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Pandey A.K.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Munjal N.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Datta M.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
PLoS ONE | Year: 2010

Background:The proinflammatory cytokine, TNFα, is a crucial mediator of the pathogenesis of several diseases, more so in cases involving the liver wherein it is critical in maintaining liver homeostasis since it is a major determiner of hepatocyte life and death. Gene expression profiling serves as an appropriate strategy to unravel the underlying signatures to envisage such varied responses and considering this, gene transcription profiling was examined in control and TNFα treated HepG2 cells. Methods and Findings:Microarray experiments between control and TNFα treated HepG2 cells indicated that TNFα could significantly alter the expression profiling of 140 genes; among those up-regulated, several GO (Gene Ontology) terms related to lipid and fat metabolism were significantly (p<.01) overrepresented indicating a global preference of fat metabolism within the hepatocyte and those within the down-regulated dataset included genes involved in several aspects of the immune response like immunoglobulin receptor activity and IgE binding thereby indicating a compromise in the immune defense mechanism(s). Conserved transcription factor binding sites were identified in identically clustered genes within a common GO term and SREBP-1 and FOXJ2 depicted increased occupation of their respective binding elements in the presence of TNFα. The interacting network of "lipid metabolism, small molecule biochemistry" was derived to be significantly overrepresented that correlated well with the top canonical pathway of "biosynthesis of steroids". Conclusions:TNFα alters the transcriptome profiling within HepG2 cells with an interesting catalog of genes being affected and those involved in lipid and steroid metabolism to be the most favored. This study represents a composite analysis of the effects of TNFα in HepG2 cells that encompasses the altered transcriptome profiling, the functional analysis of the up- and down- regulated genes and the identification of conserved transcription factor binding sites. These could possibly determine TNFα mediated alterations mainly the phenotypes of hepatic steatosis and fatty liver associated with several hepatic pathological states. © 2010 Pandey et al.


Tripathi P.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Tripathi P.,University of Pune | Nair S.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Singh B.P.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Arora N.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Free Radical Biology and Medicine | Year: 2010

Oxidative stress is implicated in the pathogenesis of asthma, and antioxidant levels are reduced in asthma patients. Previously, glutathione S-transferase (GST) with reduced IgE binding suppressed oxidative stress and modulated airway inflammation to some extent in mice. GST catalyzes the quenching of reactive oxygen species by reduced glutathione (GSH) and the absence of any one of them may limit antioxidative behavior. This study evaluates the effects of mutated (m) GST with GSH in combination and individually in limiting oxidative stress and inflammatory responses in a mouse model. BALB/c mice were immunized and challenged with ovalbumin. The mice were treated with mGST, GSH, mGST + GSH, or α-lipoic acid by inhalation and sacrificed to evaluate inflammation and oxidative stress parameters. Treatment with the mGST + GSH combination showed significantly reduced total cell (p < 0.01) and eosinophil (p < 0.01) counts in BALF compared to other groups. The lung inflammation score was lowest for the mGST + GSH group, along with reduced IL-4 (p < 0.01) and OVA-specific IgE compared to the other treatment groups. Oxidative stress as per the lipid peroxidation and 8-isoprostane level in BALF of mGST + GSH mice was reduced significantly compared to the individual antioxidants. In conclusion, mGST in combination with GSH has a synergistic effect in reducing airway inflammation compared to the individual antioxidants and has potential for the treatment of asthma. © 2010 Elsevier Inc. All rights reserved.


Yadav A.K.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Bhardwaj G.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Basak T.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Kumar D.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | And 5 more authors.
PLoS ONE | Year: 2011

Plasma is the most easily accessible source for biomarker discovery in clinical proteomics. However, identifying potential biomarkers from plasma is a challenge given the large dynamic range of proteins. The potential biomarkers in plasma are generally present at very low abundance levels and hence identification of these low abundance proteins necessitates the depletion of highly abundant proteins. Sample pre-fractionation using immuno-depletion of high abundance proteins using multi-affinity removal system (MARS) has been a popular method to deplete multiple high abundance proteins. However, depletion of these abundant proteins can result in concomitant removal of low abundant proteins. Although there are some reports suggesting the removal of non-targeted proteins, the predominant view is that number of such proteins is small. In this study, we identified proteins that are removed along with the targeted high abundant proteins. Three plasma samples were depleted using each of the three MARS (Hu-6, Hu-14 and Proteoprep 20) cartridges. The affinity bound fractions were subjected to gelC-MS using an LTQ-Orbitrap instrument. Using four database search algorithms including MassWiz (developed in house), we selected the peptides identified at <1% FDR. Peptides identified by at least two algorithms were selected for protein identification. After this rigorous bioinformatics analysis, we identified 101 proteins with high confidence. Thus, we believe that for biomarker discovery and proper quantitation of proteins, it might be better to study both bound and depleted fractions from any MARS depleted plasma sample. © 2011 Yadav et al.


Gupta M.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Moily N.S.,National Institute of Mental Health and Neuro Sciences | Kaur H.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Jajodia A.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | And 2 more authors.
Genomics | Year: 2013

Atypical antipsychotic (AAP) drugs are the preferred choice of treatment for schizophrenia patients. Patients who do not show favorable response to AAP monotherapy are subjected to random prolonged therapeutic treatment with AAP multitherapy, typical antipsychotics or a combination of both. Therefore, prior identification of patients' response to drugs can be an important step in providing efficacious and safe therapeutic treatment. We thus attempted to elucidate a genetic signature which could predict patients' response to AAP monotherapy. Our logistic regression analyses indicated the probability that 76% patients carrying combination of four SNPs will not show favorable response to AAP therapy. The robustness of this prediction model was assessed using repeated 10-fold cross validation method, and the results across n-fold cross-validations (mean accuracy. =.71.91%; 95%CI. =.71.47-72.35) suggest high accuracy and reliability of the prediction model. Further validations of these results in large sample sets are likely to establish their clinical applicability. © 2013 Elsevier Inc.


