Article

The Inhibition of Advanced Glycation End Products by Carnosine and Other Natural Dipeptides to Reduce Diabetic and Age‐Related Complications

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Abstract

As people age they are at a greater risk for many disorders including cardiovascular, renal, and neurodegenerative diseases, and these conditions are exacerbated by diabetes. An important cause of the maladies associated with both age and diabetes is the formation of advanced glycation end products (AGEs). AGE formation is initiated by glycation reactions between reducing sugars and free amine groups. A cascade of other reactions follows, leading to alterations in membrane function and damage to the proteome, such as protein crosslinking. Compounds that prevent these reactions are currently being researched, but peptides hold great potential as they tend to lack toxicity, are absorbed intact, are easily produced, and are cheaper than other options. Of the peptides researched, carnosine is the most promising. Research suggests that carnosine is absorbed into the plasma unaltered and intact. Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs. Other promising peptides and amino acids include β‐alanine, L‐histidine, homocarnosine, anserine, and glutathione. If bioactive peptides and amino acids can minimize the formation of AGEs, foods containing these peptides could be used to improve health.

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... Some peptides have been previously exploited as AGE inhibitors. In particular, the tri-peptide glutathione and some γ-glutamylcysteine derivatives from aged garlic were effective AGE inhibitors [43,44]. Additional di-peptides containing tryptophan (NW and QW), as well as di-peptides containing histidine (carnosine, homocarnosine, and anserine) were able to inhibit protein glycation [44,45]. ...
... In particular, the tri-peptide glutathione and some γ-glutamylcysteine derivatives from aged garlic were effective AGE inhibitors [43,44]. Additional di-peptides containing tryptophan (NW and QW), as well as di-peptides containing histidine (carnosine, homocarnosine, and anserine) were able to inhibit protein glycation [44,45]. It has been speculated that the antioxidant properties of these peptides may be pivotal for the inhibitory activity [45]. ...
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Inhibition of key metabolic enzymes linked to type-2-diabetes (T2D) by food-derived compounds is a preventive emerging strategy in the management of T2D. Here, the impact of Parmigiano-Reggiano (PR) cheese peptide fractions, at four different ripening times (12, 18, 24, and 30 months), on the enzymatic activity of α-glucosidase, α-amylase, and dipeptidyl peptidase-IV (DPP-IV) as well as on the formation of fluorescent advanced glycation end-products (fAGEs) was assessed. The PR peptide fractions were able to inhibit the selected enzymes and fAGEs formation. The 12-month-ripening PR sample was the most active against the three enzymes and fAGEs. Mass spectrometry analysis enabled the identification of 415 unique peptides, 54.9% of them common to the four PR samples. Forty-nine previously identified bioactive peptides were found, mostly characterized as angiotensin-converting enzyme-inhibitors. The application of an integrated approach that combined peptidomics, in silico analysis, and a structure–activity relationship led to an efficient selection of 6 peptides with potential DPP-IV and α-glucosidase inhibitory activities. Peptide APFPE was identified as a potent novel DPP-IV inhibitor (IC50 = 49.5 ± 0.5 μmol/L). In addition, the well-known anti-hypertensive tripeptide, IPP, was the only one able to inhibit the three digestive enzymes, highlighting its possible new and pivotal role in diabetes management.
... Histidine is an essential amino acid that acts as an anti-glycating agent [187], free radical scavenger [188], and metal chelator [189,190]. The dipeptide carnosine contains histidine and beta-alanine, is found at high levels in muscle and brain, and has similar physiological properties as histidine. ...
... The dipeptide carnosine contains histidine and beta-alanine, is found at high levels in muscle and brain, and has similar physiological properties as histidine. But carnosine was shown to be less toxic in cell culture studies, so is a more promising therapeutic [187]. Much data in model systems supports the potential use of carnosine for the treatment of aging-related disorders [191]. ...
Article
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Amino acids are the building blocks of protein, but also play important cellular signaling roles. The mechanisms through which altered levels of many amino acids are sensed and the signals transmitted are still largely unknown. Increasing evidence is showing that these signals may influence the aging process. In this regard, methionine restriction appears to be an evolutionary conserved mechanism to delay aging and supplementation with glycine can mimic methionine restriction to extend lifespan in rodents. Tryptophan restriction may also activate specific anti-aging pathways, but it could interfere with cognitive function. With exercise the consumption of dietary branched chain amino acids (BCAAs) may be beneficial in building muscle mass, but high levels of BCAAs as well as tyrosine and phenylalanine in the bloodstream are associated with metabolic disease such as insulin resistance. Individual supplementation or restriction of several different amino acids has shown promise in the treatment of insulin resistance in rodents. Much progress regarding the effects of amino acids on longevity has been made using yeast, nematodes, and fruit flies. Clearly, much more research is needed to understand the signaling pathways activated by amino acid imbalance before efficacious and well-tolerated dietary interventions can be developed for human aging and aging-related disorders. In this review the mechanisms through which altered dietary and cellular levels of the twenty proteogenic amino acids affect aging or aging-related disorders are discussed. Keywords: Amino acids, Aging, Lifespan, Yeast, C. elegans
... Oxidized lipids and higher processing temperature are known factors that affect the rate and amount of AGEs and ALEs formation during cooking (Poulsen et al., 2013). The capacity of carnosine to inhibit the formation of AGEs and ALEs has been reviewed (Freund et al., 2018;Ghodsi, 2019) in line with its capacity to scavenge ROS, inhibit glycation through its reaction with reducing sugars or with unsaturated aldehydic lipid oxidation products, and reverse through "transglycation" the early reaction between glucose and protein. In addition to prevent further degradation of the glycated protein, carnosine can also block the AGEs-induced cross-linking. ...
... Recently, questions on whether or not carnosine from cooked beef with HF content could by itself efficiently prevent oxidation during digestion, or if a high-meat diet could efficiently reduce AGEs formation were raised by Van Hecke et al.(2017)andFreund et al. (2018), respectively. Here, we are reporting for the first time that a 25% increase in free carnosine in ground pork significantly reduced protein carbonyls, loss of free thiols and 4-HNE during in-vitro gastric digestion irrespective of fat and cooking level of the meat, and reduced hexanal, MDA and CML up to the duodenum phase in moderately cooked lean pork. ...
Article
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Muscle carnosine represents an important health advantage of meat. Ground pork samples with intrinsic or added carnosine; fat content; and cooked under low or high intensity as a 2 × 2 × 2 factorial were digested in‐vitro. Changes in free carnosine and in markers of lipid (hexanal, 4‐hydroxynonenal (4‐HNE), malondialdehyde (MDA) and protein (protein‐carbonyls, thiols) oxidation, and of advanced glycation end‐products (AGEs) Nε‐(carboxymethyl)lysine (CML) were determined in the saliva, gastric, and duodenal digests. During digestion, the different markers overall indicated increased oxidation and decreased free carnosine. Increasing pork carnosine level significantly reduced protein carbonyls, loss of thiols, and 4‐HNE during in‐vitro gastric digestion, irrespective of fat and cooking level of the meat. Increased carnosine also significantly reduced hexanal, MDA and CML up to the duodenum phase in moderately cooked lean pork. Besides substantiating the formation of AGEs during digestion, these results show a potentially important role of dietary carnosine occurring in the gastrointestinal tract. Practical applications The ailments epidemiologically associated with red meat consumption could be counteracted by ingesting carnosine into meat. The health advantages of dietary carnosine, however, have never been demonstrated during digestion, a unique and complex oxidative environment compounded by the composition and cooking of the meat. The results obtained substantiated that AGEs formation occurred in‐vitro in the GIT. They also showed that increased carnosine had an immediate health beneficial role during pork digestion in reducing the formation of different harmful molecules, including AGEs, modulated by the composition and cooking of the meat. However, in exerting this protective role in the GIT, the remaining free level of carnosine, gradually decreased during digestion. Carnosine, as an important meat compositional factor may, depending on the fat content and cooking conditions, change the image of meat from representing a health risk to a health benefit. Carnosine level may also explain discrepancies observed in the literature.
... This drug has been proven to negate several health complications including hyperglycemia. Similar to carnisone other peptides like homocarnisone and anserine are found to reduce the glycation process and thereby limit the generation of AGEs [99]. As these peptides are naturally occurring and proven to be safe, exploring the effectiveness of these peptides for COVID-19 treatment might serve as an alternate way to reduce the generation of AGEs and their secondary complication in patients. ...
Article
Coronavirus Disease 2019 (COVID-19), caused by the novel virus SARS-CoV-2, is often more severe in older adults. Besides age, other underlying conditions such as obesity, diabetes, high blood pressure, and malignancies, which are also associated with aging, have been considered risk factors for COVID-19 mortality. A rapidly expanding body of evidence has brought up various scenarios for these observations and hyperinflammatory reactions associated with COVID-19 pathogenesis. Advanced glycation end products (AGEs) generated upon glycation of proteins, DNA, or lipids play a crucial role in the pathogenesis of age-related diseases and all of the above-mentioned COVID-19 risk factors. Interestingly, the receptor for AGEs (RAGE) is mainly expressed by type 2 epithelial cells in the alveolar sac, which has a critical role in SARS-CoV-2-associated hyper inflammation and lung injury. Here we discuss our hypothesis that AGEs, through their interaction with RAGE amongst other molecules, modulates COVID-19 pathogenesis and related comorbidities, especially in the elderly.
... Aryl amines are group of amines in which one or more hydrogen atoms of ammonia are replaced by aromatic groups. Likewise, various polyphenols, peptides, omega-3 fatty acids, steroids, alkaloid derivatives are also known to exhibit antiglycation activity and  -amyloid antiaggregation activity (Odjakova 2012;Hjorth et al., 2013;Perera et al., 2015;Porzoor et al., 2015;Sharma et al., 2017;Yeh et al., 2017;Freund et al., 2018;Giorgetti et al. 2018;Phan et al., 2019;Piwowar et al., 2019;Rajasekhar et al., 2020). ...
... The concentration of carnosine in RBCs is~10 times higher than in blood serum [82]. Carnosine has been shown to prevent the formation of MG-induced AGEs or even reverse AGEs previously formed [186]. Carnosine also promotes the proteolysis of aberrant proteins and exhibits viable antioxidant properties [187]. ...
