
Article
Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. Design: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of < 150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment) with less tight control aiming at a blood pressure of < 180/105 mm Hg. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a medial follow up of 8.4 years. Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. Results: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P < 0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P = 0.0046), 32% in deaths related to diabetes (6% to 51%) (P = 0.019), 44% in strokes (11% to 65%) (P = 0.013), and 37% in microvascular end points (11% to 56%) (P = 0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P = 0.0004) and a 47% reduced risk (7% to 70%) (P = 0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. Conclusion: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.
Article
Post-translational modifications in lens crystallins due to glycation and oxidation have been suggested to play a significant role in the development of cataracts associated with aging and diabetes. We have previously shown that α-keto acids, like pyruvate, can protect the lens against oxidation. We hypothesize that they can also prevent the glycation of proteins competitively by forming a Schiff base between their free keto groups and the free –NH2 groups of protein as well as subsequently inhibit the oxidative conversion of the initial glycation product to advanced glycation end products (AGE). The purpose of this study was to investigate these possibilities using purified crystallins. The crystallins isolated from bovine lenses were incubated with fructose in the absence and presence of pyruvate. The post-incubation mixtures were analyzed for fructose binding to the crystallins, AGE formation, and the generation of high molecular weight (HMW) proteins. In parallel experiments, the keto acid was replaced by catalase, superoxide dismutase (SOD), or diethylene triaminepentaacetic acid (DTPA). This was done to ascertain oxidative mode of pyruvate effects. Interestingly, the glycation and consequent formation of AGE from α-crystallin was more pronounced than from β-, and γ-crystallins. The changes in the crystallins brought about by incubation with fructose were prevented by pyruvate. Catalase, SOD, and DTPA were also effective. The results suggest that pyruvate prevents against fructose-mediated changes by inhibiting the initial glycation reaction as well as the conversion of the initial glycated product to AGE. Hence it is effective in early as well as late phases of the reactions associated with the formation of HMW crystallin aggregates.
Article
▪ Abstract Diabetic vascular complications affect both micro- and macrovasculature, primarily in the retina, renal glomeruli, and multiple sites in the macrovessels. This review presents a summary of the abnormal function found in vivo and in cultured vascular cells exposed to elevated levels of glucose. We also discuss the various biochemical hypotheses that have been proposed to explain the adverse effects of hyperglycemia on vascular cells.
Article
To determine the content of two crosslinks, pyridinoline (a mature crosslink) and pentosidine (a senescent crosslink), in human articular cartilage, and to examine the effect of bone and joint disorders on the content of those crosslinks in articular cartilage. After pretreatment with SP-Sephadex C-25, high-performance liquid chromatography was conducted on a hydrolysate of human articular cartilage from 53 patients with one of the following diseases: osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis, femoral head necrosis, and renal osteodystrophy (ROD). Pyridinoline levels were either unchanged with age or were slightly decreased in elderly patients. Pentosidine levels increased with age in the entire patient population. There was no significant difference in the pyridinoline content among the study groups, but there was a significant difference in pentosidine content (P < 0.001). ROD patients had the highest mean level of pentosidine (407 mumoles/mole of hydroxyproline), and RA patients had a higher mean level than age-matched OA patients (214 versus 103 mumoles/mole of hydroxyproline). Bone and joint disorders do not affect the pyridinoline content in articular cartilage, but they do not affect the pentosidine content.
Article
The glycation of proteins by glucose has been linked to the development of diabetic complications and other diseases. Early glycation is thought to involve the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiffs base and fructosamine adducts. The formation of the alpha-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone, in early glycation was investigated. Glucose (50 mM) degraded slowly at pH 7.4 and 37 degrees C to form glyoxal, methylglyoxal and 3-deoxyglucosone throughout a 3-week incubation period. Addition of t-BOC-lysine and human serum albumin increased the rate of formation of alpha-oxoaldehydes - except glyoxal and methylglyoxal concentrations were low with albumin, as expected from the high reactivity of glyoxal and methylglyoxal with arginine residues. The degradation of fructosyl-lysine also formed glyoxal, methyl-glyoxal and 3-deoxyglucosone. alpha-Oxoaldehyde formation was dependent on the concentration of phosphate buffer and availability of trace metal ions. This suggests that alpha-oxoaldehydes were formed in early glycation from the degradation of glucose and Schiffs base adduct. Since alpha-oxoaldehydes are important precursors of advanced glycation adducts, these adducts may be formed from early and advanced glycation processes. Short periods of hyperglycaemia, as occur in impaired glucose tolerance, may be sufficient to increase the concentrations of alpha-oxoaldehydes in vivo.
