Home About us Contact
|
Home About us Contact | ||
|
|
||
Glycation End Products (glycation + end_products)
Kinds of Glycation End Products Selected AbstractsThe Breakdown of Preformed Advanced Glycation End Products Reverses Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats: Preventive Versus Curative TreatmentTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006Mustafa F. Usta MD ABSTRACT Objectives., Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. Materials and Methods., Male Sprague,Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. Results., Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. Conclusions., These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED. Usta MF, Kendirci M, Gur S, Foxwell NA, Bivalacqua TJ, Cellek S, and Hellstrom WJG. The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: Preventive versus curative treatment. J Sex Med 2006;3:242,252. [source] Receptor for Advanced Glycation End Products in Donor Lungs Is Associated with Primary Graft Dysfunction After Lung TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010A. Pelaez Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD. [source] Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazideDIABETES OBESITY & METABOLISM, Issue 2 2004J.-C. Mamputu Aim:, We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events. Methods:, BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-,B (NF-,B) inhibitors. BREC proliferation was assessed by measuring [3H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-,B signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay. Results:, Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-, translocation, extracellular signal-regulated protein kinase 1/2 and NF-,B activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N -acetyl- l -cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-,B-signalling pathways. Conclusions:, Our results demonstrate the involvement of PKC, MAPK and NF-,B in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways. [source] Advanced glycation end products-induced apoptosis attenuated by PPAR, activation and epigallocatechin gallate through NF-,B pathway in human embryonic kidney cells and human mesangial cellsDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2010Yao-Jen Liang Abstract Background Diabetic nephropathy has attracted many researchers' attention. Because of the emerging evidence about the effects of advanced glycation end products (AGEs) and receptor of AGE (RAGE) on the progression of diabetic nephropathy, a number of different therapies to inhibit AGE or RAGE are under investigation. The purpose of the present study was to examine whether peroxisome proliferator-activated receptor , (PPAR,) agonist (L-165041) or epigallocatechin gallate (EGCG) alters AGE-induced pro-inflammatory gene expression and apoptosis in human embryonic kidney cells (HEK293) and human mesangial cells (HMCs). Methods The HEK cells and HMC were separated into the following groups: 100 µg/mL AGE alone for 18 h; AGE treated with 1 µM L-165041 or 10 µM EGCG, and untreated cells. Inflammatory cytokines, nuclear factor-,B pathway, RAGE expression, superoxide dismutase and cell apoptosis were determined. Results AGE significantly increased tumour necrosis factor-, (TNF-,), a major pro-inflammatory cytokine. The mRNA and protein expression of RAGE were up-regulated. These effects were significantly attenuated by pre-treatment with L-165041 or EGCG. AGE-induced nuclear factor-,B pathway activation and both cells apoptosis were also inhibited by L-165041 or EGCG. Furthermore, both L-165041 and EGCG increased superoxide dismutase levels in AGE-treated HEK cells and HMC. Conclusions This study demonstrated that PPAR, agonist and EGCG decreased the AGE-induced kidney cell inflammation and apoptosis. This study provides important insights into the molecular mechanisms of EGCG and PPAR, agonist in attenuation of kidney cell inflammation and may serve as a therapeutic modality to treat patients with diabetic nephropathy. Copyright © 2010 John Wiley & Sons, Ltd. [source] Metabolic memory in diabetes,focus on insulinDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2005Derek LeRoith Abstract Large-scale clinical trials have demonstrated that metabolic control achieved early in the course of diabetes substantially reduces development and progression of diabetes and the associated microvascular complications. Additionally, prospective observational studies have demonstrated that atherogenic and inflammatory mediators are elevated even prior to the onset of diabetes and significantly contribute to subsequent development of macrovascular complications. Collectively, these data suggest that metabolic memories are stored early in the course of diabetes. We believe that insulin suppresses