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PubMed | Pd Hinduja National Hospital & Medical Research Center, Bangur Institute of Neurosciences, University of Calcutta and Academy of Scientific & Innovative Research AcSIR
Type: | Journal: Neuroscience letters | Year: 2016

Primary Dystonia is a common movement disorder manifested by dystonic symptoms only. DYT6, a major genetic factor, plays a significant role in primary pure dystonia pathogenesis. In this study we analyzed THAP1 (DYT 6) gene in primary pure dystonia patients, which has been widely studied in other populations but not in Indians.The study cohort contained 227 index primary pure dystonia patients with the involvement of cervical region and 254 neurologically control individuals collected from East Indian population. All three exons of THAP1 and their flanking sequences, including exon-intron boundaries, were screened by PCR, DNA sequencing and/or RFLP analysis.A total of three nucleotide variants were detected, which include a reported missense mutation (c.427 A>G; p.Met143Val) in a juvenile onset generalized dystonia patient, a novel frameshift deletion mutation (c.208-209 AA; p.K70VfsX15) in a juvenile onset cervical dystonia patient and a rare variant in 3 UTR of THAP1 (c.*157 T>C) in an adult-onset blepharospasm patient. In addition, two SNPs (rs71521601 and rs111989331) were detected both in the patients and controls with the major allele of the latter being significantly over represented in the patients.Our study suggests that the THAP1 is likely to have a causative role in the pathogenesis of Indian primary pure dystonia patients. Though the phenotypic spectrum is extensively diverse, the cervical involvement with dystonic tremor and speech problem is common amongst the patients harboring mutations.

Bala V.,CSIR - Central Electrochemical Research Institute | Bala V.,Academy of Scientific & Innovative Research AcSIR | Gupta G.,CSIR - Central Electrochemical Research Institute | Sharma V.L.,CSIR - Central Electrochemical Research Institute | Sharma V.L.,Academy of Scientific & Innovative Research AcSIR
Mini-Reviews in Medicinal Chemistry | Year: 2014

Dithiocarbamates are considered as the simplest occurring organosulfur compounds exhibiting diverse chemical and medicinal versatility. Dithiocarbamates have been used as pesticide in the 20th century but thereafter they have attracted the interest of medicinal chemists due to their metal binding capacity. Recently a variety of chemical and medicinal properties of dithiocarbamates have been explored other than metal binding capacity. This review collectively describes the most significant chemical and medicinal properties of dithiocarbamate derivatives reported over the last decade. © 2014 Bentham Science Publishers.

Dar A.I.,CSIR - Central Electrochemical Research Institute | Walia S.,CSIR - Central Electrochemical Research Institute | Walia S.,Academy of Scientific & Innovative Research AcSIR | Acharya A.,CSIR - Central Electrochemical Research Institute | Acharya A.,Academy of Scientific & Innovative Research AcSIR
Journal of Nanoparticle Research | Year: 2016

Abstract: A colorimetric chemo-sensor based on citric acid-coated gold NPs (C-GNP) showed a linear increase in fluorescence intensity with increasing concentration of pesticide dimethoate (DM). The limit of detection was found to be between ~8.25± 0.3 and 20 ± 9.5 ppm. The increase in fluorescence intensity was suggested to have originated from the soft–soft interaction between C-GNPs and DM via sulfur group which is absent in pesticide dicofol (DF). Similar studies with citric acid-coated silver NPs (C-SNPs) did not result any change in the fluorescence intensity. The microscopic studies suggested aggregation of C-GNPs in the presence of DM but not in case of DF. Graphical Abstract: [Figure not available: see fulltext.] © 2016, Springer Science+Business Media Dordrecht.

Tripathi C.,CSIR - Central Electrochemical Research Institute | Tripathi C.,Academy of Scientific Innovative Research AcSIR | Tewari B.N.,University of Lucknow | Kanchan R.K.,CSIR - Central Electrochemical Research Institute | And 8 more authors.
Oncotarget | Year: 2014

TAMs, a unique and distinct M2-skewed myeloid population of tumor stroma, exhibiting pro-tumor functions is fast emerging as a potential target for anti-cancer immunotherapy. Macrophage-recruitment and M2-polarization represent key TAMs-related phenomenon that are amenable to therapeutic intervention. However successful translation of these approaches into effective therapeutic regimen requires better characterization of tumor-microenvironment derived signals that regulate macrophage recruitment and their polarization. Owing to hypoxic milieu being a persistent feature of tumor-microenvironment and a major contributor to malignancy and treatment resistance, the current study was planned with an aim to decipher tumor cell responses to hypoxia vis-a-vis macrophage homing and phenotype switching. Here, we show that hypoxia-primed cancer cells chemoattract and polarize macrophages to pro-angiogenic M2-polarized subtype via Eotaxin and Oncostatin M. Concordantly, hypoxic regions of human breast-cancer specimen exhibited elevated Eotaxin and Oncostatin M levels with concurrently elevated M2-macrophage content. Blockade of Eotaxin/Oncostatin M not only prevented hypoxic breast-cancer cells from recruiting and polarizing macrophages towards an M2-polarized phenotype and retarded tumor progression in 4T1/BALB/c-syngenic-mice-model of breast-cancer but also enhanced the efficacy of anti-angiogenic Bevacizumab. The findings established these two cytokines as novel targets for devising effective anticancer therapy particularly for tumors that are refractory or develop resistance to anti-angiogenic therapeutics.