Article
Full-text available
The paper overviews the peculiarities of carbonyl stress in nucleus-free mammal red blood cells (RBCs). Some functional features of RBCs make them exceptionally susceptible to reactive carbonyl compounds (RCC) from both blood plasma and the intracellular environment. In the first case, these compounds arise from the increased concentrations of glucose or ketone bodies in blood plasma, and in the second—from a misbalance in the glycolysis regulation. RBCs are normally exposed to RCC—methylglyoxal (MG), triglycerides—in blood plasma of diabetes patients. MG modifies lipoproteins and membrane proteins of RBCs and endothelial cells both on its own and with reactive oxygen species (ROS). Together, these phenomena may lead to arterial hypertension, atherosclerosis, hemolytic anemia, vascular occlusion, local ischemia, and hypercoagulation phenotype formation. ROS, reactive nitrogen species (RNS), and RCC might also damage hemoglobin (Hb), the most common protein in the RBC cytoplasm. It was Hb with which non-enzymatic glycation was first shown in living systems under physiological conditions. Glycated HbA1c is used as a very reliable and useful diagnostic marker. Studying the impacts of MG, ROS, and RNS on the physiological state of RBCs and Hb is of undisputed importance for basic and applied science.
... The dipeptides anserine (β-alanyl-3-methyl-L-histidine) and carnosine (β-alanyl-L-histidine) are good sources of antioxidant substances and serve as biomarkers in the muscle of chickens [9,11,12]; interestingly, their levels are higher in native chickens compared with commercial broilers and other meat [9,10]. In addition, anserine, also available for antifatigue with balancing of lactic acid, represents a physiological buffer in skeletal muscles [13][14][15]. ...
Article
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This study identified anserine and anserine/carnosine in chicken breast of Thai native chicken (TNC; 100% Thai native), Thai synthetic chicken (TSC; 50% Thai native), and Thai native crossbred chicken (TNC crossbred; 25% Thai native) compared with commercial broiler chicken (BR; 0% Thai native) using nuclear magnetic resonance (NMR) spectroscopy and the effect on antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl assay (DPPH). We conducted experiments with a completely randomized design and explored principal components analysis (PCA) and orthogonal projection to latent structure-discriminant analysis (OPLS-DA) to identify the distinguishing metabolites and relative concentrations from 1H NMR spectra among the groups. The relative concentrations and antioxidant properties among the groups were analyzed by analysis of variance (ANOVA) using the general linear model (GLM). This study revealed seven metabolites alanine, inositol monophosphate (IMP), inosine, and anserine/carnosine, lactate, anserine, and creatine. Lactate, anserine, and creatine were major components. In terms of PCA, the plots can distinguish BR from other groups. OPLS-DA revealed that anserine and anserine/carnosine in the chicken breast were significantly higher in TNC, TSC, and TNC crossbred than BR according to their relative concentrations and antioxidant properties (p < 0.01). Therefore, TNCs and their crossbreeds might have the potential to be functional meat sources.
... Natural micronutrients (like lipoic acid, vitamin B6 or carnosine) added into meats and vegetables were tested for type 2 diabetes patients with microalbuminuria or albuminuria, the result was satisfactory [176]. The commonly found carnosine in animal tissues can reverse AGEs formation by reducing blood glucose and preventing early glycation [177]. In high fat diet and streptozotocin inducing type 2 diabetes mellitus animal model, carnosine treatment decreases levels of serum lipids, creatinine, urea, lipids/proteins oxidation products and AGEs in rats, which may be useful for ameliorating renal dysfunction in diabetic rats [178]. ...
Article
Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease that inevitably progress to end-stage kidney disease. Intervention strategies such as blood glucose control is effective for preventing DKD, but many patients with DKD still reach end-stage kidney disease. Although comprehensive mechanisms shed light on the progression of DKD, the most compelling evidence has highlighted that hyperglycemia-related advanced glycation end products (AGEs) formation plays a central role in the pathogenesis of DKD. Pathologically, accumulation of AGEs-mediated receptor for AGEs (RAGE) triggers oxidative stress and inflammation, which is the major deleterious effect of AGEs in host and intestinal microenvironment of diabetic and ageing conditions. The activation of AGEs-mediated RAGE could evoke nicotinamide adenine dinucleotide phosphate oxidase-induced reactive oxygen and nitrogen species production and subsequently give rise to oxidative stress in DKD and ageing kidney. Therefore, targeting RAGE with its ligands mediated oxidative stress and chronic inflammation is considered as an additional intervention strategy for DKD and ageing kidney. In this review, we summarize AGEs/RAGE-mediated oxidative stress and inflammation signaling pathways in DKD and ageing kidney, discussing opportunities and challenges of targeting at AGEs/RAGE-induced oxidative stress that could hold the promising potential approach for improving DKD and ageing kidney.
... Studies have confirmed that AGEs can trigger excessive generation of reactive oxygen species (ROS) and induce abnormally high levels of oxidative stress (Rajan et al., 2018); on the other hand, high-dose dietary intake of AGEs is positively correlated with the occurrence of chronic inflammation (Gopalan et al., 2019). Therefore, excessive accumulation of AGEs makes individuals prone to oxidative stress and inflammation damage, both of which will eventually lead to the occurrence of most chronic diseases, such as cardiovascular, renal, neurodegenerative diseases and other diabetes complications (Freund, Chen, & Decker, 2018). ...
Article
Full-text available
Advanced glycation end products (AGEs) excessive accumulation in the body either by exogenous intake or endogenous formation makes individuals prone to oxidative stress and inflammation damage. In this study, DCFH-DA fluorescence test and qPCR experiment were carried out to study the effect of some dietary flavonoids on AGEs induced toxicity. Among four tested flavonoids, it was found that hesperetin could significantly inhibit both AGEs-induced ROS production and gene expressions of TNF-α, IL-1β, IL-6, MCP-1, COX-2 and iNOS. High-throughput transcriptome analysis showed that the protective effect of hesperetin against AGEs-induced toxicity might be attributed to inhibit the activation of MAPK, JAK, NF-κB-related pathways. Furthermore, gene set enrichment analysis was performed using the MSigDB database and twenty-three key genes related were screened. This study might provide new ideas for the prevention of AGEs-related diseases and lay a theoretical foundation for the application of dietary flavonoids.
... Amongst the possible products of MGO-induced glycation is the formation of argpyrimidine, caused by reaction to arginine residues and the lysine-derived AGE produces Nε-carboxymethyl-lysine (CML) and Nε(1-carboxyethyl) lysine (CEL) (Rabbani and Thornalley, 2008;Gkogkolou and Bohm, 2012;Freund et al., 2018). Argpyrimidine is the only of the AGE products with fluorescence at 370-550 nm wavelength upon excitation at 340 nm, following a procedure previously described (Praveen et al., 2011;Beisswenger et al., 2012). ...
Article
Full-text available
Epidemiological evidence shows an increased risk for developing Alzheimer’s disease in people affected by diabetes, a pathology associated with increased hyperglycemia. A potential factor that could explain this link could be the role that sugars may play in both diseases under the form of glycation. Contrary to glycosylation, glycation is an enzyme-free reaction that leads to formation of toxic advanced glycation end-products (AGEs). In diabetes, the islet amyloid polypeptide (IAPP or amylin) is found to be heavily glycated and to form toxic amyloid-like aggregates, similar to those observed for the Aβ peptides, often also heavily glycated, observed in Alzheimer patients. Here, we studied the effects of glycation on the structure and aggregation properties of IAPP with several biophysical techniques ranging from fluorescence to circular dichroism, mass spectrometry and atomic force microscopy. We demonstrate that glycation occurs exclusively on the N-terminal lysine leaving the only arginine (Arg11) unmodified. At variance with recent studies, we show that the dynamical interplay between glycation and aggregation affects the structure of the peptide, slows down the aggregation process and influences the aggregate morphology.
... 5,6 In the human body, L-carnosine regulates the autonomic nervous system and prevents the formation of advanced glycoxidation end-products (AGEs). 7,8 Additionally, L-carnosine inhibits the formation of amyloid-beta, which leads to damage to nerve cells. 9 As the therapeutic effects of this substance were revealed, L-carnosine was regarded as a new chemotherapeutic for diverse diseases. ...
... The first obvious option is to reduce the rate at which crosslinks and adducts are formed. This could be achieved by using different AGEs and ALEs inhibitors such as aminoguanidine (Thornalley, 2003), renin-angiotensin system antagonists (Miyata, 2002), pyridoxal 5′-phosphate and pyridoxal (Higuchi et al., 2006), hydralazine (Brown et al., 2006;Vindis et al., 2006), carnosine (Freund et al., 2018;Hipkiss et al., 1997) or histidine (Hobart et al., 2004), dPUFAs (Beaudoin-Chabot et al., 2019), quercetin (Bhuiyan et al., 2017), chebulic acid (Lee et al., 2014), GLY-230 (Kennedy et al., 2010), OPB-9195 (Wada et al., 2001), etc.. However, this approach has a disadvantage: at low concentrations, glycation inhibitors are inefficient while in high concentrations they could be toxic. ...
Article
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Damage accumulation in long-living macromolecules (especially extracellular matrix (ECM) proteins, nuclear pore complex (NPC) proteins, and histones) is a missing hallmark of aging. Stochastic non-enzymatic modifications of ECM trigger cellular senescence as well as many other hallmarks of aging affect organ barriers integrity and drive tissue fibrosis. The importance of it for aging makes it a key target for interventions. The most promising of them can be AGE inhibitors (chelators, O-acetyl group or transglycating activity compounds, amadorins and amadoriases), glucosepane breakers, stimulators of elastogenesis, and RAGE antagonists.
... Die Messung per Massenspektrometer geschah im Positive-Ionen-Modus mit einer kapillaren Spannung von 1000 V und einem beobachteten m/z-Verhältnis von 260,1 und wurde über UNIFI 1.9.3 (Waters, Milford, USA) aufgezeichnet und ausgewertet.3.2.1.11. Thiol-Konzentrationen in der NiereThiol-Konzentrationen wurde im Nierengewebe von55 Wochen alten Cndp1-Knockoutmäusen und Wildtypkontrollen in Zusammenarbeit mit dem Centre for Organismal Studies (COS) der Universität Heidelberg ermittelt. Jeweils 30 mg Nierengewebe wurde hierzu mit 300 µl 100 mmol/l HCl in einem Ultraschallbad homogenisiert und 2 Mal 10 Minuten bei 16400 g und 4 °C zentrifugiert. ...