inflammation and also suppresses glucotoxicity and lipotoxicity (and the consequences thereof, such as the formation of advanced glycation end products and epigenetic phenomena), and thus has a pivotal and beneficial role. Comprehensive metabolic control, especially when instituted early, may alter the natural history of diabetic complications by affecting this metabolic memory. Thus, our overall goal is to understand in more detail the molecular mechanisms involved in these changes, thereby affording us opportunities to reduce the long-term effects of diabetes. Copyright © 2005 John Wiley & Sons, Ltd. [source] Impact of glucose levels on advanced glycation end products in hemodialysisHEMODIALYSIS INTERNATIONAL, Issue 3 2007Amy Ruth GODFREY Abstract The current obesity epidemic throughout the western world has resulted in a considerable increase in the condition Type II diabetes mellitus. Recently, the World Health Organization has predicted that the global prevalence of Type II will increase from 175 million patients in 2003 to over 350 million by 2030. One of the major consequences of this disorder is renal failure, which presents itself as chronic kidney disease, and can progress to end-stage renal disease. Once diagnosed, patients are generally treated using dialysis due to a shortage of kidney donors. The fundamental process of dialysis still requires improvement because the survival rate of these patients is relatively poor. This has resulted in considerable research into improvements in hemodialysis membranes, and the challenge to find more suitable marker(s) in assessing the efficacy of the dialysis process. A class of compounds highlighted as a possible accumulative toxin is advanced glycation end products or AGEs. This is an article regarding the impact of hemodialysis and hemodiafiltration on glucose and AGE levels within the body and the consequences of a chronic hyperglycemic condition. It also highlights the negative aspects of using dextrose in conventional dialysis solutions (an area that has already been identified by peritoneal dialysis clinicians as problematic). The review concludes by suggesting several possible topics of future research. [source] Advanced glycation end products accumulate in the reproductive tract of men with diabetesINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2009C. Mallidis Summary Light microscopic studies comparing sperm parameters show little association between diabetes and male fertility. However, with the introduction of new analytical techniques, evidence is now emerging of previously undetectable effects of diabetes on sperm function. Specifically, a recent study has found a significantly higher sperm nuclear DNA fragmentation in diabetic men. As advanced glycation end products (AGEs) are important instigators of oxidative stress and cell dysfunction in numerous diabetic complications, we hypothesized that these compounds could also be present in the male reproductive tract. The presence and localization of the most prominent AGE, carboxymethyl-lysine (CML), in the human testis, epididymis and sperm was determined by immunohistochemistry. Parallel ELISA and Western blot analyses were performed to ascertain the amount of CML in seminal plasma and sperm from 13 diabetic and nine non-diabetic subjects. CML immunoreactivity was found throughout the seminiferous epithelium, the nuclei of spermatogonia and spermatocytes, in the basal and principle cells cytoplasm and nuclei of the caput epididymis and on most sperm tails, mid pieces and all cytoplasmic droplets. The acrosomal cap, especially the equatorial band, was prominently stained in diabetic samples only. The amount of CML was significantly higher (p = 0.004) in sperm from non-diabetic men. Considering the known detrimental actions of AGEs in other organs, the presence, location and quantity of CML, particularly the increased expression found in diabetic men, suggest that these compounds may play a hitherto unrecognized role in male infertility. [source] Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2009Lorena Perrone Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-,B signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-,B-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy. J. Cell. Physiol. 