02537nas a2200193 4500008004100000022001400041245010300055210006900158260011000227300001400337490000600351520172700357100002502084700002702109700002402136700002502160700002902185856012902214 2013 eng d a1742-206X00aNovel mechanism for antiglycative action of limonene through stabilization of protein conformation0 aNovel mechanism for antiglycative action of limonene through sta aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcJUN a2463-24720 v93 a

Inhibition of protein glycation is known to ameliorate secondary complications in diabetes. In the present study antiglycative properties of limonene, a natural product, were evaluated using BSA as a model protein. AMG (aminoguanidine) was used as a positive control. Measurement of total AGEs (Advanced Glycation End-products) and specific AGEs revealed that limonene could inhibit protein glycation to the extent of 56.3% and 75.1% respectively at 50 mu M concentration as against 54.4% and 82.2% by AMG at 1 mM. Congo red binding and CD (Circular Dichroism) analysis revealed inhibition of alpha-helix to beta-sheet transition wherein 18.5% beta-sheet structures were observed in glycated BSA (bovine serum albumin) as against 4.9% with limonene. Glycation of protein in the presence of urea was enhanced by 18%, while in the presence of limonene it was reduced by 23% revealing the stabilizing effect of limonene. Electrophoretic mobility was similar to the normal control and a zeta potential value of -12.1 mV as against -15.1 mV in diabetic control was observed. Inhibition of glycation in limonene treated samples was confirmed through LC-MS analysis wherein AGEs such as pentosidine, CML (N-epsilon-(carboxymethyl)lysine), CEL (N-epsilon-(carboxyethyl) lysine), MOLD (methylglyoxal-lysine dimer) and imidazolone observed in glycated samples were absent in limonene treated samples. PatchDock studies revealed that limonene could bind to the major glycation sites IB, IIA and IIB sub domains and AMG to the IIIA sub domain. Thus limonene is a potent protein glycation inhibitor that prevents protein glycation through a novel mechanism of stabilization of protein structure through hydrophobic interactions.

1 aJoglekar, Madhav, M.1 aPanaskar, Shrimant, N.1 aChougale, Ashok, D.1 aKulkarni, Mahesh, J.1 aArvindekar, Akalpita, U. uhttp://library.ncl.res.in/content/novel-mechanism-antiglycative-action-limonene-through-stabilization-protein-conformation-002139nas a2200217 4500008004100000022001400041245007400055210006900129260011000198300001600308490000600324520132500330100002201655700002401677700002301701700002401724700002101748700002501769700002401794856010301818 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

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.

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 uhttp://library.ncl.res.in/content/n-3-aminoalkylproline-derivatives-potent-antigycation-activity-002192nas a2200241 4500008004100000022001400041245009400055210006900149260000800218300001600226490000600242520135800248100003201606700002501638700001701663700002301680700002201703700002401725700002801749700002801777700002501805856012001830 2023 eng d a2470-134300aNanopore sequencing of RAGE gene polymorphisms and their association with type 2 diabetes0 aNanopore sequencing of RAGE gene polymorphisms and their associa cJUL a25727-257380 v83 a

The receptor foradvanced glycation end products (RAGE)is a transmembraneprotein that interacts with its ligands, advanced glycation end products(AGEs). AGEs are elevated in diabetes and diabetic complications,leading to increased oxidative stress and activation of pro-inflammatorypathways facilitated by AGE-RAGE signaling. Polymorphisms inthe RAGE gene can potentially affect AGE-RAGEinteraction and its downstream signaling, which plays a crucial rolein the progression of diabetes and its complications. In this study,we used nanopore sequencing for genotyping of RAGE polymorphism and identified a maximum number of 33 polymorphisms,including two previously unreported novel mutations in a cohort ofhealthy, type 2 diabetics without nephropathy and type 2 diabeticswith nephropathy in order to identify associations. Two novel RAGE polymorphisms in the intron 8 and 3 & PRIME;UTR regionat genomic locations 32181834 and 32181132, respectively, were detectedwith a low frequency. For four previously reported polymorphisms,cross-validation by PCR-RFLP showed 99.75% concordance with nanoporesequencing. Analysis of genotype distribution and allele frequenciesrevealed that five single nucleotide polymorphisms, i.e., rs1800625,rs3131300, rs3134940, rs2070600, and rs9391855, were associated withan increased risk for type 2 diabetes.

1 aChaurasiya, Arvindkumar, H.1 aKhilari, Ajinkya, A.1 aKazi, Rubina1 aJaiswal, Meera, R.1 aBhoite, Gouri, M.1 aPadwal, Meghana, K.1 aMomin, Abdulrahaman, A.1 aShanmugam, Dhanasekaran1 aKulkarni, Mahesh, J. uhttp://library.ncl.res.in/content/nanopore-sequencing-rage-gene-polymorphisms-and-their-association-type-2-diabetes