Thesis
Eine protektive Wirkung von Carnosin und seines Derivats Anserin gegen Diabetes mellitus und diabetische Spätkomplikationen wie die diabetische Nephropathie wurde in zahlreichen Zell- und Mausmodellen gezeigt, ohne den zugrundeliegenden Mechanismus zu verstehen. Teilweise kontrovers diskutiert werden unterschiedliche lokale renale Schutzmechanismen wie eine anti-oxidative Wirkung oder das Abfangen und Inaktivieren verschiedener reaktiver Metabolite. In vielen, aber nicht allen, Studien mit diabetischen Tieren konnte auch ein systemischer Effekt mit einer verbesserten Glukosehomöostase gezeigt werden. Aus diesem Grund wurden Untersuchungen in einem Mausmodell mit einem Knockout des für das Carnosin abbauende Enzym Carnosinase 1 kodierenden Gens (Enzym: CN1; Gen: Cndp1) durchgeführt. In Wildtypmäusen konnte eine Carnosin abbauende Aktivität ausschließlich in der Niere gemessen werden, jedoch nicht im Gehirn, in der Leber, im Muskel, im Herz, in den Lungen, im Serum oder im Pankreas. Der dadurch quasi nierenspezifische homozygote Knockout des Cndp1-Gens erwies sich somit als weitgehend ideales Modell zur Untersuchung der Bedeutung des renalen Carnosinmetabolismus im Hinblick auf die Funktionalität und Morphologie der Nieren, nephroprotektive Systeme und anderer potenzielle Schutzmechanismen gegen den Diabetes mellitus bzw. die diabetische Nephropathie.
... In another study, Park et al. (2005) found that the serum carnosine levels were increased after 15 min from 0 to 46.0 mM/L of plasma in participants who received beef patties, and reaching the highest after 3.5 h beef consumption. The ability of carnosine to absorb intactly suggests that carnosine could be a crucial dietary intervention to suppress advanced glycation end products (AGEs) formation (Freund et al. 2018). A recent study by Cripps et al. (2017) revealed that carnosine is effective in scavenging the glucolipotoxic free radicals, for instance, RONS. ...
Book
The average life expectancy has increased worldwide in recent decades. This has presented new challenges as old age brings the onset of diseases such as cancer, neurodegenerative disorders, cardiovascular disease, type 2 diabetes, arthritis, osteoporosis, stroke, and Alzheimer’s disease. Studies and research have shown the potential preventive and therapeutic roles of antioxidants in aging and age-related diseases by inhibiting the formation or disrupting the propagation of free radicals and thus increasing healthy longevity, enhancing immune function, and decreasing oxidative stress. This has made an antioxidant rich diet of increasing importance in battling the detrimental effects of the aging process. “The Role of Antioxidants in Longevity and Age-Related Diseases” is the book that compiles research on antioxidants and their biological mechanisms that mediate age-related diseases. This book covers the major issues linked to antioxidants, aging, and age-related diseases, including changes in organ systems over the lifespan, age-related oxidative stress-induced redox imbalance, inflammaging, implications of inflammation in aging and age-related diseases, and the important role of antioxidant-rich foods in their prevention and treatment of various age-related diseases. For researchers seeking a comprehensive single source on antioxidants and their roles in aging and age-related diseases, this novel text provides an up-to-date overview.
... In particular, it has been reported that marine mammals, unlike other mammals, have skeletal muscles rich in BAL [2,3]. These compounds appear to have many beneficial effects on physiological functions such as buffering [4], antioxidative activity [5][6][7], and advanced glycation end-product inhibitory activities [8] and, consequently, may reflect the health condition of animal species. We hypothesized that serum IDPs may be useful indicators of the health of aquarium dolphins and aimed to develop an analytical method to measure the IDP content in the serum of bottlenose dolphins. ...
Article
Full-text available
The quantification of histidine-containing dipeptides (anserine, carnosine, and balenine) in serum might be a diagnostic tool to assess the health condition of animals. In this study, an existing reversed-phase ion-pair high-performance liquid chromatography (HPLC)–ultraviolet detection method was improved and validated to quantify serum anserine, carnosine, and balenine levels in the dolphin. The serum was deproteinized with trichloroacetic acid and directly injected into the HPLC system. Chromatographic separation of the three histidine-containing dipeptides was achieved on a TSK–gel ODS-80Ts (4.6 mm × 150 mm, 5 µm) analytical column using a mobile phase of 50 mmol/L potassium dihydrogen phosphate (pH 3.4) containing 6 mmol/L 1-heptanesulfonic acid and acetonitrile (96:4). The standard curve ranged from 0.1 µmol/L to 250 µmol/L. The average accuracy of the intra- and inter-analysis of anserine, carnosine, and balenine was 97–106%. The relative standard deviations of total precision (RSDr) of anserine, carnosine, and balenine in dolphin serum were 5.9%, 4.1%, and 2.6%, respectively. The lower limit of quantification of these compounds was 0.11–0.21 µmol/L. These results indicate that the improved method is reliable and concise for the simultaneous determination of anserine, carnosine, and balenine in dolphin serum, and may be useful for evaluation of health conditions in dolphins. Furthermore, this method can also be applied to other biological samples.
... Michael A et al. reported that the inhibition of AGEs by strongly nucleophilic amino acids (e.g., cysteine and histidine) helps reduce diabetic and age-related complications. Since cysteine has a greater potency to inhibit AGEs, it could be an alternative for preventing diabetes-related complications via reduced AGE formation [38]. In the case of cystine, LR-20, a cystine derivative, demonstrated very high post-amadori inhibitory and metal chelation properties, but with low to moderate carbonyl scavenger properties. ...
Article
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Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a key precursor of the formation of advanced glycation end products (AGEs). MGO and MGO-AGEs were reportedly increased in patients with diabetic dysfunction, including diabetic nephropathy. The activation of glyoxalase-I (GLO-I) increases MGO and MGO-AGE detoxification. MGO-mediated glucotoxicity can also be ameliorated by MGO scavengers such as N-acetylcysteine (NAC), aminoguanidine (AG), and metformin. In this study, we noted that l-cysteine demonstrated protective effects against MGO-induced glucotoxicity in renal mesangial cells. l-cysteine prevented MGO-induced apoptosis and necrosis, together with a reduction of reactive oxygen species (ROS) production in MES13 cells. Interestingly, l-cysteine significantly reduced MGO-AGE formation and also acted as an MGO-AGE crosslink breaker. Furthermore, l-cysteine treatment accelerated MGO catabolism to D-lactate via the upregulation of GLO-I. The reduction of AGE formation and induction of AGE breakdown, following l-cysteine treatment, further supports the potential use of l-cysteine as an alternative for the therapeutic control of MGO-induced renal complications in diabetes, especially against diabetic nephropathy.
... In another study, Park et al. (2005) found that the serum carnosine levels were increased after 15 min from 0 to 46.0 mM/L of plasma in participants who received beef patties, and reaching the highest after 3.5 h beef consumption. The ability of carnosine to absorb intactly suggests that carnosine could be a crucial dietary intervention to suppress advanced glycation end products (AGEs) formation (Freund et al. 2018). A recent study by Cripps et al. (2017) revealed that carnosine is effective in scavenging the glucolipotoxic free radicals, for instance, RONS. ...
Chapter
Substantial studies have suggested that natural compounds rich in antioxidants can enhance the immune system and decrease oxidative stress. These substances facilitate in scavenging the reactive species that initiate the peroxidation, inhibit the formation of peroxides, breaking the autoxidative chain reaction, and quenching •O2⁻. The molecules with antioxidants properties such as low molecular weight antioxidant, glutathione, polyphenol, carotenoids, minerals, ascorbic acid, vitamin E, ubiquinone, organosulfur compounds, ergothioneine, betalains, and carnosine/anserine have demonstrated their potential in the alleviation of age-related diseases. However, the exact molecular mechanisms of these molecules involved in the prevention of age-related diseases are worth discussing further. In this chapter, we discussed the biological mechanism of molecules with antioxidant activity against age-related diseases. Overall, a better understanding of the mode of action of antioxidants involved in the redox imbalance in age-related diseases would provide a useful approach in mediating diseases.
... It traps reactive carbonyl precursor such as MGO, GO, and 3-DG to non-hazardous product (Jud & Sourij, 2019). Alagebrium chloride (ALT-711) (Freund, Chen, & Decker, 2018), SGLT2 (Hemmler et al., 2017), metformin, irbesartan (Wei & Huang, 2017), thiazolidinediones, OPB-9195, ACE inhibitors, carnosine, AT1 antagonists, aspirin, benfotiamine (Sourris, Harcourt, & Forbes, 2009), calcium antagonists, amlodipine, kinetin, quinine, 6-dimethylaminopyridoxamine (Peng, Ma, Chen, & Wang, 2011) are some of the synthetic inhibitors. The synthetic inhibitor inhibit the AGEs but there is a safety concerns and side effects of these synthetic inhibitors, like weakened liver, anemia, vomiting, gastrointestinal disorders, diarrhea, dizziness, headache flu and lupus like symptoms and also an ANCA-related vasculitis, that's why the usage of synthetic inhibitors in food products have been banned by the food laws (Peng et al., 2011;Taguchi, Sugiura, Hamada, & Miwa, 1998;Wei & Huang, 2017). ...
... These new generated species are important in the light scattering of eye lenses. The acetylated form of carnosine has also been indicated to inhibit the protein crosslinking due to AGE formation in the lenticular tissues [62,63]. The DLS results (Fig. 7) also suggest the significant protection of carnosine against MGO-induced oligomeric shift of the eye lens proteins to the larger sizes. ...
Article
Full-text available
The elevated lenticular level of methylglyoxal (MGO) in diabetic patients is an important risk factor for the development of age-related (senile) cataract disorders. Carnosine (β-alanyl L-histidine), a natural antioxidant dipeptide product, has been indicated to prevent the development of cataract diseases. Therefore, it is possible that the anti-cataract activity of this naturally occurring compound is mediated by its anti-glycoxidation effect. In this study, the eye lens proteins were treated with MGO in the presence of carnosine. Then, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis and several spectroscopic evaluations were used with the aim to investigate the possible inhibitory activity of carnosine against the MGO-induced structural damages of eye lens proteins. Our results indicated that MGO causes a substantial structural alteration in the lens proteins. The results of fluorescence assessments also suggested that MGO-induced structural changes were accompanied with the formation of additional chromophores in the protein structure. Also, in the presence of carnosine, a notable reduction in the protein structural damages was observed. Our results may highlight an important protective role of carnosine against MGO-induced structural insults in the lens proteins. This study suggests carnosine supplementation as a possible preventive strategy against development of the diabetic cataracts in human.