221: 262,272, 2009. © 2009 Wiley-Liss, Inc [source] Rapid method for the preparation of an AGE-BSA standard calibrator using thermal glycationJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 1 2005A.D. Bhatwadekar Abstract Estimation of advanced glycation end products (AGEs) by determining fluorescence is based on the use of a standard calibrator prepared by incubating bovine serum albumin (BSA) and glucose at 37°C for 60 days. In the present study we attempted to reduce the duration of incubation to 4 days by increasing the temperature to 50°C. It is noteworthy that incubation at 50°C resulted in the rapid production of an AGE-BSA standard calibrator within 4 days. Aminoguanidine reduced the intensity of the glycation-induced fluorescence, while the addition of lysine intensified the reaction, as shown by the calibrator incubated at 37°C. The protein carbonyl content was shown to increase in the rapidly-formed standard calibrator. Thus we conclude that a simple increase in temperature and the addition of lysine (0.1M) can accelerate the process of glycation-induced fluorescence. This calibrator can be used effectively in fluorescence assays of AGEs. J. Clin. Lab. Anal. 19:11,15, 2005. © 2005 Wiley-Liss, Inc. [source] Association of salivary lysozyme and C-reactive protein with metabolic syndromeJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 9 2010Markku Qvarnstrom Qvarnstrom M, Janket S-J, Jones JA, Jethwani K, Nuutinen P, Garcia RI, Baird AE, Van Dyke TE and Meurman JH. Association of salivary lysozyme and C-reactive protein with metabolic syndrome. J Clin Periodontol 2010; 37: 805,811. doi: 10.1111/j.1600-051X.2010.01605.x. Abstract Introduction: Salivary lysozyme (SLZ) is a proteolytic enzyme secreted by oral leucocytes and contains a domain that has an affinity to advanced glycation end products (AGE). Thus, we hypothesized that SLZ would be associated with metabolic syndrome (metS), a pro-inflammatory state. Methods: Utilizing cross-sectional data from 250 coronary artery disease (CAD) and 250 non-CAD patients, the association of SLZ with metS was tested by logistic regression analyses controlling for age, sex, smoking, total cholesterol and C-reactive protein (CRP) levels. The analyses were stratified by CAD status to control for the possible effects of CAD. Results: MetS was found in 122 persons. The adjusted odds ratio (OR) for metS associated with the highest quartile of SLZ was 1.95 with 95% confidence interval (CI) 1.20,3.12, p -value=0.007, compared with the lower three quartiles combined. Among the 40 subjects with metS but without CAD, the OR was 1.63 (CI: 0.64,4.15, p=0.31), whereas in the CAD group, SLZ was significantly associated with metS [OR=1.96 (1.09,3.52), p=0.02]. In both subgroups, CRP was not significantly associated with metS. Conclusion: SLZ was significantly associated with metS (OR=1.95) independent of CRP level. Future longitudinal research is warranted. [source] Biomarkers of aging in DrosophilaAGING CELL, Issue 4 2010Jake Jacobson Summary Low environmental temperature and dietary restriction (DR) extend lifespan in diverse organisms. In the fruit fly Drosophila, switching flies between temperatures alters the rate at which mortality subsequently increases with age but does not reverse mortality rate. In contrast, DR acts acutely to lower mortality risk; flies switched between control feeding and DR show a rapid reversal of mortality rate. Dietary restriction thus does not slow accumulation of aging-related damage. Molecular species that track the effects of temperatures on mortality but are unaltered with switches in diet are therefore potential biomarkers of aging-related damage. However, molecular species that switch upon instigation or withdrawal of DR are thus potential biomarkers of mechanisms underlying risk of mortality, but not of aging-related damage. Using this approach, we assessed several commonly used biomarkers of aging-related damage. Accumulation of fluorescent advanced glycation end products (AGEs) correlated strongly with mortality rate of flies at different temperatures but was independent of diet. Hence, fluorescent AGEs are biomarkers of aging-related damage in flies. In contrast, five oxidized and glycated protein adducts accumulated with age, but were reversible with both temperature and diet, and are therefore not markers either of acute risk of dying or of aging-related damage. Our approach provides a powerful method for identification of biomarkers of aging. [source] Meaurement of advanced glycation end products may change NASH managmentJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2007Valerio Nobili [source] Advanced glycation end product in familial amyloidotic polyneuropathy (FAP)JOURNAL OF INTERNAL MEDICINE, Issue 4 2000N. Nyhlin Abstract. Nyhlin N, Ando Y, Nagai R, Suhr O, El Sahly M, Terazaki H, Yamashita T, Ando M, Horiuchi S (Umeå University Hospital, Umeå, Sweden and Kumamoto University School of Medicine, Kumamoto, Japan). Advanced glycation end product in familial amyloidotic polyneuropathy (FAP). J Intern Med 2000; 247: 485,492. Objectives. Advanced glycation end products (AGE) are present in amyloid deposits in ,2 -microglobulin amyloidosis, and it has been postulated that glycation of ,2 -microglobulin may be involved in fibril formation. The aim of this paper