DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2010
Yao-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]

Sensitive and simultaneous analysis of five transgenic maizes using multiplex polymerase chain reaction, capillary gel electrophoresis, and laser-induced fluorescence

ELECTROPHORESIS, Issue 14 2004
Virginia García-Cañas
Abstract The benefits of using multiplex polymerase chain reaction (PCR) followed by capillary gel electrophoresis with laser-induced fluorescence (CGE-LIF) for the simultaneous detection of five transgenic maizes (Bt11, T25, MON810, GA21, and Bt176) are demonstrated. The method uses a hexaplex PCR protocol to amplify the five mentioned transgenic amplicons plus the zein gene used as reference, followed by a CGE-LIF method to analyze the six DNA fragments. CGE-LIF was demonstrated very useful and informative for optimizing multiplex PCR parameters such as time extension, PCR buffer concentration and primers concentration. The method developed is highly sensitive and allows the simultaneous detection in a single run of percentages of transgenic maize as low as 0.054% of Bt11, 0.057% of T25, 0.036% of MON810, 0.064% of GA21, and 0.018% of Bt176 in flour obtaining signals still far from the detection limit (namely, the signal/noise ratios for the corresponding DNA peaks were 41, 124, 98, 250, 252, and 473, respectively). These percentages are well below the minimum threshold marked by the European Regulation for transgenic food labeling (i.e., 0.5,0.9%). A study on the reproducibility of the multiplex PCR-CGE-LIF procedure was also performed. Thus, values of RSD lower than 0.67 and 6.80% were obtained for migration times and corrected peak areas, respectively, for the same sample and three different days (n = 12). On the other hand, the reproducibility of the whole procedure, including four different multiplex PCR amplifications, was determined to be better than 0.66 and 23.3% for migration times and corrected peak areas, respectively. Agarose gel electrophoresis (AGE) and CGE-LIF were compared in terms of resolution and sensitivity for detecting PCR products, demonstrating that CGE-LIF can solve false positives induced by artifacts from the multiplex PCR reaction that could not be addressed by AGE. Moreover, CGE-LIF provides better resolution and sensitivity. To our knowledge, these results demonstrate for the first time that multiplex PCR-CGE-LIF is a solid alternative to determine multiple genetically modified organisms in maize flours in a single run. [source]

IS THE AGE OF THE EARTH ONE OF OUR "SOREST TROUBLES?"

EVOLUTION, Issue 3 2010
STUDENTS' PERCEPTIONS ABOUT DEEP TIME AFFECT THEIR ACCEPTANCE OF EVOLUTIONARY THEORY
First page of article [source]

THE EFFECTS OF GENOTYPE, AGE, AND SOCIAL ENVIRONMENT ON MALE ORNAMENTATION, MATING BEHAVIOR, AND ATTRACTIVENESS

EVOLUTION, Issue 11 2005
Lisa K. Miller
Abstract The traits thought to advertise genetic quality are often highly susceptible to environmental variation and prone to change with age. These factors may either undermine or reinforce the potential for advertisement traits to signal quality depending on the magnitude of age-dependent expression, environmental variation, and genotype-age and genotype-environment interaction. Measurements of the magnitude of these effects are thus a necessary step toward assessing the implications of age dependence and environmental variability for the evolution of signals of quality. We conducted a longitudinal study of male guppies (Poecilia reticulata) from 22 full-sibling families. Each fish was assigned at maturity to one of three treatments in order to manipulate his allocation of resources to reproduction: a control in which the male was kept alone, a courtship-only treatment in which he could see and court a female across a clear partition, and a mating treatment in which he interacted freely with a female. We measured each male's size, ornamental color patterns, courtship, attractiveness to females, and mating success at three ages. Size was influenced by treatment and age-treatment interactions, indicating that courtship and mating may impose costs on growth. Tail size and color patterns were influenced by age but not by treatment, suggesting fixed age-dependent trajectories in these advertisement traits. By contrast, display rate and attempted sneak copulation rate differed among treatments but not among ages, suggesting greater plasticity of these behavioral traits. As a result of the different patterns of variation in ornamentation and behavior, male attractiveness and mating success responded to male age, treatment, and the interaction between age and treatment. Neither age nor treatment obscured the presence of genetic variation, and the genetic relationship between male ornamentation and attractiveness remained the same among treatments. Our findings suggest that neither age-dependent variation nor environmentally induced variation in reproductive effort is likely to undermine the reliability of male signaling. [source]