Article
This meta-analysis was conducted to compare skin autofluorescence (SAF) levels as a measure of advanced glycation end products (AGEs) accumulation between diabetic and non-diabetic dialysis patients. Relevant studies were identified primarily by searching PubMed/MEDLINE and other online databases and manual searching of cross-references. Random-effects model was used to obtain standardized mean differences (SMD) as a summary statistic. Heterogeneity was tested with meta-regression and sub-group analyses. Publication bias and robustness of this meta-analysis were tested using funnel plot and sensitivity analyses. A total of 11 reports comparing SAF between diabetic and non-diabetic dialysis patients were finally included in this meta-analysis. Dialysis patients with diabetes showed significantly higher circulatory SAF levels than their non-diabetic counterparts (SMD = 0.39; P < 0.0001). The difference was more evident in hemodialysis modality (SMD = 0.40; P < 0.0001). A one-study leave-out sensitivity analysis validated the robustness of this meta-analysis. The presence of diabetes in dialysis patients is associated with increased AGEs accumulation reflected through SAF measurements using a novel and non-invasive AGE-Reader™ technology. Our findings are in support of considering anti-AGE therapeutic strategies in addition to standard glycemic management in dialysis patients with diabetes.
Chapter
Nonenzymic glycation of proteins is believed to be the root cause of high dietary sugar–associated pathophysiological maladies in type II diabetes. Chronic persistence of reducing sugars in the intracellular milieu results in the formation of Schiff base adducts in proteins involving the terminal amino groups, side chains of arginine and lysine residues, and free thiol groups of cysteines. Glycation eventualize in accumulation of a cluster of terminally misfolded proteins termed as advanced glycation end products (AGEs) whose formation is accelerated under oxidative stress. The AGEs and the intermediate glycated isoforms have diverse consequences inside the body. They can lead to deposition of toxic amyloid fibrils or mediate irreversible cross-linking of extracellular matrix proteins; most significantly, they are responsible for activation of the AGE–receptor for AGE (RAGE) signaling pathway leading to a plethora of cellular responses including inflammation and apoptosis. Although many of the consequences of glycation-mediated cellular damage have been delineated in much detail, we are yet to understand completely many the structure–function relationships of the AGE isoforms and the basis of their increased half-life under in vivo conditions. It is also insightful to investigate on an evolutionary perspective that whether the RAGE signaling pathway is a cellular defense mechanism to counter the recalcitrant AGE from creating a misfolded protein-induced cellular wreckage. Recent understandings of the molecular basis of AGE formation have suggested that maintenance of a healthy lifestyle with regular workouts along with consumption of low-carbohydrate diet rich in antioxidants are the keys to keep diabetes at bay.
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Haskap (Lonicera caerulea L.) is a recently commercialized fruit crop in Canada. Berries of four cultivars, Aurora, Rebecca, Larissa, and Evie, were harvested at five harvesting dates (H1-H5) and assessed for their polyphenol composition and anti-diabetic potential in vitro. The analyses revealed that the interaction effect of cultivar and harvesting date influenced the concentration of anthocyanins. Cyanidin-3-O-glucoside represents about 79 % of total anthocyanins present in ripened haskap berries. Total anthocyanins estimated by a non-destructive method showed a strong correlation for quantified anthocyanin by liquid chromatography-mass spectrometry (UPLC-ESI-MS), indicating the potential application of the non-destructive method for deciding the berry maturity for mechanical harvesting of haskap berry for value-added processing. Extracts derived from five maturity stages of four cultivars showed anti-diabetic properties including inhibition of activities of alpha-amylase (IC50 ranges from 2380 to 5080 μg/mL), alpha-glucosidase (IC50 ranges from 1130 to 2120 μg/mL), dipeptidyl peptidase-4 (DPP-4, IC50 ranges from 2150 to 11,600 μg/mL), and formation of advanced glycation end-products (AGE, IC50 ranges from 1200 to 4790 μg/mL) in vitro. Though the impact of harvesting date on polyphenol composition is very distinct, the extracts of late harvesting date (H5) reduced the anti-diabetic activities in vitro only in Aurora and Larisa cultivars. Inhibition of DPP-4 and AGE formation dependent on cultivar and harvesting date. Haskap berry warrants further investigation as a dietary therapeutic to manage type 2 diabetes.
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Metabolic syndrome (MS) is a prominent cause of death worldwide, posing a threat to the global economy and public health. A mechanism that causes the oxidation of low-density lipoproteins (LDL) is associated with metabolic abnormalities. Various processes are involved in oxidative stress (OS) of lipoprotein. Although the concept of the syndrome has been fiercely debated, this confluence of risk factors is associated with a higher chance of acquiring type 2 diabetes mellitus (T2DM) and atherosclerosis. Insulin resistance has been found to play a significant role in the progression of these metabolism-associated conditions. It causes lipid profile abnormalities, including greater sensitivity to lipid peroxidation, contributing to the increased prevalence of T2DM and atherosclerosis. This review aims to cover the most recent scientific developments in dietary OS, the consequence of metabolic disorders, and their most significant clinical manifestations (T2DM and atherosclerosis). It will also emphasize the effects of dietary approaches in alleviating OS in MS.
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The ability of histidine to scavenge sugar-derived 1,2-dicarbonyl compounds was investigated using aqueous methanolic model systems containing histidine or histamine in the presence of glucose, methylglyoxal, or glyoxal. The samples were prepared either at room temperature (RT) or at 150 °C and analyzed using ESI-qTOF-MS/MS and isotope labeling technique. Replacing glucose with [U-¹³C6]glucose allowed the identification of glucose carbon atoms incorporated in the products. Various sugar-generated carbonyl compounds ranging in size from C1 to C6 were captured by histidine or histamine. The majority of the fragments incorporated were either C3 or C2 units originating from glyoxal (C2) or methylglyoxal (C3). The ESI-qTOF-MS/MS analysis indicated that histamine could react with either of the two carbonyl carbons of methylglyoxal utilizing the α-amino group and/or the imidazolium moiety. Furthermore, when histidine was added to 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) generating model system, it completely suppressed the formation of PhIP due to scavenging of phenylacetaldehyde.
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Contaminated poultry meat is a major source of human foodborne illnesses. Many interventions have been developed to reduce and/or eliminate human foodborne pathogens in poultry products; however, treatments with cold plasma or carnosine or their combination have not been extensively investigated. In this study, the bacterial microflora of poultry meat samples after treatments with cold plasma and carnosine were characterized with EcoPlates in the OmniLog system. The plates were incubated at 25°C for 7 days in the OmniLog chamber, and bacterial growth was monitored by recording formazan production every 30 min at an optical density of 590 nm. The kinetics of lag, log, and stationary phases of bacterial growth followed the Gompertz sigmoidal model but with different inflection times and asymptotes at the log phase and the stationary phase, respectively. Results indicated that treatment of poultry meat samples with cold plasma technology and carnosine could inhibit growth of the bacteria in the treated meat samples. Of 31 chemicals tested, phenylethylamine, α-d-lactose, d,l-α-glycerol phosphate, 2-hydroxybenzoic acid, γ-hydroxybutyric acid, α-ketobutyric acid, and d-malic acid could not be metabolized by bacteria in the meat samples. Future research is required to determine whether these seven chemicals that inhibited growth of bacteria in these meat samples can be used as food preservatives for extending the shelf life of these products. Whether the bacterial flora can be an indicator of effectiveness for meat samples treated with cold plasma, carnosine, or both needs further study. Highlights:
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The inhibition effect of urea on ovalbumin (OVA) glycation was investigated, and the mechanism was evaluated through the changes in protein structure as well as glycation sites and average degree of substitution per peptide molecule (DSP) by conventional spectrometry and liquid chromatography-high resolution mass spectrometry (LC-HRMS). A urea concentration of 3 M was chosen as the optimum condition. Ultraviolet and fluorescence spectra suggested that both glycation and urea treatment could unfold the OVA, but urea inhibited the glycation-induced protein unfolding. Circular dichroism spectra showed that urea treatment could increase the β-sheet content and reduce the α-helix content of OVA. LC-HRMS indicated that the number of glycation sites was reduced from 15 to 3, and DSP values decreased with urea treatment. In conclusion, urea could significantly inhibit the OVA-glucose glycation, and the sites competition as well as structure unfolding inhibition resulted from urea could be the main factors.
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Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease that inevitably progress to end-stage kidney disease. Intervention strategies such as blood glucose control is effective for preventing DKD, but many patients with DKD still reach end-stage kidney disease. Although comprehensive mechanisms shed light on the progression of DKD, the most compelling evidence has highlighted that hyperglycemia-related advanced glycation end products (AGEs) formation plays a central role in the pathogenesis of DKD. Pathologically, accumulation of AGEs-mediated receptor for AGEs (RAGE) triggers oxidative stress and inflammation, which is the major deleterious effect of AGEs in host and intestinal microenvironment of diabetic and ageing conditions. The activation of AGEs-mediated RAGE could evoke nicotinamide adenine dinucleotide phosphate oxidase-induced reactive oxygen and nitrogen species production and subsequently give rise to oxidative stress in DKD and ageing kidney. Therefore, targeting RAGE with its ligands mediated oxidative stress and chronic inflammation is considered as an additional intervention strategy for DKD and ageing kidney. In this review, we summarize AGEs/RAGE-mediated oxidative stress and inflammation signaling pathways in DKD and ageing kidney, discussing opportunities and challenges of targeting at AGEs/RAGE-induced oxidative stress that could hold the promising potential approach for improving DKD and ageing kidney.