was to ascertain whether AGE occur in amyloid deposits in familial amyloidotic polyneuropathy (FAP). Setting. Department of Medicine, Umeå University Hospital and First Department of Internal Medicine, Kumamoto University School of Medicine. Design. The presence of AGE was sought immunohistochemically and biochemically in amyloid-rich tissues from patients with FAP. Subjects. Biopsy specimens from nine patients and 10 controls were used for the immunohistochemical analysis. For amyloid preparation, vitreous samples from three FAP patients were used. Results. Immunohistochemical studies using a polyclonal anti-AGE antibody revealed positive immunoreactivity in intestinal materials, but the pattern of reactivity was unevenly distributed; it was often present in the border of amyloid deposits, or surrounding them. Non-amyloid associated immunoreactivity was also observed in a few regions of the specimens, although the AGE-positive structures were situated in areas containing amyloid deposits. Western blotting of purified amyloid from the vitreous body of FAP patients revealed a significant association of AGE with amyloid fibrils. Conclusion. The immunoreactivity for the AGE antibody suggests that AGE may be involved in fibril formation in FAP. [source] Advanced glycation end products: a highly complex set of biologically relevant compounds detected by mass spectrometry,JOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 4 2001Annunziata Lapolla Abstract Structural information on ,AGE-peptides,' a class of substances belonging to advanced glycation end products (AGE) and originating by proteolysis of glycated proteins, was gained through various analytical approaches on the mixture produced by proteinase K digestion of in vitro glycated bovine serum albumin. Both matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and high-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) were employed, and the results were compared with those from conventional spectroscopic methods (UV, fluorescence, gel permeation). The data acquired by the various techniques all depict the digestion mixtures as highly complex, with components exhibiting molecular mass in the range 300,3500 Da. In the analysis of HPLC/ESI-MS data, identification of AGE-peptides was facilitated by 3D mapping. Structural information was gained by means of multiple mass spectrometric experiments. Copyright © 2001 John Wiley & Sons, Ltd. [source] Site-specific synthesis of Amadori-modified peptides on solid phaseJOURNAL OF PEPTIDE SCIENCE, Issue 6 2006Andrej Frolov Abstract Glycation of peptides and proteins is a slow chemical reaction of reducing sugars modifying the amino groups. The first intermediates of this nonenzymatic glycosylation are the Amadori products that can undergo further chemical reactions, finally leading to advanced glycation end products (AGEs). The formation of AGEs was not only linked to aging of tissues and organs in general but also to several diseases such as diabetes mellitus and Alzheimer's disease. Because of the importance of these modifications and their potential use as diagnostic markers, a global postsynthetic approach on solid phase was developed. The peptides were synthesized by Fmoc/tBu-chemistry, with the lysine residue to be modified being protected with the very acid-labile methyltrityl group. Incubation of the peptides with D -glucose in DMF at elevated temperatures resulted in product yields of 35%. Neighboring residues with bulky protecting groups reduced the yields only slightly. The major by-products were the unmodified peptide and an oxidation product. Whereas the unmodified peptide eluted before the glycated peptide, all other by-products eluted later in RP-HPLC, allowing simple purification. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Current Treatment and Recent Clinical Research in Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Judith Neugroschl MD Abstract The transition from either epidemiological observation or the bench to rigorously tested clinical trials in patients with Alzheimer's disease is crucial in understanding which treatments are beneficial to patients. The amyloid hypothesis has undergone scrutiny recently, as many trials aimed at reducing amyloid and plaque have been completed or are in the testing phase. Examples include modulation of the secretases involved in beta amyloid formation, anti-aggregation agents, and immunotherapeutic trials. Other therapies targeting hyperphosphorylated tau and novel targets such as enhancement of mitochondrial function, serotonin receptors, receptor for advanced glycation end products, and nerve growth factor, as well as other strategies, are discussed. A brief review of the current Food and Drug Administration,approved treatments is included. Mt Sinai J Med 77:3&–16, 