MEASURING PROBABILISTIC REACTION NORMS FOR AGE AND SIZE AT MATURATION

EVOLUTION, Issue 4 2002
Mikko Heino
Abstract We present a new probabilistic concept of reaction norms for age and size at maturation that is applicable when observations are carried out at discrete time intervals. This approach can also be used to estimate reaction norms for age and size at metamorphosis or at other ontogenetic transitions. Such estimations are critical for understanding phenotypic plasticity and life-history changes in variable environments, assessing genetic changes in the presence of phenotypic plasticity, and calibrating size- and age-structured population models. We show that previous approaches to this problem, based on regressing size against age at maturation, give results that are systematically biased when compared to the probabilistic reaction norms. The bias can be substantial and is likely to lead to qualitatively incorrect conclusions; it is caused by failing to account for the probabilistic nature of the maturation process. We explain why, instead, robust estimations of maturation reaction norms should be based on logistic regression or on other statistical models that treat the probability of maturing as a dependent variable. We demonstrate the utility of our approach with two examples. First, the analysis of data generated for a known reaction norm highlights some crucial limitations of previous approaches. Second, application to the northeast arctic cod (Gadus morhua) illustrates how our approach can be used to shed new light on existing real-world data. [source]

Circulating T-Cell Response to Helicobacter pylori Infection in Chronic Gastritis

HELICOBACTER, Issue 3 2000
Zhigang Ren
Background.Helicobacter pylori elicits a specific humoral and cellular immune response. There is increasing evidence that the type of T-cell response contributes to clinical outcome in H. pylori infection. Materials and Methods. The host response to H. pylori infection in 34 subjects with chronic gastritis was examined in terms of T-cell proliferation and cytokine production in whole-blood cultures stimulated or unstimulated with H. pylori acid-glycine extract antigens (AGE). Results. The proliferative response in whole-blood cultures was similar for both H. pylori,positive and ,negative subjects stimulated with H. pylori AGE. While an increase in interferon-, (IFN-,) production was observed from both H. pylori,positive and ,negative subjects with gastritis, significantly higher levels of IFN-, were detected in the former when stimulated with H. pylori AGE. In contrast, interleukin 4 (IL-4) was undetectable regardless of antigen stimulation. However, if an in situ IL-4 antibody capture assay was used, antigen-independent production of IL-4 was detected, but there was no difference between H. pylori,positive and ,negative subjects with gastritis. After eradication of H. pylori, antigen-induced production of IL-4 was increased, with no decrease in the levels of secretion of IFN-,. IL-4 production was dependent on CD4+ T cells, as addition of anti-CD4 but not anti-CD8 mouse monoclonal antibody or matched IgG isotype to the whole-blood culture inhibited the production of IL-4. Conclusion. The results suggest that a shift toward a balanced Th1-Th2 response due to an increase in antigen-induced IL-4 production from CD4+ T cells follows eradication. We suggest that the downregulation of mucosal inflammation consequent on reduction in antigen levels or removal of downregulation after eradication of H. pylori contributes to this shift in cytokine balance. [source]

HISTORY AND RELIGION IN THE MODERN AGE

HISTORY AND THEORY, Issue 4 2006
CONSTANTIN FASOLT
ABSTRACT This essay seeks to clarify the relationship between history and religion in the modern age. It proceeds in three steps. First, it draws attention to the radical asymmetry between first-person and third-person statements that Wittgenstein's Philosophical Investigations rescued from the metaphysical exile to which it had been condemned by Descartes's definition of the self as a thing. Second, it argues that religion is designed to alleviate the peculiarly human kind of suffering arising from this asymmetry. Third, it maintains that history relies on the same means as religion in order to achieve the same results. The turn to historical evidence performed by historians and their readers is more than just a path to knowledge. It is a religious ritual designed to make participants at home in their natural and social environments. Quite like the ritual representation of the death and resurrection of Christ in the Mass, the historical representation of the past underwrites the faith in human liberty and the hope in redemption from suffering. It helps human beings to find their bearings in the modern age without having to go to pre-industrial churches and pray in old agrarian ways. History does not conflict with the historical religions merely because it reveals them to have been founded on beliefs that cannot be supported by the evidence. History conflicts with the historical religions because it is a rival religion. [source]