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Advanced glycation end products (AGEs) are a group of complex compounds generated by nonenzymatic interactions between proteins and reducing sugars or lipids. AGEs accumulate in vivo and activate various signaling pathways closely related to the occurrence of various chronic metabolic diseases. In this paper, we describe the process through which AGEs are formed, the classification of AGEs, and biological effects of AGEs on human health. Most importantly, we review recent progress in natural compound-based AGE formation inhibitors. Major classes of natural inhibitors, including polyphenols, polysaccharides, terpenoids, vitamins and alkaloids, have been described. Their mechanisms of action have been summarized as scavenging free radicals, chelating metal ions, capturing active carbonyl compounds, protecting protein glycation sites, and lowering blood glucose levels. Although these natural compounds have good antiglycation activity, to date, they are not widely used in the clinic, likely because of their low content levels. However, these natural compounds and their molecular frameworks will play a valuable role in inspiring drug discovery.
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Advanced glycosylation end products (AGEs) and N-nitrosamines (NAs) are common hazards in the processing of meat products. AGEs are produced by Maillard reaction and fat oxidation during processing and storage, whereas NAs are produced by nitrosation after the addition of nitrite during meat processing. They may have some relevance to human diseases, such as diabetes and cancer. Literature revealed that the contents of fat and protein in meat products and processing methods have a remarkable influence on the formation of AGEs and NAs. These two hazardous substances can be detected in a variety of meat products, and adding antioxidants can effectively inhibit the production of AGEs and NAs. This paper reviews the formation mechanism, influencing factors, detection methods, and inhibition methods of AGEs and NAs in meat products and discusses their exposure values in meat products to provide reference for people's healthy diet and understand and control the levels of AGEs and NAs in meat products.
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This study shows the inhibitory effect of sea buckthorn (Hippophae rhamnoides L.) extracts, sea buckthorn leaf (HRL) and berry (HRB), on the formation of advanced glycation endproducts (AGEs), closely linked to diverse disease. In vitro assay revealed the superior inhibitory effect of HRL on the AGEs formation and AGEs-induced collagen crosslinking compared with that of HRB. Ultra-performance liquid chromatography-mass spectrometry results revealed that HRL displays a higher inhibition efficiency on the AGEs formation at 30 AGEs binding sites in bovine serum albumin than HRB. The high concentration of 3-sophoroside-7-rhamnoside in HRL compared with that in HRB may result in the strong inhibitory effect of HRL compared with that of HRB. HRL also exhibited significantly higher ABTS and DPPH radical scavenging activities than HRB. Overall, this study demonstrated that HRL has excellent potential as a dietary agent for controlling various diseases mediated by AGEs and oxidative stress.
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Various harmful Maillard reaction products such as lactulosyl-lysine (furosine), furfurals, and advanced glycation end products (AGEs) could be formed during the thermal processing of dairy products, which could lead to various chronic diseases. In this review, the furosine, furfurals, and AGEs formation, occurrence, analysis methods, and toxicological and health aspects in various dairy products were summarized to better monitor and control the levels of harmful Maillard reaction products in processed dairy products. It was observed that all types of dairy products, including raw milk, contain harmful Maillard reaction products, with the highest in whey cheese and condensed milk. High-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the common method for the determination of furosine and furfurals and AGEs in dairy products, respectively. However, the simple, rapid, environment-friendly, and accurate methods of determination are still to be developed. Incorporating resveratrol, pectin oligosaccharides (POS) in milk are effective methods to inhibit AGEs formation. This review provides a guide not only for consumers regarding the selection and consumption of dairy products, but also for monitoring and controlling the quality of dairy products.
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Glycated protein is a kind of substance that often exists in the human body through the combination of sugar and protein under enzyme or non-enzyme conditions. Enzyme-catalyzed glycated proteins are widely distributed in the human body and participate in life activities such as human growth and immune regulation. Non-enzymatic glycated protein is often related to cancer, aging, diabetes and other diseases, but in vitro non-enzymatic glycated protein has utility value after modification. This review not only discussed the effects of enzymatic glycated protein on human intestinal health, immune regulation and cancer prevention. The inhibition methods of non-enzymatic glycated protein in food processing, digestion, absorption and metabolism were also elucidated.
Chapter
Through a long evolutionary process, cyanobacteria have become extremely environmentally adaptable, by developing unique survival strategies. As a result, cyanobacteria are distributed throughout Earth, including in extreme environments such as hypersaline lakes, hot springs, deserts, volcanoes, highlands, and polar regions. Cyanobacteria that live in extreme environments are outlined in Chapter 7. Cyanobacteria are known to biosynthesize specific secondary metabolites, as one of their molecular mechanisms for adapting to their environment. Of these secondary metabolites, osmotic pressure-compatible solutes will be described in detail in Chapter 9. The current chapter will focus on mycosporine-like amino acids (MAAs) and scytonemin, which are multifunctional secondary metabolites that cyanobacteria are able to accumulate. We will also discuss the relevant properties and potential applications of these substances.
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The accumulation of advanced glycation end-products (AGEs) in the organic matrix of bone with aging and chronic disease such as diabetes is thought to increase fracture risk independently of bone mass. However, to date, there has not been a clinical trial to determine whether inhibiting the accumulation of AGEs is effective in preventing low-energy, fragility fractures. Moreover, unlike with cardiovascular or kidney disease, there are also no pre-clinical studies demonstrating that AGE inhibitors or breakers can prevent the age- or diabetes-related decrease in the ability of bone to resist fracture. In this review, we critically examine the case for a long-standing hypothesis that AGE accumulation in bone tissue degrades the toughening mechanisms by which bone resists fracture. Prior research into the role of AGEs in bone has primarily measured pentosidine, an AGE crosslink, or bulk fluorescence of hydrolysates of bone. While significant correlations exist between these measurements and mechanical properties of bone, multiple AGEs are both non-fluorescent and non-crosslinking. Since clinical studies are equivocal on whether circulating pentosidine is an indicator of elevated fracture risk, there needs to be a more complete understanding of the different types of AGEs including non-crosslinking adducts and multiple non-enzymatic crosslinks in bone extracellular matrix and their specific contributions to hindering fracture resistance (biophysical and biological). By doing so, effective strategies to target AGE accumulation in bone with minimal side effects could be investigated in pre-clinical and clinical studies that aim to prevent fragility fractures in conditions that bone mass is not the underlying culprit.
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Introduction: Currently, 424 million people aged between 20-79 years worldwide are diabetic. More than 25% of adults aged over 65 years in North America have Type 2 diabetes mellitus (DM). Diabetes-induced osteoporosis (DM-OS) is caused by chronic hyperglycemia, advanced glycated end products and oxidative stress. The increase in the prevalence of DM-OS has prompted researchers to develop new biological therapies for the management of DM-OS. Areas covered: This review covered the current and novel biological agents used in the management of DM-OS. Data were retrieved from PubMed, Scopus, American Diabetes Association and International Osteoporosis Foundation websites, and ClinicalTrials.gov. The keywords for the search included: DM, osteoporosis, and management. Expert opinion: Several biological molecules have been examined in order to find efficient drugs for the treatment of DM-OS. These biological agents include anti-osteoporosis drugs: net anabolics (parathyroid hormone/analogues, androgens, calcilytics, anti-sclerostin antibody), net anti-resorptive osteoporosis drugs (calcitonin, estrogen, selective estrogen receptor modulators, bisphosphonates, RANKL antibody) and anti-diabetic drugs (alpha glucosidase inhibitors, sulfonylureas, biguanides, meglitinides, thiazolidinediones, GLP-1 receptor agonists, dipeptidylpeptidase-4 inhibitors, sodium glucose co-transporter-2 inhibitors, insulin). Biological medications that effectively decrease hyperglycemia and, at the same time, maintain bone health would be an ideal drug/drug combination for the treatment of DM-OS.
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Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG-AGEs) in MI using transgenic mice that over-express the MG-metabolizing enzyme glyoxalase-1 (GLO1). MI was induced in GLO1 mice and wild-type (WT) littermates. At 6 h post-MI, mass spectrometry revealed that MG-H1 (a principal MG-AGE) was increased in the hearts of WT mice, and immunohistochemistry demonstrated that this persisted for 4 weeks. GLO1 over-expression reduced MG-AGE levels at 6 h and 4 weeks, and GLO1 mice exhibited superior cardiac function at 4 weeks post-MI compared to WT mice. Immunohistochemistry revealed greater vascular density and reduced cardiomyocyte apoptosis in GLO1 vs. WT mice. The recruitment of c-kit⁺ cells and their incorporation into the vasculature (c-kit⁺CD31⁺ cells) was higher in the infarcted myocardium of GLO1 mice. MG-AGEs appeared to accumulate in type I collagen surrounding arterioles, prompting investigation in vitro. In culture, the interaction of angiogenic bone marrow cells with MG-modified collagen resulted in reduced cell adhesion, increased susceptibility to apoptosis, fewer progenitor cells, and reduced angiogenic potential. This study reveals that MG-AGEs are produced post-MI and identifies a causative role for their accumulation in the cellular changes, adverse remodeling and functional loss of the heart after MI. MG may represent a novel target for preventing damage and improving function of the infarcted heart.
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Background Advanced glycation end-products (AGEs) are elevated under diabetic conditions and associated with insulin resistance, endothelial dysfunction and vascular inflammation in humans. It has been demonstrated that AGEs evoke oxidative and inflammatory reactions in endothelial cells through the interaction with a receptor for AGEs (RAGE). Here, we aimed to identify the cellular mechanisms by which AGEs exacerbate the endothelial dysfunction in human coronary artery endothelial cells (HCAECs). Methods 30 type 2 diabetic patients with or without coronary artery atherosclerosis were recruited for this study. Plasma levels of AGE peptides (AGE-p) were analyzed using flow injection assay. Endothelial function was tested by brachial artery flow-mediated vasodilatation (FMD). Further investigations were performed to determine the effects and mechanisms of AGEs on endothelial dysfunction in HCAECs. Results AGE-p was inversely associated with FMD in diabetic patients with coronary artery atherosclerosis in our study. After treated with AGEs, HCAECs showed significant reductions of eNOS mRNA and protein levels including eNOS and phospho-eNOS Ser1177, eNOS mRNA stability, eNOS enzyme activity, and cellular nitric oxide (NO) levels, whereas superoxide anion production was significantly increased. In addition, AGEs significantly decreased mitochondrial membrane potential, ATP content and catalase and superoxyde dismutase (SOD) activities, whereas it increased NADPH oxidase activity. Treatment of the cells with antioxidants SeMet, SOD mimetic MnTBAP and mitochondrial inhibitor thenoyltrifluoroacetone (TTFA) effectively blocked these effects induced by AGEs. AGEs also increased phosphorylation of the mitogen-activated protein kinases p38 and ERK1/2, whereas the specific inhibitors of p38, ERK1/2, and TTFA effectively blocked AGEs-induced reactive oxygen species production and eNOS downregulation. Conclusions AGEs cause endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in HCAECs through activation of p38 and ERK1/2. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0531-9) contains supplementary material, which is available to authorized users.