PubMed | CSIR - Central Electrochemical Research Institute, Academy of Scientific & Innovative Research AcSIR and All India Institute of Medical Sciences
Type: Journal Article | Journal: International journal of computer assisted radiology and surgery | Year: 2016

To evaluate the accuracy of three-dimensional cephalometric measurements obtained through an automatic landmark detection algorithm compared to those obtained through manual identification.The study demonstrates a comparison of 51 cephalometric measurements (28 linear, 16 angles and 7 ratios) on 30 CBCT (cone beam computed tomography) images. The analysis was performed to compare measurements based on 21 cephalometric landmarks detected automatically and those identified manually by three observers.Inter-observer ICC for each landmark was found to be excellent ([Formula: see text]) among three observers. The unpaired t-test revealed that there was no statistically significant difference in the measurements based on automatically detected and manually identified landmarks. The difference between the manual and automatic observation for each measurement was reported as an error. The highest mean error in the linear and angular measurements was found to be 2.63mm ([Formula: see text] distance) and [Formula: see text] ([Formula: see text]-Me angle), respectively. The highest mean error in the group of distance ratios was 0.03 (for N-Me/N-ANS and [Formula: see text]).Cephalometric measurements computed from automatic detection of landmarks on 3D CBCT image were as accurate as those computed from manual identification.

PubMed | Academy of Scientific &Innovative Research AcSIR, Center for Cellular and Molecular Biology and Indian Institute of Integrative Medicine
Type: | Journal: Scientific reports | Year: 2016

The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, we confirmed that 3-AWA efficiently suppressed tumor growth and metastasis in different mouse models. Given that 3-AWA inhibits c-FLIP through abrogation of translation initiation by co-targeting mTOR and Mnk-eIF4E, it (3-AWA) can be exploited as a lead pharmacophore for promising anti-cancer therapeutic development.

PubMed | Indian Institute of Integrative Medicine, Academy of Scientific & Innovative Research AcSIR and University of Nebraska Medical Center
Type: Journal Article | Journal: Age (Dordrecht, Netherlands) | Year: 2016

Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA--gal stains; showed characteristic p21(waf1) upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21(waf1), confirming that the modulation in p21(waf1) by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21(waf1) expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model.

PubMed | Indian Institute of Integrative Medicine and Academy of Scientific & Innovative Research AcSIR
Type: Journal Article | Journal: Applied microbiology and biotechnology | Year: 2016

Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10M. The most potent inhibitor (5631296) showed an IC50 value of 5.10M0.6. The leads were further evaluated for the activity against multidrug-resistant (MDR)-TB, Gram-positive and Gram-negative bacterial strains, mode of action, docking simulations, and combinatorial study with three frontline anti-TB drugs. Compound 5491210 displayed a nearly synergistic activity with rifampicin, isoniazid, and ethambutol while compound 5631296 was synergistic with rifampicin. In vitro cytotoxicity against HepG2 cell line was evaluated and barring one compound; all were found to be non-toxic (SI>10). In order to rule out mitochondrial toxicity, the promising inhibitors were also evaluated for cell cytotoxicity using galactose medium where compounds 5631296 and 5122752 appeared non-toxic. Upon comprehensive analysis, compound 5631296 was found to be the most promising MtSK inhibitor that was safe, synergistic with rifampicin, and bactericidal against M. tuberculosis.

Ganguli P.,CSIR - National Chemical Laboratory | Chowdhury S.,CSIR - National Chemical Laboratory | Chowdhury S.,Academy of Scientific & Innovative Research AcSIR | Bhowmick R.,CSIR - National Chemical Laboratory | And 2 more authors.
Journal of Biosciences | Year: 2015

Various T-cell co-receptor molecules and calcium channel CRAC play a pivotal role in the maintenance of cell’s functional responses by regulating the production of effector molecules (mostly cytokines) that aids in immune clearance and also maintaining the cell in a functionally active state. Any defect in these co-receptor signalling pathways may lead to an altered expression pattern of the effector molecules. To study the propagation of such defects with time and their effect on the intracellular protein expression patterns, a comprehensive and largest pathway map of T-cell activation network is reconstructed manually. The entire pathway reactions are then translated using logical equations and simulated using the published time series microarray expression data as inputs. After validating the model, the effect of in silico knock down of co-receptor molecules on the expression patterns of their downstream proteins is studied and simultaneously the changes in the phenotypic behaviours of the T-cell population are predicted, which shows significant variations among the proteins expression and the signalling routes through which the response is propagated in the cytoplasm. This integrative computational approach serves as a valuable technique to study the changes in protein expression patterns and helps to predict variations in the cellular behaviour. © 2015, Indian Academy of Sciences.

Arya P.,Academy of Scientific & Innovative Research AcSIR | Kumar G.,Academy of Scientific & Innovative Research AcSIR | Acharya V.,Academy of Scientific & Innovative Research AcSIR | Singh A.K.,Academy of Scientific & Innovative Research AcSIR
PloS one | Year: 2014

Nucleotide binding site leucine-rich repeats (NBS-LRR) disease resistance proteins play an important role in plant defense against pathogen attack. A number of recent studies have been carried out to identify and characterize NBS-LRR gene families in many important plant species. In this study, we identified NBS-LRR gene family comprising of 1015 NBS-LRRs using highly stringent computational methods. These NBS-LRRs were characterized on the basis of conserved protein motifs, gene duplication events, chromosomal locations, phylogenetic relationships and digital gene expression analysis. Surprisingly, equal distribution of Toll/interleukin-1 receptor (TIR) and coiled coil (CC) (1 ∶ 1) was detected in apple while the unequal distribution was reported in majority of all other known plant genome studies. Prediction of gene duplication events intriguingly revealed that not only tandem duplication but also segmental duplication may equally be responsible for the expansion of the apple NBS-LRR gene family. Gene expression profiling using expressed sequence tags database of apple and quantitative real-time PCR (qRT-PCR) revealed the expression of these genes in wide range of tissues and disease conditions, respectively. Taken together, this study will provide a blueprint for future efforts towards improvement of disease resistance in apple.

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