Advanced glycation end products accumulate in the reproductive tract of men with diabetes

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 4 2009
C. 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]

AGE AND ACUTE MOUNTAIN SICKNESS: EXAMINING THE DATA

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 4 2005
Jeremy Graham DO
No abstract is available for this article. [source]

Association of salivary lysozyme and C-reactive protein with metabolic syndrome

JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 9 2010
Markku 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]

Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2009
H. Fukuchi MS
Summary Objective:, To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (nonmem) in Japanese patients treated with oral therapy. Method:, Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. Results:, Estimates generated using nonmem indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0·16 · TBW · 0·53AGE , 65 · 0·78BMI , 25 · DD0·51, Vd (L) = 10·2 · TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) ,65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m2) ,25 = 1 for patient was 25 kg/m2 or over and 0 otherwise and Vd is apparent volume of distribution. The clearance of AMD decreased significantly by 22·3% with a BMI higher than 25 kg/m2. The clearance of AMD also decreased significantly by 46·9% when patient age was more than 65 years. Conclusion:, Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD. [source]

Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patients

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2005
E. Yukawa PhD
Summary Objective:, To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. Method:, A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. Results:, The final pharmacokinetic model was Cl (L/h) = 3·75·TBW0·567·AGE,0·374·Conc,0·719·1·48DOSE , 5, Vd (L/kg) = 4·13 and ka (h,1) = 0·363, where Cl is total body clearance, Vd is apparent volume of distribution, ka is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (,g/mL), and DOSE , 5 = 1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. Conclusion:, Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect. [source]

Aldose Reductase and AGE,RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats

AGING CELL, Issue 5 2010
Kellie McCormick Hallam
Summary Aging is inevitably accompanied by gradual and irreversible innate endothelial dysfunction. In this study, we tested the hypothesis that accentuation of glucose metabolism via the aldose reductase (AR) pathway contributes to age-related vascular dysfunction. AR protein and activity levels were significantly increased in aged vs. young aortic homogenates from Fischer 344 rats. Immunostaining revealed that the principal site of increased AR protein was the aortic endothelium as well as smooth muscle cells. Studies revealed that endothelial-dependent relaxation (EDR) in response to acetylcholine was impaired in aged rats compared to young rats and that treatment with the AR inhibitor (ARI) zopolrestat significantly improved EDR in aged rats. Methylglyoxal (MG), a key precursor of advanced glycation endproducts (AGEs), was significantly increased in the aortas of aged rats vs. young rats. Consistent with central roles for AR in generation of MG in aging, ARI treatment significantly reduced MG levels in aged rat aorta to those in young rats. Treatment of aged rats with soluble(s) RAGE, a soluble form of the chief signal transduction receptor for AGEs, RAGE, significantly improved EDR in aged rats, thus establishing the contribution of age-related increases in AGEs to endothelial dysfunction. These findings reveal that significant increases in AR expression and activity in aged rat vasculature linked to endothelial dysfunction may be mitigated, at least in part, via ARI and that aging-linked increased flux via AR generates AGEs; species which transduce endothelial injury consequent to their interaction with RAGE. These data demonstrate for the first time that AR mediates aging-related vascular dysfunction, at least in part, via RAGE. [source]

Oxidative stress: A cause and therapeutic target of diabetic complications

JOURNAL OF DIABETES INVESTIGATION, Issue 3 2010
Eiichi Araki
Abstract Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti-oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end-products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), which reflects mitochondrial oxidative damage, and further reported that 8-OHdG was elevated in subjects with diabetic micro- and macro- vascular complications. We recently created vascular endothelial cell-specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia-induced mtROS production by the induction of PPAR, coactivator-1, (PGC-1,) and MnSOD and/or activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK,PGC-1, pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00013.x, 2010) [source]

Protein modification and replicative senescence of WI-38 human embryonic fibroblasts