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Background: The consumption of advanced glycation end products (AGEs) has increased because of modern food processing and has been linked to the development of type 2 diabetes in rodents. Objective: We determined whether changing dietary AGE intake could modulate insulin sensitivity and secretion in healthy, overweight individuals. Design: We performed a double-blind, randomized, crossover trial of diets in 20 participants [6 women and 14 men; mean ± SD body mass index (in kg/m(2)): 29.8 ± 3.7]. Isoenergetic- and macronutrient-matched diets that were high or low in AGE content were alternately consumed for 2 wk and separated by a 4-wk washout period. At the beginning and end of each dietary period, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test were performed. Dietary, plasma and urinary AGEsN(€)-(carboxymethyl)lysine (CML),N(€)-(carboxyethyl)lysin (CEL), and methylglyoxal-derived hydroimadazolidine (MG-H1) were measured with the use of mass spectrometry. Results: Participants consumed less CML, CEL, and MG-H1 during the low-AGE dietary period than during the high-AGE period (allP< 0.05), which was confirmed by changes in urinary AGE excretion. There was an overall difference in insulin sensitivity of -2.1 mg · kg(-1)· min(-1)between diets (P= 0.001). Insulin sensitivity increased by 1.3 mg · kg(-1)· min(-1)after the low-AGE diet (P= 0.004), whereas it showed a tendency to decrease by 0.8 mg · kg(-1)· min(-1)after the high-AGE diet (P= 0.086). There was no difference in body weight or insulin secretion between diets (P= NS). Conclusions: A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity. Hence, a restriction in dietary AGE content may be an effective strategy to decrease diabetes and cardiovascular disease risks in overweight individuals. This trial was registered atclinicaltrials.govasNCT00422253.
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There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic.
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Background: The influence of mixed dietary patterns on cognitive changes is unknown. Methods: A total of 2223 dementia-free participants aged ≥60 were followed up for 6 years to examine the impact of dietary patterns on cognitive decline. Mini-mental state examination (MMSE) was administrated. Diet was assessed by a food frequency questionnaire. By factor analysis, Western and prudent dietary patterns emerged. Mixed-effect models for longitudinal data with repeated measurements were used. Results: Compared with the lowest adherence to each pattern, the highest adherence to prudent pattern was related to less MMSE decline (β = 0.106, P = .011), whereas the highest adherence to Western pattern was associated with more MMSE decline (β = -0.156, P < .001). The decline associated with Western diet was attenuated when accompanied by high adherence to prudent pattern. Conclusion: High adherence to prudent diet may diminish the adverse effects of high adherence to Western diet on cognitive decline.
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Significance Suppression of NAD ⁺ -dependent sirtuin 1 (SIRT1) is linked to dementia or Alzheimer’s disease (AD) and the metabolic syndrome (MS). Because advanced glycation end products (AGEs) promote MS and neurotoxicity, we conducted studies of C57BL6 mice fed isocaloric diets containing defined AGEs [methyl-glyoxal derivatives (MG)] to determine whether food AGEs promote AD and MS. MG ⁺ -fed, but not MG ⁻ -fed, mice developed brain SIRT1 deficiency, amyloid-β deposits, cognitive and motor deficits, and MS. These findings were validated in older healthy humans with high baseline circulating MG levels by a time-dependent decline in cognition and insulin sensitivity. The data suggest that food-derived AGEs, an environmental factor, contribute to both AD and MS by causing chronic SIRT1 suppression. Importantly, reduction of food-derived AGEs is feasible and may provide an effective treatment strategy for both these epidemics.
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N-(Carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugated dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate; only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML, was also formed during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
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Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 ± 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 ± 4.4% of baseline (B), P = 0.007; AGI to 41 ± 7.3% of B, P = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 ± 2.7% of B, P = 0.02; stroke volume index (SVindex) to 173.1 ± 40.1% of B, P = 0.01; and systolic fractional shortening to 180 ± 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SVindex, an estimate of total LV vascular load, decreased to 60 ± 12.1% of B (P = 0.02). The LV end systolic diameter/SVindex, an estimate of arterio-ventricular coupling, was improved (decreased to 54.3 ± 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.
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OBJECTIVES Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified β-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T(0)), 90 (T(90)), and 180 (T(180)) min.RESULTSFollowing the AGE-BLG, FMD decreased at T(90) by 80% from baseline and remained decreased by 42% at T(180) (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T(90) and 51% at T(180) (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T(180)) and nitrate (T(90) and T(180)), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage.CONCLUSIONS In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment.
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This is an introduction to a collection of review articles by leading investigators in the field of protein glycation research, see following articles in this issue. With this we launch a section of this journal now established for presentation of research results, reviews and commentaries on protein glycation and related topics. Glycation is the spontaneous, non-enzymatic reaction of protein with saccharides and saccharide derivatives. Although studied in the modern scientific era for over 100 years, its importance in the biology, medicine, food and nutrition, pharmacology and toxicology, and technological processing remains intriguingly undisclosed. In this section of amino acids, research on glycation is a qualifier for publication. Glycation research now has a place to call home.
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Increased oxidative stress (OS) and impaired anti-OS defenses are important in the development and persistence of insulin resistance (IR). Several anti-inflammatory and cell-protective mechanisms, including advanced glycation end product (AGE) receptor-1 (AGER1) and sirtuin (silent mating-type information regulation 2 homolog) 1 (SIRT1) are suppressed in diabetes. Because basal OS in type 2 diabetic patients is influenced by the consumption of AGEs, we examined whether AGE consumption also affects IR and whether AGER1 and SIRT1 are involved. The study randomly assigned 36 subjects, 18 type 2 diabetic patients (age 61±4 years) and 18 healthy subjects (age 67±1.4 years), to a standard diet (>20 AGE equivalents [Eq]/day) or an isocaloric AGE-restricted diet (<10 AGE Eq/day) for 4 months. Circulating metabolic and inflammatory markers were assessed. Expression and activities of AGER1 and SIRT1 were examined in patients' peripheral blood mononuclear cells (PMNC) and in AGE-stimulated, AGER1-transduced (AGER1+), or AGER1-silenced human monocyte-like THP-1 cells. Insulin and homeostasis model assessment, leptin, tumor necrosis factor-α and nuclear factor-κB p65 acetylation, serum AGEs, and 8-isoprostanes decreased in AGE-restricted type 2 diabetic patients, whereas PMNC AGER1 and SIRT1 mRNA, and protein levels normalized and adiponectin markedly increased. AGEs suppressed AGER1, SIRT-1, and NAD+ levels in THP-1 cells. These effects were inhibited in AGER1+ but were enhanced in AGER1-silenced cells. Food-derived pro-oxidant AGEs may contribute to IR in clinical type 2 diabetes and suppress protective mechanisms, AGER1 and SIRT1. AGE restriction may preserve native defenses and insulin sensitivity by maintaining lower basal OS.
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To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness. We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of N(ε)-(carboxymethyl)lysine, N(ε)-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6-12.5) years. During the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03-1.66) and HR = 1.27 (1.00-1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness. Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.
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Aging is a complex multifactorial process characterized by accumulation of deleterious changes in cells and tissues, progressive deterioration of structural integrity and physiological function across multiple organ systems, and increased risk of death. We conducted a review of the scientific literature on the relationship of advanced glycation end products (AGEs) with aging. AGEs are a heterogeneous group of bioactive molecules that are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids. Humans are exposed to AGEs produced in the body, especially in individuals with abnormal glucose metabolism, and AGEs ingested in foods. AGEs cause widespread damage to tissues through upregulation of inflammation and cross-linking of collagen and other proteins. AGEs have been shown to adversely affect virtually all cells, tissues, and organ systems. Recent epidemiological studies demonstrate that elevated circulating AGEs are associated with increased risk of developing many chronic diseases that disproportionally affect older individuals. Based on these data, we propose that accumulation of AGEs accelerate the multisystem functional decline that occurs with aging, and therefore contribute to the aging phenotype. Exposure to AGEs can be reduced by restriction of dietary intake of AGEs and drug treatment with AGE inhibitors and AGE breakers. Modification of intake and circulating levels of AGEs may be a possible strategy to promote health in old age, especially because most Western foods are processed at high temperature and are rich in AGEs.
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The modern Western lifestyle is characterized by the consumption of high-heat-treated foods because of their characteristic taste and flavor. However, it has been shown that treating food at high temperatures can generate potentially harmful compounds that promote inflammation and cardiovascular disease in subjects with diabetes. The aim of this study was to determine whether high-heat-treated foods also pose a risk for healthy subjects. A randomized, crossover, diet-controlled intervention trial with 62 volunteers was designed to compare the potential metabolic effects of 2 diets, one that was based on mild steam cooking and another that was based on high-temperature cooking. These 2 diets differed mainly in their contents of Maillard reaction products (MRPs). MRPs were assessed in the diet and in subjects' feces, blood, and urine samples, with N(epsilon)-carboxymethyllysine as an indicator of MRPs. Biological indicators of glucose and lipid metabolism as well as oxidative stress were analyzed in subjects after 1 mo on each diet. In comparison with the steamed diet, 1 mo of consuming the high-heat-treated diet induced significantly lower insulin sensitivity and plasma concentrations of long-chain n-3 (omega-3) fatty acids and vitamins C and E [-17% (P < 0.002), -13% (P < 0.0001), and -8% (P < 0.01), respectively]. However, concentrations of plasma cholesterol and triglycerides increased [+5% (P < 0.01) and +9% (P < 0.01), respectively]. A diet that is based on high-heat-treated foods increases markers associated with an enhanced risk of type 2 diabetes and cardiovascular diseases in healthy people. Replacing high-heat-treatment techniques by mild cooking techniques may help to positively modulate biomarkers associated with an increased risk of diabetes mellitus and cardiovascular diseases.
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Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus. Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A1c and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.
