02257nas a2200217   4500008004100000022001400041245010300055210006900158260009100227300001200318490000600330520141100336100002301747700001901770700002501789700002501814700002201839700002501861700002501886856012801911       2014                        eng d  a1932-620300aMolecular investigations of protriptyline as a multi-target directed ligand in alzheimer's disease0 aMolecular investigations of protriptyline as a multitarget direc  a1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USAbPUBLIC LIBRARY SCIENCEcAUG  ae1051960 v93 a<p>Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), beta-secretase (BACE-1), and amyloid beta (A beta) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment.</p>1 aBansode, Sneha, B.1 aJana, Asis, K.1 aBatkulwar, Kedar, B.1 aWarkad, Shrikant, D.1 aJoshi, Rakesh, S.1 aSengupta, Neelanjana1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/molecular-investigations-protriptyline-multi-target-directed-ligand-alzheimers-disease-002638nas a2200277   4500008004100000022001400041245011500055210006900170260000900239300001100248490000900259520174400268653000802012653001302020653001402033653001802047653001202065653000902077100002202086700002302108700002102131700003202152700002202184700002502206856012902231       2021                        eng d  a0925-443900aMolecular investigation of glycated insulin-induced insulin resistance via insulin signaling and AGE-RAGE axis0 aMolecular investigation of glycated insulininduced insulin resis  cFEB   a1660290 v18673 a<p>Hyperglycemic condition in diabetes promotes glycation of various plasma proteins including insulin. Glycation of insulin has been reported to reduce its biological activity. Reduced biological activity of glycated insulin could be either due to reduced affinity for the insulin receptor and impaired insulin signaling, or it can act as a ligand for the receptor for advanced glycation end products (RAGE) and activates oxidative stress and pro-inflammatory pathways leading to insulin resistance. This study investigates the effect of glycated insulin on both insulin and RAGE signaling. Glycated insulin treatment to Chinese hamster ovary (CHO-IR-GLUT4) cells stably expressing insulin receptor (IR) and glucose transporter fused with a green fluorescent protein (GLUT4-GFP) resulted in the impairment of insulin signaling, as the phosphorylation of IR and AKT significantly reduced, which affected GLUT4 translocation and glucose uptake. Moreover, it also activated RAGE signaling as observed by increased expression of NADPH oxidase accompanied by an increase in reactive oxygen species (ROS). Immunofluorescence study indicated the translocation of NF-kappa B to the nucleus upon treatment of glycated insulin. This was associated with increased RAGE expression, Caspase 3, and cell death. Downregulation of RAGE with the losartan treatment restored the impaired insulin signaling and glucose uptake. Additionally, in silico study demonstrated that glycated insulin has reduced binding affinity to insulin receptor and increased binding affinity to RAGE. Overall, this study demonstrates the role of glycated insulin in exacerbating insulin resistance by impairing insulin signaling as well as stimulating AGE-RAGE signaling.</p>
10aAGE10aDiabetes10aGlycation10aHyperglycemia10ainsulin10aRAGE1 aWalke, Prachi, B.1 aBansode, Sneha, B.1 aMore, Nikita, P.1 aChaurasiya, Arvindkumar, H.1 aJoshi, Rakesh, S.1 aKulkarni, Mahesh, J.  uhttps://library.ncl.res.in/content/molecular-investigation-glycated-insulin-induced-insulin-resistance-insulin-signaling-and