AGING CELL, Issue 2 2010
Emad K. Ahmed
Summary Oxidized proteins as well as proteins modified by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) and by glycation (AGE) have been shown to accumulate with aging in vivo and during replicative senescence in vitro. To better understand the mechanisms by which these damaged proteins build up and potentially affect cellular function during replicative senescence of WI-38 fibroblasts, proteins targeted by these modifications have been identified using a bidimensional gel electrophoresis-based proteomic approach coupled with immunodetection of HNE-, AGE-modified and carbonylated proteins. Thirty-seven proteins targeted for either one of these modifications were identified by mass spectrometry and are involved in different cellular functions such as protein quality control, energy metabolism and cytoskeleton. Almost half of the identified proteins were found to be mitochondrial, which reflects a preferential accumulation of damaged proteins within the mitochondria during cellular senescence. Accumulation of AGE-modified proteins could be explained by the senescence-associated decreased activity of glyoxalase-I, the major enzyme involved in the detoxification of the glycating agents methylglyoxal and glyoxal, in both cytosol and mitochondria. This finding suggests a role of detoxification systems in the age-related build-up of damaged proteins. Moreover, the oxidized protein repair system methionine sulfoxide reductase was more affected in the mitochondria than in the cytosol during cellular senescence. Finally, in contrast to the proteasome, the activity of which is decreased in senescent fibroblasts, the mitochondrial matrix ATP-stimulated Lon-like proteolytic activity is increased in senescent cells but does not seem to be sufficient to cope with the increased load of modified mitochondrial proteins. [source]

Advanced glycation end product in familial amyloidotic polyneuropathy (FAP)

JOURNAL OF INTERNAL MEDICINE, Issue 4 2000
N. 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 2001
Annunziata 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]

Age-Induced Neuropathy In Rats

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 3 2000
S Yagihashi
We studied the effects of exogenously administered advanced glycation end-products (AGE) on the peripheral nerve function and structure in normal rats. Normal Wistar rats aged 6 weeks were injected intraperitoneally with purified AGE (20 mg/kg/day) produced by incubation of glucose with bovine serum albumin (BSA) for 12 weeks. Control rats were treated with BSA alone. One of AGE-treated groups was co-treated with 50 mg/kg aminoguanidine (AG). During the experimental period, body weight and blood glucose levels were not affected in AGE-treated rats. Serum AGE levels were elevated two fold in AGE-treated group whereas BSA treated rats maintained normal levels, whereas tissue AGE levels in sciatic nerve were not increased in treated group. AG did not alter the levels of serum AGE. AGE-treated rats exhibited significant delay of motor nerve conduction velocity by 30% and reduction of sciatic nerve in Na,K-ATPase activity by 25% in AGE-treated rats. AG treatment significantly inhibited these changes. Immunostains on the cross-sections of sciatic nerve demonstrated significant increase in cells positive for 8 hydroxy-deoxyguanosine, a marker of oxidative stress-induced DNA injury, in AGE-treated group. AG treatment significantly inhibited this reaction. There was no difference in morphometric data on myelinated fibers in sural nerve among the experimental groups. AGE-injected rats thus showed the neuropathic changes, similar to those found in experimentally-induced diabetic animals and it is therefore suggested that AGE have a pathogenetic role in the development of diabetic neuropathy through induction of excessive oxidative stress. Supported by Juvenile Diabetes Foundation International (1-2000-263), Japan Diabetes Foundation, Japanese Ministry of Science, Education, Sports and Culture. [source]

A FIELD-BASED METHOD FOR ESTIMATING AGE IN FREE-RANGING STELLER SEA LIONS (EUMETOPIAS JUBATUS) LESS THAN TWENTY-FOUR MONTHS OF AGE