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It has been extensively reported that diabetes mellitus (DM) patients have a higher risk of developing Alzheimer's disease (AD), but a mechanistic connection between both pathologies has not been provided so far. Carbohydrate-derived advanced glycation endproducts (AGEs) have been implicated in the chronic complications of DM and have been reported to play an important role in the pathogenesis of AD. The earliest histopathological manifestation of AD is the apparition of extracellular aggregates of the amyloid beta peptide (Abeta). To investigate possible correlations between AGEs and Abeta aggregates with both pathologies, we have performed an immuhistochemical study in human post-mortem samples of AD, AD with diabetes (ADD), diabetic and nondemented controls. ADD brains showed increased number of Abeta dense plaques and receptor for AGEs (RAGE)-positive and Tau-positive cells, higher AGEs levels and major microglial activation, compared to AD brain. Our results indicate that ADD patients present a significant increase of cell damage through a RAGE-dependent mechanism, suggesting that AGEs may promote the generation of an oxidative stress vicious cycle, which can explain the severe progression of patients with both pathologies.
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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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To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality. The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, double dagger 65 years, in Baltimore, Maryland. During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [HR] for highest vs lower three quartiles, 1.94, 95% Confidence Interval [CI] 1.08-3.48, p=0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (HR per 1 Standard Deviation [SD] 1.27, 95% CI 0.98-1.65, p=0.07; HR 1.28, 95% CI 1.02-1.63, p=0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (HR for highest vs lower three quartiles, 2.29, 95% CI 1.21-4.34, p=0.01; HR per 1 SD, 1.24, 95% CI 0.92-1.65, p=0.16; HR per 1 SD 1.45, 95% CI 1.08-1.93, p=0.01), after adjusting for the same covariates. High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.
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Glucose reacts nonenzymatically with proteins in vivo, chemically forming covalently attached glucose-addition products and cross-links between proteins. The excessive accumulation of rearranged late-glucose-addition products, or advanced glycosylation end products (AGEs), is believed to contribute to the chronic complications of diabetes mellitus. To elucidate the relation of AGEs to diabetic complications, we used a radioreceptor assay to measure serum and tissue AGEs in diabetic (Types I and Type II) and nondiabetic patients with different levels of renal function. Serum AGEs were measured as a low-molecular-weight (less than or equal to 10 kd) peptide fraction and a high-molecular-weight (greater than 10 kd) protein fraction. The mean (+/- SD) AGE content of samples of arterial-wall collagen from 9 diabetic patients was significantly higher than that of samples from 18 nondiabetic patients (14.5 +/- 5.2 vs. 3.6 +/- 1.5 AGE units per milligram, P less than 0.001). Moreover, diabetic patients with end-stage renal disease had almost twice as much AGE in tissue as diabetic patients without renal disease (21.3 +/- 2.8 vs. 11.5 +/- 1.9 AGE units per milligram, P less than 0.001). The AGE levels in both serum fractions were elevated in the patients with diabetes, and the levels of AGE peptides correlated directly with serum creatinine (P less than 0.001) and inversely with creatinine clearance (P less than 0.005), suggesting that levels of AGE peptides increased with the severity of diabetic nephropathy. In six patients with diabetes who required hemodialysis, the levels of AGE peptides were five times higher than in eight normal subjects (82.8 +/- 9.4 vs. 15.6 +/- 3.4 AGE units per milliliter, P less than 0.001). In another group of diabetic patients the mean serum creatinine level, which decreased by 75 percent during a session of hemodialysis, whereas the level of AGE peptides decreased by only 24 percent. Serum levels of AGE peptides were normal in two patients with normal serum creatinine levels after renal transplantation. AGEs accumulate at a faster-than-normal rate in arteries and the circulation of patients with diabetes; the increase in circulating AGE peptides parallels the severity of renal functional impairment in diabetic nephropathy.
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The extended interaction of aldoses with proteins or lipids results in nonenzymatic glycation and oxidation, ultimately forming AGEs, the presence of which in the plasma and vessel wall is associated with diabetic vascular complications. We show here that AGE albumin in the intravascular space interacts with the vessel wall via binding to an integral membrane protein, receptor for AGE (RAGE), a member of the immunoglobulin superfamily, resulting in clearance from the plasma and induction of interleukin 6 mRNA. Intravenously infused 125I-AGE albumin showed a rapid phase of plasma clearance with deposition in several organs. Rapid removal of 125I-AGE albumin from the plasma was prevented by administration of a soluble, truncated form of RAGE, which blocked binding of 125I-labeled AGE albumin to cultured endothelial cells and mononuclear phagocytes, as well as by pretreatment with anti-RAGE IgG. Ultrastructural studies with AGE albumin-colloidal gold conjugates perfused in situ showed that in murine coronary vasculature this probe was taken up by endothelial plasmalemmal vesicles followed by transport either to the abluminal surface or by accumulation in intracellular vesicular structures reminiscent of endosomes and lysosomes. Consequences of AGE-RAGE interaction included induction of interleukin 6 mRNA expression in mice. These data indicate that RAGE mediates the interaction of AGEs with the vessel wall, both for removal of these glycated proteins from the plasma and for changes in gene expression.
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Objective: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes. Research design and methods: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: (1) a subcohort of the Veterans Affairs Diabetes Trial (VADT) (n = 445) and (2) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (n = 271). Results: Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A1c. In the VADT, increased risk of incident CVD events (n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28-0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events (n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event (P = 0.002). Conclusions: Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes.
Article
Advanced glycation end products (AGE) have been demonstrated to induce the osteogenic trans-differentiation of vascular smooth muscle cells (VSMC). Strontium ranelate (SR) is an anti-osteoporotic agent that has both anti-catabolic and anabolic actions on bone tissue. However, in the last years SR has been associated with an increase of cardiovascular risk. We hypothesize that SR can increase the osteoblastic trans-differentiation of VSMC and the induction of extracellular calcifications, an effect that could be potentiated in the presence of AGE and inhibited by simultaneous administration of vitamin D. The present results of our in vitro experiments demonstrate that AGE and SR alone or in combination, stimulate L-type calcium channels, causing an increase in reactive oxygen species and activation of both ERK and NFkB, with the final effect of promoting the osteogenic shift of VSMC. Importantly, these in vitro effects of AGE and/or SR can be prevented by co-incubation with vitamin D.
Article
Background & aims Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels. Methods In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress. Results We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (βCML = 0.253 (95% CI 0.086; 0.415), βCEL = 0.194 (95% CI 0.040; 0.339), βMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and βCML = 0.223 (95% CI 0.049; 0.393), βCEL = 0.180 (95% CI 0.019; 0.332), βMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs. Conclusion We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs.
Article
The aim of this study was to investigate the effects of high-advanced glycation end products (AGEs) diet on diabetic vascular complications. The Streptozocin (STZ)-induced diabetic mice were fed with high-AGEs diet. Diabetic characteristics, indicators of renal and cardiovascular functions, and pathohistology of pancreas, heart and renal were evaluated. AGEs/RAGE/ROS pathway parameters were determined. During the experiments, the diabetic mice exhibited typical characteristics including weight loss, polydipsia, polyphagia, polyuria, high-blood glucose, and low-serum insulin levels. However, high-AGEs diet effectively aggravated these diabetic characteristics. It also increased the 24-h urine protein levels, serum levels of urea nitrogen, creatinine, c-reactive protein (CRP), low density lipoprotein (LDL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the diabetic mice. High-AGEs diet deteriorated the histology of pancreas, heart, and kidneys, and caused structural alterations of endothelial cells, mesangial cells and podocytes in renal cortex. Eventually, high-AGEs diet contributed to the high-AGE levels in serum and kidneys, high-levels of reactive oxygen species (ROS) and low-levels of superoxide dismutase (SOD) in serum, heart, and kidneys. It also upregulated RAGE mRNA and protein expression in heart and kidneys. Our results showed that high-AGEs diet deteriorated vascular complications in the diabetic mice. The activation of AGEs/RAGE/ROS pathway may be involved in the pathogenesis of vascular complications in diabetes.
Article
The accumulation of advanced glycation end products (AGE) and the enhanced interaction of AGE with their cellular receptor (RAGE) have been implicated in the progression of chronic kidney disease. The purpose of this study was to examine whether the AGE/RAGE-induced nephrotoxic effects are associated with inflammasome activation and endothelial dysfunction. Chronic renal injury was examined in BALB/c mice by the long-term administration of carbonyl-AGE for 16 weeks. Endothelial dysfunction was detected by measuring the number of circulating endothelial progenitor cells (EPCs) and the levels of nitric oxide synthase (eNOS) and nitric oxide (NO) in kidneys. Results showed that administration of methylglyoxal-BSA (MG-BSA) AGE accelerated renal MG, carboxyethyl lysine (CEL), carboxymethyl lysine (CML), and malondialdehyde (MDA) formation and, in parallel, the levels of serum creatinine (Cr) and blood urea nitrogen (BUN) were significantly increased. Expression of RAGE and NLRP3 inflammasome-related proteins (TXNIP, NLRP3, procaspase-1, and caspase-1) and IL-1β secretion were upregulated, whereas the levels of EPCs, eNOS, and NO were lower in MG-BSA-treated mice. This induction by MG-BSA was significantly inhibited by RAGE antagonist. Our results firstly reveal a possible mechanism of AGE-mediated renal dysfunction upon NLRP3 inflammasome activation. Therapeutic blockade of RAGE may ameliorate renal and endothelial functions in subjects under high AGE burden.
Article
The effects of carnosine and related compounds (CRC) including anserine, homocarnosine, histidine, and beta-alanine, found in most mammalian tissues, were investigated on in, vitro glucose oxidation and glycation of human serum albumin (HSA). Carnosine and anserine were more reactive with D-glucose than with L-lysine, In the presence of 10 mu M Cu (II), although carnosine and anserine at low concentrations effectively inhibited formation of alpha-ketoaldehyde from D-glucose, they increased generation of H2O2 in a dose-dependent manner. Carnosine, homocarnosine, anserine, and histidine effectively inhibited hydroxylation of salicylate and deoxyribose degradation in the presence of glucose and 10 mu M Cu (II), In the presence of 25 mM D-glucose, copper and ascorbic acid stimulated carbonyl formation from HSA, Except for beta-alanine, CRC effectively inhibited the copper-catalyzed carbonyl formation from HSA, The addition of 25 mM D-glucose and/or 10 mu M Cu (II) to low density lipoprotein (LDL) increased formation of conjugated dienes. CRC effectively inhibited the glucose and/or copper-catalyzed LDL oxidation, CRC also inhibited glycation of HSA as determined by hydroxymethyl furfural and lysine with free epsilon-amino group. These results suggest that CRC may play an important role in protecting against diabetic complications by reacting with sugars, chelating copper, and scavenging free radicals.
