02643nas a2200301   4500008004100000022001400041245005500055210005500110260006700165300001200232490000700244520171800251653001701969653001201986653001401998653001102012653002002023653000902043100002502052700002302077700002102100700002402121700002102145700003602166700002802202700002502230856008602255       2015                        eng d  a1615-985300aInvestigation of phosphoproteome in RAGE signaling0 aInvestigation of phosphoproteome in RAGE signaling  a111 RIVER ST, HOBOKEN 07030-5774, NJ USAbWILEY-BLACKWELLcJAN  a245-2590 v153 a<p>The receptor for advanced glycation end products (RAGE) is one of the most important proteins implicated in diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It is a pattern recognition receptor by virtue of its ability to interact with multiple ligands, RAGE activates several signal transduction pathways through involvement of various kinases that phosphorylate their respective substrates. Only few substrates have been known to be phosphorylated in response to activation by RAGE (e.g., nuclear factor kappa B); however, it is possible that these kinases can phosphorylate multiple substrates depending upon their expression and localization, leading to altered cellular responses in different cell types and conditions. One such example is, glycogen synthase kinase 3 beta which is known to phosphorylate glycogen synthase, acts downstream to RAGE, and hyperphosphorylates microtubule-associated protein tau causing neuronal damage. Thus, it is important to understand the role of various RAGE-activated kinases and their substrates. Therefore, we have reviewed here the details of RAGE-activated kinases in response to different ligands and their respective phosphoproteome. Furthermore, we discuss the analysis of the data mined for known substrates of these kinases from the PhosphoSitePlus (http://www.phosphosite.org) database, and the role of some of the important substrates involved in cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In summary, this review provides information on RAGE-activated kinases and their phosphoproteome, which will be helpful in understanding the possible role of RAGE and its ligands in progression of diseases.</p>10aCell biology10aDisease10aGlycation10aKinase10aPhosphoproteome10aRAGE1 aBatkulwar, Kedar, B.1 aBansode, Sneha, B.1 aPatil, Gouri, V.1 aGodbole, Rashmi, K.1 aKazi, Rubina, S.1 aChinnathambi, Subashchandrabose1 aShanmugam, Dhanasekaran1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/investigation-phosphoproteome-rage-signaling-002140nas a2200217   4500008004100000022001400041245007400055210006900129260011000198300001600308490000600324520132500330100002201655700002401677700002301701700002401724700002101748700002501769700002401794856010401818       2015                        eng d  a2046-206900aN-(3-Aminoalkyl)proline derivatives with potent antigycation activity0 aN3Aminoalkylproline derivatives with potent antigycation activit  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcSEP  a77332-773400 v53 a<p>The importance of amino acids in the therapy of conditions such as renal failure, neurological disorders and congenital defects has been documented. Some amino acids such as lysine and glycine have also been reported to have antiglycating activity. Herein we report the synthesis of a new series of N-(3-aminoalkyl)proline derivatives which are non-natural in nature. The compounds were unambiguously characterized by NMR, mass and IR spectroscopy. Their in vitro antiglycation activity was studied by circular dichroism and fluorescence spectrometry. The mechanism of action was also studied and found to take place by inhibition of Amadori product formation. The inhibition of AGE formation was further confirmed by western blot and LC-MS/MS analyses and the IC50 values of the potent compounds were determined. Compounds containing hydroxyl substituents at C4 were found to have superior antiglycation properties than those containing azide substituents at the same position. The compounds were additionally found to possess good anti-oxidant properties, which could lead to further reduction in AGE formation. Moreover, the title compounds were found to have low cytotoxicity in mammalian cells, another important attribute. Thus, the title compounds represent a novel promising class of antiglycating agents.</p>1 aChilukuri, Harsha1 aKolekar, Yogesh, M.1 aBhosle, Govind, S.1 aGodbole, Rashmi, K.1 aKazi, Rubina, S.1 aKulkarni, Mahesh, J.1 aFernandes, Moneesha  uhttps://library.ncl.res.in/content/n-3-aminoalkylproline-derivatives-potent-antigycation-activity-002880nas a2200193   4500008004100000245017800041210006900219260000800288300001200296490000800308520208800316100002102404700002402425700002402449700002102473700003902494700002502533856012802558       2017                        eng d00aGlycation inhibitors extend yeast chronological lifespan by reducing advanced glycation end products and by back regulation of proteins involved in mitochondrial respiration0 aGlycation inhibitors extend yeast chronological lifespan by redu  cMAR  a104-1120 v1563 aAdvanced Glycation End products (AGEs) are implicated in aging process. Thus, reducing AGEs by using glycation inhibitors may help in attenuating the aging process. In this study using Saccharomyces cerevisiae yeast system, we show that Aminoguanidine (AMG), a well-known glycation inhibitor, decreases the AGE modification of proteins in non-calorie restriction (NR) (2% glucose) and extends chronological lifespan (CLS) similar to that of calorie restriction (CR) condition (0.5% glucose). Proteomic analysis revealed that AMG back regulates the expression of differentially expressed proteins especially those involved in mitochondrial respiration in NR condition, suggesting that it switches metabolism from fermentation to respiration, mimicking CR. AMG induced back regulation of differentially expressed proteins could be possibly due to its chemical effect or indirectly by glycation inhibition. To delineate this, Metformin (MET), a structural analog of AMG and a mild glycation inhibitor and Hydralazine (HYD), another potent glycation inhibitor but not structural analog of AMG were used. HYD was more effective than MET in mimicking AMG suggesting that glycation inhibition was responsible for restoration of differentially expressed proteins. Thus glycation inhibitors particularly AMG, HYD and MET extend yeast CLS by reducing AGEs, modulating the expression of proteins involved in mitochondrial respiration and possibly by scavenging glucose. 