MARINE MAMMAL SCIENCE, Issue 2 2007
James C. King
Abstract Studies of health, survival, and development of juvenile Alaskan Steller sea lions (Eumetopias jubatus, SSL) require accurate estimates of age for wild-captured animals. However, the value and accuracy of several potential predictors of age have not been assessed with data from known-age free-ranging animals. During 2001,2005, forty-six individual SSL originally branded or tagged at ,6 mo of age were recaptured by the Alaska Department of Fish and Game (ADF&G). Using a series of general linear models, we evaluated the ability of morphometrics measurements: permanent canine tooth length (CTL), diastema (DIAS), whisker length (WHIS), and dorsal standard length (DSL) to predict the age of forty-six known-age juveniles (n= 46 ,23 mo of age). Permanent CTL was the strongest individual predictor (r2= 0.80); followed by DSL, DIAS, and WHIS (r2= 0.70, 0.56, and 0.45, respectively). The inclusion of a single sample from a 44-mo-old sea lion suggested quadratic relationships between age and all predictors for older animals. Only models including CTL predicted age to within 6 mo of known age. The equation Age = (,3.0112 +[0.6726 * CTL]+[0.4965 * DIAS]) allows for accurate age estimates of SSL ,23 mo for both sexes. [source]

Mass spectrometry for the study of protein glycation in disease

MASS SPECTROMETRY REVIEWS, Issue 5 2006
Toshimitsu Niwa
Abstract The structural elucidation of advanced glycation end-product (AGE)-modified proteins and quantitative analysis of free AGEs have been successfully performed, by use of mass spectrometry (MS) in plasma and tissues of patients with AGE-related diseases, such as diabetes mellitus, uremia, cataract, and liver cirrhosis. Matrix-assisted laser desorption/ionization (MALDI)-MS made it possible to directly analyze the AGE-modified proteins such as albumin and IgG. However, because the direct structural analysis of intact AGE-modified proteins is often not easy due to the formation of broad and poorly resolved peaks, peptide mapping after enzymatic hydrolysis was introduced into the analysis of AGE-modified proteins and the site-specific analysis of defined AGEs by MALDI-MS. Liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) has been employed not only for the structural elucidation of enzymatically hydrolyzed AGEs-modified peptides but also for simultaneous quantification of free AGEs in plasma and tissues of patients. Based on many studies that use MS for the analysis of AGEs, there is no doubt as to the important role of protein-linked AGEs in several diseases. © 2006 Wiley-Liss, Inc. [source]

COSMOPOLITANISM AND HUMAN RIGHTS: RADICALISM IN A GLOBAL AGE

METAPHILOSOPHY, Issue 1 2009
ROBERT FINE
Abstract: The cosmopolitan imagination constructs a world order in which the idea of human rights is an operative principle of justice. Does it also construct an idealisation of human rights? The radicality of Enlightenment cosmopolitanism, as developed by Kant, lay in its analysis of the roots of organised violence in the modern world and its visionary programme for changing the world. Today, the temptation that faces the cosmopolitan imagination is to turn itself into an endorsement of the existing order of human rights without a corresponding critical analysis of the roots of contemporary violence. Is the critical idealism associated with Kantian cosmopolitanism at risk of transmutation into an uncritical positivism? We find two prevailing approaches: either the constitutional framework of the existing world order is presented as the realisation of the cosmopolitan vision, or cosmopolitanism is turned into a utopian vision of a world order in which power is subordinated to the rule of international law. I suggest that the difficulties associated with both wings of cosmopolitanism threaten the legitimacy of the project and call for an understanding and culture of human rights that is less exclusively "conceptual" and more firmly grounded in social theory. [source]

HISTORY, BELIEF AND IMAGINATION IN CHARLES TAYLOR'S A SECULAR AGE

MODERN THEOLOGY, Issue 3 2010
GRAHAM WARD
In this essay I explore, from a theologian's perspective, two questions which arise from the Taylor's development of a genre addressing two quite different audiences: the social scientists and the theologians. In particular, it examines the relationship between theology and history and the relationship between believing, an act of faith and the imaginary. While accepting the conditions for believing in the age of enchantment differ from those in a secular and disenchanted age, the essay concludes by questioning whether an act of faith was any less difficult and by pointing out that if it was less difficult then theologically we need a more nuanced account of the relationship between God and history. [source]

"LONG LIVE THE WEEDS AND THE WILDERNESS YET": REFLECTIONS ON A SECULAR AGE

MODERN THEOLOGY, Issue 3 2010
STANLEY HAUERWAS
While we are deeply appreciative of Taylor's A Secular Age, we nonetheless worry that his use of the immanent/transcendent duality may introduce a certain kind of Christian Constantinianism that he wants to disavow. In particular, we worry that the immanent/transcendent duality is far too formal in its character. In order to develop this concern, we draw on Talal Asad's account of the secular to suggest how liturgy may provide an alternative way of understanding as well as challenging Taylor's worries about "the immanent frame." [source]