2010. © 2010 Mount Sinai School of Medicine [source] Transforming growth factor-, and Smad signalling in kidney diseasesNEPHROLOGY, Issue 1 2005Review Article SUMMARY: Extensive studies have demonstrated that transforming growth factor-beta (TGF-,) plays an important role in the progression of renal diseases. TGF-, exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGF-,'s pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGF-, still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGF-,. They can also cause renal fibrosis via the ERK/p38 MAP kinase,Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-,, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGF-, has anti-inflammatory and immune-regulatory properties. Our most recent studies demonstrated that TGF-, transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF.,B activation via induction of I,B,, is a central mechanism by which TGF-, inhibits renal inflammation. In conclusion, TGF-, signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases. [source] Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophyNEUROPATHOLOGY, Issue 2 2006Reiko Oyamada Myotonic dystrophy (MyD) is a neuromuscular degenerative disorder that is neuropathologically characterized by minor changes, such as the presence of neurofibrillary tangles (NFT), thalamic inclusions and functional brainstem lesions. In the current study, we conducted an immunohistochemical analysis to examine the distribution of NFT and formation of oxidative products in the brain specimens of 12 patients with MyD. Neurofibrillary tangles were found in the limbic system and/or the brainstem of all the cases examined but there were no senile plaques. The density of distribution of the NFT was not significantly correlated with clinicopathological findings, although cases with fewer NFT in the brain frequently showed sleep disturbances and lack of spontaneity. Nuclear and cytoplasmic immunoreactivities for 8-hydroxy-2,-deoxyguanosine and advanced glycation end products were observed in the glial cells and/or neurons in the brainstem, but not in the cerebral cortex. On the other hand, 10 out of the 12 cases showed cytoplasmic immunoreactivity for 4-hydroxy-2-nonenal-modified protein (4-HNE) in neurons of the temporal cortex and raphe nucleus. Deposition of 4-HNE was also recognized in the hippocampus and mesencephalic central gray matter, but not in the subiculum. The distribution pattern of the immunoreactivity for 4-HNE showed no clear correlation with either the psychological disturbances or the distribution of the NFT. Altered expression of monoaminergic neurons in the brainstem of MyD patients has already been reported, and it is worth noting that most of our cases showed NFT in the brainstem. The selective deposition of 4-HNE in the limbic system and brainstem suggests that lipid peroxidation may be involved in the neurodegenerative process in MyD. Using immunohistochemical analysis to determine the distribution of neurotransmitters in the mesencephalic central gray matter and/or pontine raphe nucleus may help elucidate the relationship between the clinical abnormalities, distribuion of NFT, and 4-HNE deposition in the brain in patients with MyD. [source] Mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic ratsPHYTOTHERAPY RESEARCH, Issue 6 2010Xuan Li Abstract Diabetic nephropathy is one of the most severe diabetic microangiopathies and accounting for approximately one-third of all cases of end-stage renal disease. In the present study, we investigated the effect of mangiferin, a polyphenol from Anemarrhena asphodeloides Bge. or Mangifera indica L., on diabetic nephropathy and the possible mechanisms by using a developed diabetic nephropathy rat model and cultured rat mesangial cells. Serum-advanced glycation end-products level, malonaldehyde level, sorbitol concentration of red blood cell, 24,h albuminuria excretion were significantly decreased, whereas activity of serum superoxide dismutase and glutathione peroxidase and creatinine clearance rate were increased by mangiferin. Blood glucose level remained unaffected. Mangiferin significantly inhibited glomerular extracellular matrix expansion and accumulation and transforming growth factor-beta 1 overexpression in glomeruli of diabetic nephropathy rats. Moreover, mangiferin was observed to inhibit proliferation of mesangial cells induced by high glucose and the overexpression of collagen type IV of mesangial cells induced by advanced glycation end products. In summary, mangiferin could significantly prevent progression of diabetic nephropathy and improve renal function. Copyright © 2009 John Wiley & Sons, Ltd. [source] Antioxidant and antiglycation properties of total saponins extracted from traditional Chinese medicine used to treat diabetes mellitusPHYTOTHERAPY