Article
Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment.
Article
Hyperglycemia is one of the most prominent factors associated with diabetic vascular disease, the development of which is initated by functional and morphological alterations of the endothelium. The review summarizes several issues of glycemia and advanced glycation end products induced changes concerning soluble as well as cell bound endothelial adhesion molecules, and further addresses the aspect of apoptosis in the light of diabetic vascular complications.
Article
This chapter focuses on the biochemical basis of advanced glycosylation and discusses the diverse effects of advanced glycosylation products in biology and medicine. The chemical and biological conception of the advanced glycosylation process has evolved considerably since early studies on the formation of HbA1c. Despite difficulties in the structural elucidation of advanced glycosylation products, the ensuing years have yielded much insights into the biochemistry of AGEs, in large part assisted by consideration of related pathways in the Maillard reaction. Studies of biological processes have been motivated by the multiorgan pathology that occurs during chronic hyperglycemia. The basis of much of this pathology is still poorly understood. Related investigations of normal, age-related processes are only now beginning to bear insight into some of the clinicopathological sequalae that characterize normal aging. Given the slow, progressive nature of AGE accumulation in vivo and the active cell-mediated processes that appear to be required for AGE removal, it is likely that the investigation of advanced glycosylation mechanisms will continue to provide insight into a variety of additional biological and pathological processes that are characterized by long-term, age-related, and degenerative changes.
Article
Previous assays for nonenzymatic advanced glycosylation end products (AGEs) formed in tissues and/or circulating in blood are unsatisfactory. Based on our earlier identification of AGE-specific receptors on the macrophagelike tumor cell line RAW 264.7, a new assay system for AGEs has been devised. RAW 264.7 cells were used in competitive radioreceptor assays (RRA) after a 3-day culture in 96-well plates with 1 mu CI/ml [3H]glycine. Bovine serum albumin (BSA), modified extensively by incubation with glucose-6-phosphate in vitro to form AGE-BSA, was labeled with 125I and was used as a model ligand at a concn of 10 micrograms/ml. One unit of AGE was defined as the amount of test protein required to inhibit 50% of the specific binding of [125I]-labeled AGE-BSA to the AGE-receptors of intact RAW 264.7 cells. Nonlabeled AGE-BSA was used as a specific competitor to construct standard curves. The reproducibility of the assay was assessed at AGE levels equivalent to mean, maximum, and minimum levels of sensitivity for assays run on a single day and over an extended period, and the RRA had a reproducibility (coefficient of variation) between 5.9 and 14.7%. Protease hydrolysis of in vitro glycosylated proteins before assay increases the competitive ability of these proteins in proportion to their glycosylation. Little or no AGE cross-reactivity was detected in native BSA, Amadori-BSA, maleylated BSA, formaldehyde-treated BSA, palmitic acid-BSA, and acetylated low-density lipoproteins (acetyl-LDL). Polyanions such as heparin or fucoidan strongly interfere with this receptor binding assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Antibodies directed against advanced glycosylation end products (AGEs) formed during a Maillard reaction have been generated and characterized. Since protein-bound AGEs recognized by the antibodies were labile to acid hydrolysis, the antibodies were further characterized by using the AGE-alpha-acetyl-L-lysine methyl ester (AGE-ALME) with a brown and fluorescent property as well as the AGE-proteins. The antibodies reacted with fluorescent compounds, rather than brown pigment compounds, in the AGE-ALME. The fluorescent compounds in the AGE-ALME were separated into four fluorescent compounds by reversed-phase thin layer chromatography (TLC). Of the fluorescent compounds tested, compound 3 (Rf = 0.63), as designated on a TLC plate, showed the highest affinity for the antibodies. In addition, the antibody recognition to the cross-linked oligomers with fluorescence in the AGE-protein was investigated by using bovine pancreatic ribonuclease A (RNase), which is known as a model protein for studying AGE-induced cross-linking. Fluorescence in the AGE-RNase existed in both of the oligomers and the monomer. The cross-linked oligomers exhibited higher affinity to the antibodies than did the monomer, which has a similar degree of fluorescent intensity. These results indicate that our antibodies against cross-linked protein-bound AGEs may serve as a useful tool to elucidate pathophysiological roles of advanced Maillard reaction in diabetic complications and aging processes.