Article
The effects of carnosine and related compounds (CRC) including anserine, homocarnosine, histidine, and -alanine, found in most mammalian tissues, were investigated on in vitro glucose oxidation and glycation of human serum albumin (HSA). Carnosin and anserine were more reactive with D-glucose than with L-lysine. In the presence of Cu (II), although carnosine and anserine at low concentrations effectively inhibited formation of -ketoaldehyde from D-glucose, they increased generation of in a dose-dependent manner. Carnosine, homocarnosine, anserine, and histidine effectively inhibited hydroxylation of salicylate and deoxyribose degradation in the presence of glucose and Cu (II). In the presence of 25 mM D-glucose, copper and ascorbic acid stimulated carbonyl formation from HSA. Except for -alanine, CRC effectively inhibited the copper-catalyzed carbonyl formation from HSA. The addition of 25 mM D-glucose and/or Cu (II) to low density lipoprotein (LDL) increased formation of conjugated dienes. CRC effectively inhibited the glucose and/or copper-catalyzed LDL oxidation. CRC also inhibited glycation of HSA as determined by hydroxymethyl furfural and lysine with free -amino group. These results suggest that CRC may play an important role in protecting against diabetic complications by reacting with sugars, chelating copper, and scavenging free radicals.
Article
We recently reported that serum methylglyoxal (sMG) is associated with a faster rate of decline in a global measure of cognition in the very elderly. We here provide for the first time evidence in which high levels of dietary AGE (dAGE) are associated with faster rate of decline in memory in 49 initially non-demented young elderly (p=0.012 in mixed regression models adjusting for sociodemographic and cardiovascular factors). Since modifying the levels of AGEs in the diet may be relatively easy, these preliminary results suggest a simple strategy to diminish cognitive compromise in the elderly and warrant further investigation.
Article
The imidazole dipeptide carnosine and its methylated anserine analogues are the major histidine containing dipeptides in vertebrate tissue, especially in skeletal muscle, the heart, and the central nervous system. In this study, the carnosine and anserine content in chicken from different parts and of differing ages was determined and their physiological activities were compared. Anserine was more dominant than carnosine in these tissues and both of them significantly decreased with aging in all parts of chicken muscles. Chicken breast muscle showed the highest content of carnosine and anserine than drumstick and wing. Advanced glycated end-product (AGE) formation was inhibited up to 60% by the extract from 20 wk chicken breast and decreased with aging (90 wk). Anti-oxidation activity was also significantly reduced from 61.2% to 52.9% with aging. As results, anti-glycation and anti-oxidation activity of carnosine and anserine extract from chicken muscle increased proportionally to the amount of those peptides in the muscle, while these decreased with the aging process.
Article
Objective: Methylglyoxal (MG), a reactive carbonyl compound formed primarily from triose phosphates, appears to be involved in the molecular mechanisms of diabetes, end-stage renal disease and neurodegenerative diseases. Methylglyoxal exerts several biological activities. Among these it promotes advanced glycation end products (AGEs), which are crucial in pathogenesis of human disease. Previous studies have demonstrated that MG reacts with proteins and compositional modifications reflect loss of biological activity. The aim of the study was to investigate the effect of in vitro MG-induced glycation on human high density lipoprotein (HDL) and on the activity of the enzyme paraoxonase-1 (PON1). Methods: HDL was incubated in the absence or in the presence of MG (0.2mmol/L and 1.0mmol/L) (MG-HDL) for different times (3, 6, 24h) at 37° C. We evaluated apoprotein compositional changes, in both control and MG treated HDL, using intrinsic fluorescence of tryptophan and monitoring the decrease of free amino groups. Furthermore we evaluated fluorescent advanced glycation end products (Ex=370nm, Em=440nm) and the activity of HDL-paraoxonase. Results: We demonstrated that human HDL is susceptible to glycation by MG (0.2mmol/L and 1mmol/L). The decrease of free amino groups and of intrinsic fluorescence of tryptophan demonstrates HDL apoprotein modifications in HDL incubated with MG. The compositional changes are associated with a significant increase in fluorescent advanced glycation end products and with a significant decrease of paraoxonase-1 enzyme activity associated with the HDL surface. Conclusions: HDL-associated paraoxonase is responsible for the anti-inflammatory and anti-oxidative properties of HDL and detoxification against homocysteine-thiolactone. Therefore, modifications of apoprotein composition and the decrease of paraoxonase-1 activity in MG-treated HDL could affect the protective effect exerted by HDL against oxidative damage and could contribute to complications in patients affected by diseases associated with aging and oxidative stress.
Article
Advanced glycation end-products (AGEs) levels are high in western diets and contribute to tissue injury via activation of RAGE (receptor for AGEs) and generation of reactive oxygen species (ROS). Here, we determined if high dietary AGE intake worsens progression of non-alcoholic fatty liver disease (NAFLD). Male Sprague Dawley rats were fed a methionine choline deficient (MCD) diet for 6 weeks before 6 weeks of a high AGE MCD diet through baking. They were compared with animals on MCD diet or a methionine choline replete (MCR) diet alone for 12 weeks. Hepatic ROS, triglycerides, biochemistry, picro-sirius morphometry, hepatic mRNA expression and immunohistochemistry were determined. Primary hepatic stellate cells (HSCs) from both MCR and MCD animals were exposed to AGEs. ROS, proliferation and mRNA expression were determined. The high AGE MCD diet increased hepatic AGE content and elevated triglycerides, NADPH dependent superoxide production, HNE adducts, steatosis, steatohepatitis (CD43, IL-6, TNF-α) and fibrosis (α-SMA, CTGF, COL1A, picrosirius) compared to MCD alone. In HSCs, AGEs significantly increased ROS production, bromodeoxyuridine proliferation and MCP-1, IL-6, α-SMA and RAGE expression in HSCs from MCD but not MCR animals. These effects were abrogated by RAGE or NADPH oxidase blockade. In the MCD model of NAFLD, high dietary AGEs increases hepatic AGE content and exacerbates liver injury, inflammation, and liver fibrosis via oxidative stress and RAGE dependent profibrotic effects of AGEs on activated HSCs. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
Article
Previous studies have shown that the Trp residue contributes to a high oxygen radical absorbance capacity (ORAC). Therefore, in this study, a Trp-containing dipeptide derived from a computer-aided simulation of pepsin hydrolysis of the yam tuber, dioscorin-namely, Asn-Trp (NW), and its analogue, Gln-Trp (QW)-were synthesised to compare their antioxidant and antiglycation activities with carnosine, homocarnosine, or glutathione (GSH). The antioxidant assays included hydroxyl radical-scavenging activity, anti-AAPH-induced hemolysis, and ORAC activity. NW had a significantly higher antioxidant activity than had QW and performed much better than carnosine, homocarnosine, or GSH. Using bovine serum albumin (BSA)/galactose or BSA/glucose as experimental models, NW had better antiglycation effects than had QW, as detected by an anti-N(ε)-(carboxymethyl)lysine (anti-CML) antibody. Moreover, NW and QW (50-200μM) showed protection against methylglyoxal-induced cell deaths in human umbilical vein endothelial cells. These results suggest that NW, derived from computer-aided simulation of dioscorin hydrolysis, exhibits antioxidant and antiglycation activities, which thus shows the benefits of the yam tuber as an antioxidant-rich food.
Article
A number of natural or synthetic compounds as AGE inhibitors have been proposed, discovered or currently being advanced by others and us. We have identified two new classes of aromatic compounds; aryl- (and heterocyclic) ureido and aryl (and heterocyclic) carboxamido phenoxyisobutyric acids, and benzoic acid derivatives and related compounds, as potential inhibitors of glycation and AGE formation. Some of these novel compounds also showed “AGE-breaking” activities in vitro. Current evidence is that chelation of transition metals and/or trapping or indirect inhibition of formation of reactive carbonyl compounds are involved in the mechanisms of action of these novel AGE inhibitors and breakers. Here, we review the inhibitors of glycation and AGE-breakers published to date and present the results of our in vitro and in vivo investigations on a number of these novel AGE inhibitors. These AGE-inhibitors and AGE-breakers may find therapeutic use in the treatment of diseases that AGE formation and accumulation may be responsible for their pathogenesis such as diabetes, Alzheimer’s, rheumatoid arthritis, and atherosclerosis.
Article
Commercial samples of beef and turkey meat were prepared by commonly used cooking methods with standard cooking times: (1) broiled at 200°C for 10min, (2) broiled at a medium temperature (140°C) for 10min, (3) cooked by microwave (MW) for 3min and then grilled (MW/grill) for 7min, (4) cooked in a domestic microwave oven for 10min, and (5) boiled in water for 10min. The raw and cooked meats were then analysed to determine the carnosine, anserine, homocarnosine, pentosidine, and thiobarbituric acid-reactive substance (TBARS) contents. It was observed that boiling beef caused a loss of approximately 50% of the carnosine, probably because of the high water solubility of carnosine and its homologues; cooking by microwave caused a medium loss of the anti-oxidants of approximately 20%; cooking by MW/grill led to a reduction in carnosine of approximately 10%. As far as the anserine and homocarnosine contents were concerned, a greater loss was observed for the boiling method (approximately 70%) while, for the other cooking methods, the value ranged from 30% to 70%. The data oscillate more for the turkey meat: the minimum carnosine decrease was observed in the cases of MW/grill and broiling at high temperature (25%). Analogously, the anserine and homocarnosine contents decreased slightly in the case of MW/grill and broiling at a high temperature (2–7%) and by 10–30% in the other cases. No analysed meat sample showed any traces of pentosidine above the instrumental determination limits. The cooked beef showed an increased TBARS value compared to the raw meat, and the highest values were found when the beef was broiled at a high temperature, cooked by microwave or boiled in water. The TBARS value of the turkey meat decreased for all the cooking methods in comparison to the TBARS value of the fresh meat.