THE RESPONSE OF A THEOLOGIAN TO CHARLES TAYLOR'S A SECULAR AGE

MODERN THEOLOGY, Issue 3 2010
GREGORY BAUM
The author of this article confirms Charles Taylor's thesis that despite the growing spread of unbelief in modern society, i) religion remains an independent variable, ii) a creative "back and forth" continues to occur between secular wisdom and religious faith, and iii) the difference between these two does not necessarily produce opposition between them. The author also agrees with the importance Taylor attaches to the emergence of immanent humanism. Yet the author disagrees with Taylor's account of contemporary culture and religion as expressions of people's quest of identity; the article demonstrates instead that religion participates in all contemporary social movements. [source]

Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 3 2008
Rhea Mehta
Abstract Carbonyls generated by autoxidation of carbohydrates or lipid peroxidation have been implicated in advanced glycation end product (AGE) formation in tissues adversely affected by diabetes complications. Tissue AGE and associated pathology have been decreased by vitamin B1/B6 in trials involving diabetic animal models. To understand the molecular cytoprotective mechanisms involved, the effects of B1/B6 vitamers against cytotoxicity induced by AGE/advanced lipid end product (ALE) carbonyl precursors (glyoxal/acrolein) have been compared to cytotoxicity induced by oxidative stress (hydroperoxide) or mitochondrial toxins (cyanide/copper). Thiamin was found to be best at preventing cell death induced by carbonyl stress and mitochondrial toxins but not oxidative stress cell death suggesting that thiamin pyrophosphate restored pyruvate and ,-ketoglutarate dehydrogenases inhibited by mitochondrial toxicity. However, B6 vitamers were most effective at preventing oxidative stress or lipid peroxidation cytotoxicity suggesting that pyridoxal or pyridoxal phosphate were antioxidants and/or Fe/Cu chelators. A therapeutic vitamin cocktail could provide maximal prevention against carbonyl stress toxicity associated with diabetic complications. [source]

Copper-catalyzed ascorbate oxidation results in glyoxal/AGE formation and cytotoxicity

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4 2007
Nandita Shangari
Abstract Previously we showed that 10 ,M glyoxal compromised hepatocyte resistance to hydrogen peroxide (H2O2) by increasing glutathione (GSH) and NADPH oxidation and decreasing mitochondrial membrane potential (MMP) before cytotoxicity ensued. Since transition metal-catalyzed oxidation of ascorbate (Asc) has been shown to result in the generation of both glyoxal and H2O2, we hypothesized that glyoxal formation during this process compromises hepatocyte resistance to H2O2. We used isolated rat hepatocytes and incubated them with Asc/copper and measured cytotoxicity, glyoxal levels, H2O2, GSH levels, and MMP. To investigate the role of Asc/copper on glyoxal-BSA adducts, we measured the appearance of advanced glycation end-products (AGE) in the presence and absence of catalase or aminoguanidine (AG). Asc/copper increased glyoxal and H2O2 formation. Hepatocyte GSH levels were decreased and cytotoxicity ensued after a collapse of the hepatocyte MMP. Glyoxal traps protected hepatocytes against Asc/copper-induced cytotoxicity. In cell-free studies with BSA, incubation with Asc and copper resulted in glyoxal-hydroimidazolone formation, which was decreased by both AG and catalase. To the best of our knowledge, this is the first study that illustrates the importance of glyoxal production by transition metal-catalyzed Asc autoxidation. Understanding this mechanism of toxicity could lead to the development of novel copper chelating drug therapies to treat diabetic complications. [source]

Off-line liquid chromatography-MALDI by with various matrices and tandem mass spectrometry for analysis of glycated human serum albumin tryptic peptides

MOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4 2007
Annunziata Lapolla
Abstract Advanced glycation end-product (AGE)/peptides, arising from in vivo digestion of glycated proteins, are biologically important compounds, due to their reactivity against circulating and tissue proteins. For information on their possible structure, in vitro glycation of HSA and its further enzymatic digestion were performed. The resulting digestion product mixture was analysed directly by MALDI MS with various matrices [2,5-dihydroxy benzoic acid (DHB) and ,-cyano-4-hydroxy cinnamic acid (CHCA)]. Alternatively, offline microbore LC prior to MALDI analysis was used, and showed that 63% of the free amino groups prone to glycation are modified, indicating the contemporary presence of unglycated peptides. This result proves that, regardless of the high glucose concentration employed for HSA incubation, glycation does not go to completion. Further studies showed that the collisionally activated decomposition of singly charged glycated peptides leads to specific fragmentation pathways, all related to the condensed glucose molecule. These unique product ions can be used as effective markers to establish the presence of a glucose molecule within a peptide ion. [source]

Advanced oxidative protein products are independently associated with endothelial function in peritoneal dialysis patients

NEPHROLOGY, Issue 3 2009
HUSEYIN KOCAK
SUMMARY Aim: Oxidative stress (OS) and asymmetric dimethylarginine (ADMA) are accepted as non-classical cardiovascular risk factors in end-stage renal disease patients. To clarify the role of these factors in the atherosclerotic process, we investigated if OS and ADMA are associated with endothelial function (EF) in peritoneal dialysis (PD) patients. Methods: Fifty-two non-diabetic PD patients without known atherosclerotic disease as well as 30 age- and sex-matched healthy individuals were included. We measured serum thiobarbituric acid-reactive substances (TBARS), malondialdehyde (MDA), advanced glycation end-product (AGE), pentosidine, advanced oxidation protein products (AOPP), ADMA and EF as described by Celermejer et al. in all subjects. Results: TBARS, MDA, AOPP, AGE, pentosidine and ADMA levels were significantly higher in PD patients than in controls (P < 0.001). Flow-mediated dilatation (FMD)% and nitrate mediated dilatation (NMD)% in PD patients were lower than in the control group (7.7 ± 4.0% vs 11.70 ± 5.50%, P < 0.01 and 17.6 ± 8.3% vs 26.4 ± 4.6%, P < 0.01). Additionally, it was found that AOPP are independently correlated with FMD% and NMD% in PD patients (, = ,463, P < 0.01 and , = ,420, P < 0.05). Conclusion: This study shows that PD patients without known atherosclerotic disease can also be characterized by endothelial dysfunction and AOPP levels independently predict endothelial function level in PD patients. [source]

Transforming growth factor-, and Smad signalling in kidney diseases

NEPHROLOGY, Issue 1 2005
Review 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]

Glycosaminoglycans and the peritoneaum

NEPHROLOGY, Issue 5 2002
Susan YUNG
SUMMARY: The introduction of peritoneal dialysis (PD) over two decades ago has allowed us to manipulate the peritoneal membrane to perform as a continuous dialysing organ. to maximize the efficacy of solute transport and waste removal, conventional PD fluids require unphysiological concentrations of glucose to provide the osmotic drive, lactate to alleviate metabolic acidosis, and a low pH to prevent the caramelization of glucose during the preparation of the solutions. These factors either alone or in combination, are irritants to the peritoneal membrane. Thus, continuous exposure of the peritoneum to PD solutions, together with frequent episodes of peritonitis confers a chronic inflammatory response within the peritoneum. It is, therefore, not unexpected that with time, long-term PD patients develop structural and functional changes within the peritoneum, which in many cases develop into peritoneal fibrosis of varying degrees and compromises the peritoneal membrane as a dialysing organ. to date, numerous studies have investigated methods to improve the efficiency of PD and preserve the structure of the peritoneal membrane. Recently, a number of reports have documented the beneficial effects of intraperitoneal administration of glycosaminoglycans (GAGs) on both the structural and functional qualities of the peritoneum. In this context, GAGs have been demonstrated to inhibit collagen synthesis within the peritoneum, decrease peritoneal advanced glycosylated end-products (AGE) deposition, and modulate cytokine and growth factor synthesis. This review will examine the available data with regards to the potential role of GAGs in maintaining ultrafiltration, solute transport and the structural integrity of the peritoneum. [source]