RESEARCH, Issue 2 2008Miaomiao Xi Abstract Eleven antidiabetic traditional Chinese medicine (TCM) extracts rich in saponins were examined for their antioxidant and antiglycation activities. The antioxidant activities of these extracts were evaluated by studying the inhibition of lipid peroxidation in rat liver microsomes induced by ascorbate/Fe2+, cumine hydroperoxide (CHP) or CCl4/reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH). The antioxidant capacities were also evaluated by studying the scavenging of 2,2,-diphenyl-1-picrylhydrazyl (DPPH) free radical. The antiglycation activities of these extracts were evaluated by hemoglobin- , -gluconolactone (, -Glu) assay, bovine serum albumin (BSA)-glucose assay and N-acetyl-glycyl-lysine methyl ester (GK peptide)-ribose assay. Aralia taibaiensis outperformed other extracts in most of the assays except inhibition of early glycation products formation, where Acanthopanax senticosus showed higher activity. Aralia taibaiensis was particularly potent in inhibiting the late glycation and formation of advanced glycation end products (AGEs) on proteins. The antioxidant and antiglycation activities of most extracts were correlated with the saponin content. The results demonstrate that the antidiabetic activities of most extracts could be explained, at least in part, by their combined antioxidant and antiglycation properties. Copyright © 2007 John Wiley & Sons, Ltd. [source] Thymoquinone decreases AGE-induced NF- ,B activation in proximal tubular epithelial cellsPHYTOTHERAPY RESEARCH, Issue 9 2007Ahmed Amir Radwan Sayed Abstract The inhibitory effects of thymoquinone (TQ) on activation of the redox-sensitive transcription factor nuclear factor kappa B (NF- ,B) and interleukin-6 (IL-6) were studied in vitro. Human proximal tubular epithelial cells (pTECs) were cultivated and stimulated with advanced glycation end products (AGEs) and the effects of TQ were studied. A significant reduction of AGE-induced NF- ,B-activation and Il-6 expression was observed. This points to potential antioxidative qualities of TQ. Copyright © 2007 John Wiley & Sons, Ltd. [source] ORIGINAL ARTICLE: Glycation Endproducts, Soluble Receptor for Advanced Glycation Endproducts and Cytokines in Diabetic and Non-diabetic PregnanciesAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2009Magdalena Perty, ska-Marczewska Problem, Cytokines, advanced glycation end products (AGEs), and their receptor RAGE have been recently suggested to play a role in human pregnancy. In this study, we sought to determine the alterations of plasma AGEs, soluble RAGE (sRAGE), and proinflammatory cytokines in normal pregnancies and those complicated with type 1 diabetes mellitus. Method of study, These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (HP), and pregnant diabetic (DP) women. Results, In the first trimester, DP showed lower sRAGE and higher AGEs compared to HP. In the DP group, significant negative correlations were seen between TNF-, and lipopolysaccharide (LPS)-stimulated ,L-6 in the first trimester and sRAGE in the third trimester. LPS-stimulated IL-12 was positively correlated with levels of AGEs in the third trimester. Conclusion, We detected several differences in the levels of AGEs, sRAGE, and proinflammatory cytokines between euglycemic and diabetic pregnancies. [source] The Breakdown of Preformed Advanced Glycation End Products Reverses Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats: Preventive Versus Curative TreatmentTHE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006Mustafa F. Usta MD ABSTRACT Objectives., Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. Materials and Methods., Male Sprague,Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. Results., Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. Conclusions., These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED. Usta MF, Kendirci M, Gur S, Foxwell NA, Bivalacqua TJ, Cellek S, and Hellstrom WJG. The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: Preventive versus curative treatment. J Sex Med 2006;3:242,252. [source] Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytesARTHRITIS & RHEUMATISM, Issue 3 2009Raghunatha R. Yammani Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1, (IL-1,), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1,. IL-7 activated the JAK/STAT pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7,mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7,mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA. [source] Asymmetric Dimethylarginine in Hemodialysis, Hemodiafiltration, and Peritoneal DialysisARTIFICIAL ORGANS, Issue 5 2010Jaromír Eiselt Abstract Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction. Production and elimination of ADMA may be affected by the type of renal