Significance: This study reports the role of glycation in aging process. In the non-caloric restriction condition, carbohydrates such as glucose promote protein glycation and reduce CLS. While, the inhibitors of glycation such as AMC, HYD, MET mimic the caloric restriction condition by back regulating deregulated proteins involved in mitochondria( respiration which could facilitate shift of metabolism from fermentation to respiration and extend yeast CLS. These findings suggest that glycation inhibitors can be potential molecules that can be used in management of aging. (C) 2017 Elsevier B.V. All rights reserved.1 aKazi, Rubina, S.1 aBanarjee, Reema, M.1 aDeshmukh, Arati, B.1 aPatil, Gouri, V.1 aJagadeeshaprasad, Mashanipalya, G.1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/glycation-inhibitors-extend-yeast-chronological-lifespan-reducing-advanced-glycation-end02820nas a2200241   4500008004100000245011400041210006900155260000800224300001400232490000700246520197800253100002402231700002002255700001502275700002102290700002002311700002402331700002402355700002202379700002302401700002502424856012902449       2017                        eng d00aMethylglyoxal attenuates insulin signaling and downregulates the enzymes involved in cholesterol biosynthesis0 aMethylglyoxal attenuates insulin signaling and downregulates the  cNOV  a2338-23490 v133 a<p>Methylglyoxal (MG) is a highly reactive dicarbonyl known to be elevated under the hyperglycemic conditions of diabetes and is implicated in the development of diabetic complications. Therefore, the current study investigates the role of MG in exacerbating insulin resistance at the insulin signaling level, as well as its effect on the global proteomic level. By using insulin sensitive rat muscle cells (L6) and Chinese hamster ovary (CHO) cells stably expressing the insulin receptor (IR) and a glucose transporter fused with green fluorescent protein (GLUT4-GFP), we have observed that MG impairs insulin signaling, inhibits GLUT4 translocation and reduces glucose uptake. SWATH MS analysis, a label-free quantitative mass spectrometric approach, showed altered expression of 99 proteins out of 2404 identified in response to MG treatment. These proteins are mainly involved in stress response, protein folding and proteolysis. Some of the deregulated proteins such as thioredoxin 2, glutathione S transferase, T complex protein 1 subunit beta (tcbp1), heat shock protein 90 and E3 ubiquitin ligase were previously reported to be associated with either diabetes or insulin resistance. Interestingly, aminoguanidine (AMG), a potent dicarbonyl scavenger, restored the deleterious effects of MG. For the first time, we report that MG induces downregulation of enzymes involved in cholesterol biosynthesis such as acetyl-CoA acetyltransferase, hydroxymethylglutaryl-CoA synthase, farnesyl pyrophosphate synthetase, squalene monooxygenase, and lanosterol synthase. GC MS analysis for sterol metabolites corroborated the proteomic results; MG significantly reduced cholesterol production whereas AMG treatment restored cholesterol production to levels similar to the control. Thus, MG leads to primary defects in insulin signaling and cellular abnormalities at the proteomic and metabolic levels, both of which may contribute to the development of insulin resistance.</p>
1 aDeshmukh, Arati, B.1 aBai, Shakuntala1 aAarthy, T.1 aKazi, Rubina, S.1 aBanarjee, Reema1 aRathore, Rajeshwari1 aVijayakumar, M., V.1 aThulasiram, H. V.1 aBhat, Manoj, Kumar1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/methylglyoxal-attenuates-insulin-signaling-and-downregulates-enzymes-involved-cholesterol02148nas a2200301   4500008004100000022001400041245013100055210006900186260000800255300001100263490000800274520114300282653002001425653002501445653001701470653003501487653001901522653001301541653001201554653001401566653002001580100002101600700002201621700002101643700002501664700002501689856013201714       2020                        eng d  a0306-987700aPossible role of glycation in the regulation of amyloid beta precursor protein processing leading to amyloid beta accumulation0 aPossible role of glycation in the regulation of amyloid beta pre  cSEP  a1097990 v1423 a<p>Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases amongst the aged population. The disease is multifactorial, and diabetes has been considered as one of the major risk factors for the development of AD. Chronic hyperglycemic condition in diabetes promotes non-enzymatic protein modification by glucose termed as glycation, which affects protein structure and function. Previous studies have shown that many of the enzymes, including proteases, are affected by glycation. Conversely, glycated proteins are known to become resistant to protease action. In these hypotheses, we have extended these two concepts to the regulation of amyloid-beta protein precursor (A beta PP) by secretases leading to amyloid-beta (Af3) accumulation. The first hypothesis deals with the glycation of alpha-secretases leading to its reduced activity, while in the second hypothesis, A beta PP glycation may prevent a-secretases action, rendering its processing by beta secretase. As diabetes is a risk factor for the development of AD, either or both these pathways may operate, leading to the manifestation of AD.</p>
10aAlpha-secretase10aAlzheimer `s disease10aAmyloid-beta10aAmyloid-beta protein precursor10aBeta-secretase10aDiabetes10aglucose10aGlycation10aType-3 diabetes1 aPatil, Gouri, V.1 aJoshi, Rakesh, S.1 aKazi, Rubina, S.1 aKulsange, Shabda, E.1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/possible-role-glycation-regulation-amyloid-beta-precursor-protein-processing-leading-amyloid