replacement therapy used and oxidative stress. Plasma ADMA, advanced glycation end products (AGE), and homocysteine were assessed in 59 subjects: 20 hemodialysis (HD) patients, 19 patients undergoing peritoneal dialysis (PD), and 20 controls. Results were compared between the groups. The effect of 8 weeks of HD and high-volume predilution hemodiafiltration (HDF) was compared in a randomized study. HD patients showed higher ADMA (1.20 [0.90,1.39 µmol/L]) compared to controls (0.89 [0.77,0.98], P < 0.01), while ADMA in PD did not differ from controls (0.96 [0.88,1.28]). AGE and homocysteine were highest in HD, lower in PD (P < 0.01 vs. HD), and lowest in controls (P < 0.001 vs. HD and PD). PD patients had higher residual renal function than HD (P < 0.01). The decrease in ADMA at the end of HD (from 1.25 [0.97,1.33] to 0.66 [0.57,0.73], P < 0.001) was comparable to that of HDF. Switching from HD to HDF led to a decrease in predialysis homocysteine level in 8 weeks (P < 0.05), while ADMA and AGE did not change. Increased ADMA levels in patients undergoing HD, as compared to PD, may be caused by higher oxidative stress and lower residual renal function in HD. Other factors, such as diabetes and statin therapy, may also be at play. The decrease in ADMA at the end of HD and HDF is comparable. Switching from HD to HDF decreases in 8 weeks the predialysis levels of homocysteine without affecting ADMA. [source] Plasma levels of advanced glycation end products are associated with haemolysis-related organ complications in sickle cell patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Erfan Nur Summary Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Plasma levels of advanced glycation end products (AGEs) are increased under oxidative conditions and are associated with disease severity in diabetes and inflammatory diseases. We investigated whether AGEs are increased in sickle cell patients and whether they are associated with SCD-related complications. Plasma levels of the AGEs pentosidine, N, -(carboxymethyl)lysine (CML) and N, -(carboxyethyl)lysine (CEL) were measured using single-column high performance liquid chromatography with fluorescence detection (pentosidine) and ultra performance liquid chromatography-tandem mass spectrometry (CML and CEL). Plasma levels of pentosidine and CML were increased in HbSS/HbS,0 -thalassaemia (n = 60) and HbSC/HbS,+ -thalassaemia (n = 42) patients during steady state as compared to healthy HbAA controls (n = 30) without increments during painful crisis. CEL levels were comparable between all groups. Pentosidine and CML levels correlated significantly to haemolytic rate during the clinically asymptomatic state while pentosidine was significantly related to the number of haemolysis-related organ complications. The increased plasma AGE levels in sickle cell patients and their association with haemolysis and haemolysis-related complications suggest AGEs might be implicated in the pathophysiology of the haemolytic phenotype of SCD. Measurement of AGEs might be useful in predicting organ complications in SCD. [source] Rosiglitazone via upregulation of Akt/eNOS pathways attenuates dysfunction of endothelial progenitor cells, induced by advanced glycation end productsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2009Chun Liang Background and purpose:, Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play key roles in pathogenesis of diabetes-related vascular complications. AGEs can induce dysfunction in EPCs. The peroxisome proliferator-activated receptor-gamma (PPAR,) agonists are widely used in the treatment of type 2 diabetes, and it remains unknown if they could attenuate EPC dysfunction induced by AGEs. Experimental approach:, EPCs isolated from healthy adults were cultured with various concentrations of AGEs (0, 50, 100 and 200 mg·L,1) with or without rosiglitazone (10 nM), antibody for the receptors for AGE-human serum albumin (anti-receptor for advanced glycation end products (RAGE); 50 µg·mL,1), phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002, 5 µM), nitric oxide (NO) synthase inhibitor (L-NG -nitro-arginine methyl ester (L-NAME), 100 µM) or sodium nitroprusside (SNP, 25 µM). Proliferation, apoptosis, cell adhesion, migration and NO production in EPCs were assessed, and expressions of endothelial NO synthase (eNOS) and Akt were determined. Key results:, Number, proliferation/migration capacities, eNOS and Akt phosphorylation as well as NO synthesized by EPCs were increased by rosiglitazone and reduced by AGEs. AGEs promoted while rosiglitazone reduced EPC apoptosis. The AGE-induced effects were significantly ameliorated by pre-incubation with rosiglitazone, RAGE antibody and SNP. The beneficial effects of rosiglitazone could be blocked by pretreatment with L-NAME and LY294002. Conclusions and implications:, The PPAR, agonist rosiglitazone increased EPC function and attenuated EPC dysfunction induced by AGEs via upregulating the Akt-eNOS signal pathways of EPCs. [source] Serum-soluble receptor for advanced glycation end product levels in patients with amyotrophic lateral sclerosisACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009eckaArticle first published online: 2 DEC 200 Objectives,,, Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. There is evidence that oxidative stress is implicated in the pathophysiology of the neurodegenerative disorders, including ALS. Data from the literature suggests that the receptor for advanced glycation end products (RAGE) participates in pathological conditions, including oxidative stress and neurodegeneration. Materials and methods,,, The study involved 20 patients with ALS and 20 patients from the control group. The serum-soluble RAGE (sRAGE) levels were measured using the enzyme-linked immunosorbent method. Results,,, The study showed that sRAGE levels are significantly decreased in serum of the patients with ALS comparing to the control group (P < 0.05). The correlation between the serum sRAGE levels and clinical parameters of the disease was not significant (P > 0.05). Conclusions,,, The results indicate that sRAGE participates in pathophysiology of the ALS. It is possible that low sRAGE levels may influence neurodegeneration. [source] Up-regulation of pro-inflammatory genes as adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironmentCANCER SCIENCE, Issue 4 2010Marco Tafani The role of tumor cells in synthesizing pro-inflammatory molecules is still controversial. Here we report that hypoxic treatment of the MCF-7 human mammary adenocarcinoma cell line induced activation of hypoxia-inducible factor 1, (HIF-1,) and nuclear factor-kappa B (NF-,B). Importantly, hypoxia regulated expression of alarmin receptors such as the receptor for advanced glycation end products (RAGE) and the purinoreceptor (P2X7R), and up-regulated inflammatory response (IR) genes such as the inducible enzymes nitric oxide synthase (NOS2), cycloxygenase (COX2), and the acute-phase protein pentraxin-3 (PTX3). Hypoxia also stimulated chemokine (C-X-C motif) receptor 4 (CXCR4) mRNA synthesis. In fact, the CXCR4 ligand stromal-derived factor-1, (SDF-1,) increased invasion and migration of hypoxic MCF-7 cells. Inhibition of HIF-1, by chetomin and NF-,B by parthenolide reduced mRNA and protein expression of the studied molecules and prevented invasion of hypoxic MCF-7 cells. Moreover, solid invasive mammary tumor microenvironment was analyzed after laser-capture microdissection (LCMD) comparing tumor versus host normal tissue. Nuclear translocation of HIF-1, and NF-,B and up-regulation of IR, CXCR4, estrogen receptor , (ER,), and epithelial growth factor receptor (EGFR) was observed in tumor but not in host normal tissue in the absence of a local inflammatory leukocyte infiltrate. We conclude that under hypoxic conditions MCF-7 cells acquire a pro-inflammatory phenotype, and that solid human mammary carcinoma evidenced a similar activation of HIF-1,, NF-,B, and IR genes in malignant tumor cells as compared to the normal host tissues. We suggest a role for IR activation in the malignant progression of transformed cells. (Cancer Sci 2010; 101: 1014,1023) [source] Co-treatment with deoxycholic acid and azoxymethane accelerates secretion of HMGB1 in IEC6 intestinal epithelial cellsCELL PROLIFERATION, Issue 5 2009K. Fujii Objectives:, High-mobility group box 1 (HMGB1) is a nuclear protein that acts as a ligand of the receptor for advanced glycation end products (RAGE) and its expression enhances progression of cancer. However, the mechanism underlying HMGB1 secretion is still unclear. In this study, we examined the effect of deoxycholic acid (DCA), a promoter of colon carcinogenesis, on HMGB1 secretion. Materials and Methods:, We used an in vitro transformation model comprised of IEC6 intestinal epithelial cells treated with azoxymethane (AOM) and/or DCA. HMGB1 expression and secretion were examined by Western and Northern blot analyses, and ELISA. Intracellular translocation of HMGB1 was examined by protein fractionation. Results:, AOM + DCA-treated IEC6 cells showed upregulation of HMGB1 mRNA expression and increased level of HMGB1 protein in culture medium, but decreased level of HMGB1 protein in the nucleus. AOM + DCA treatment increased level of histone H4 acetylation, which induced translocation of HMGB1 from the nucleus to the cytoplasm and increased HMGB1 secretion. Leptomycin B inhibited extranuclear translocation and secretion of the HMGB1 protein. Conclusion:, These findings suggest that DCA affects intracellular localization and secretion of HMGB1. [source] | ||||||||||||||||||||||||||||||||||