Singh G.P.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research | Dash D.,Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
PLoS ONE | Year: 2013

A majority of E. coli proteins when overexpressed inhibit its growth, but the reasons behind overexpression toxicity of proteins remain unknown. Understanding the mechanism of overexpression toxicity is important from evolutionary, biotechnological and possibly clinical perspectives. Here we study sequence and functional features of cytosolic proteins of E. coli associated with overexpression toxicity to understand its mechanism. We find that number of positively charged residues is significantly higher in proteins showing overexpression toxicity. Very long proteins also show high overexpression toxicity. Among the functional classes, transcription factors and regulatory proteins are enriched in toxic proteins, while catalytic proteins are depleted. Overexpression toxicity could be predicted with reasonable accuracy using these few properties. The importance of charged residues in overexpression toxicity indicates that nonspecific electrostatic interactions resulting from protein overexpression cause toxicity of these proteins and suggests ways to improve the expression level of native and foreign proteins in E. coli for basic research and biotechnology. These results might also be applicable to other bacterial species. © 2013 Singh and Dash.


PubMed | Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Type: Journal Article | Journal: Free radical biology & medicine | Year: 2010

Oxidative stress is implicated in the pathogenesis of asthma, and antioxidant levels are reduced in asthma patients. Previously, glutathione S-transferase (GST) with reduced IgE binding suppressed oxidative stress and modulated airway inflammation to some extent in mice. GST catalyzes the quenching of reactive oxygen species by reduced glutathione (GSH) and the absence of any one of them may limit antioxidative behavior. This study evaluates the effects of mutated (m) GST with GSH in combination and individually in limiting oxidative stress and inflammatory responses in a mouse model. BALB/c mice were immunized and challenged with ovalbumin. The mice were treated with mGST, GSH, mGST + GSH, or alpha-lipoic acid by inhalation and sacrificed to evaluate inflammation and oxidative stress parameters. Treatment with the mGST + GSH combination showed significantly reduced total cell (p<0.01) and eosinophil (p<0.01) counts in BALF compared to other groups. The lung inflammation score was lowest for the mGST + GSH group, along with reduced IL-4 (p<0.01) and OVA-specific IgE compared to the other treatment groups. Oxidative stress as per the lipid peroxidation and 8-isoprostane level in BALF of mGST + GSH mice was reduced significantly compared to the individual antioxidants. In conclusion, mGST in combination with GSH has a synergistic effect in reducing airway inflammation compared to the individual antioxidants and has potential for the treatment of asthma.


PubMed | GB Pant Hospital, All India Institute of Medical Sciences and Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Type: Journal Article | Journal: Neurology India | Year: 2016

Subependymal giant cell astrocytomas (SEGA) are slow-growing benign intraventricular tumors, the pathogenesis of which is debated. Recent studies have shown that tuberous sclerosis complex (TSC) 1 and TSC2 genes are linked to the mammalian target of rapamycin (mTOR) cell signaling pathway. We aimed to analyze TSC1 and TSC2 gene mutation, hamartin and tuberin protein expression, and protein expression of mTOR signaling cascade in a series of SEGA to determine their role in pathogenesis.Twenty-eight SEGA cases were retrieved from archival material. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue using antibodies against tuberin, hamartin, phospho-p70S6 kinase, S6 ribosomal protein, phospho-S6 ribosomal protein, phospho-4E-BP1, Stat3, and phospho-Stat3. Mutation analysis of TSC1 (exons 15 and 17) and TSC2 (exons 33, 39, and 40) was done by DNA sequencing.Loss of immunoexpression of either hamartin or tuberin was found in 19 cases (68%). Pathogenic point mutations in selected exons of TSC1 and TSC2 genes were present in 5 of 20 cases studied. Robust expression of mTOR downstream signaling molecules phospho-p70S6 kinase (100%), S6 ribosomal protein (82%), phospho-S6 ribosomal protein (64%), phospho-4E-BP1 (64%), and Stat3 (100%) was seen. Four cases (14%) showed immunopositivity for phospho-Stat3. There was no significant correlation of these markers with immunoloss of tuberin and hamartin.There is a definite role for TSC1 and TSC2 genes in the pathogenesis of SEGA as evidenced by loss of protein expression and presence of mutations. Strong expression of mTOR downstream signaling proteins indicates activation of mTOR pathway in these tumors, suggesting that proteins in this pathway may have the potential to serve as therapeutic targets in these patients.


PubMed | Panjab University and Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Type: Journal Article | Journal: PloS one | Year: 2013

Chlorophytum borivilianum, an endangered medicinal plant species is highly recognized for its aphrodisiac properties provided by saponins present in the plant. The transcriptome information of this species is limited and only few hundred expressed sequence tags (ESTs) are available in the public databases. To gain molecular insight of this plant, high throughput transcriptome sequencing of leaf RNA was carried out using Illuminas HiSeq 2000 sequencing platform. A total of 22,161,444 single end reads were retrieved after quality filtering. Available (e.g., De-Bruijn/Eulerian graph) and in-house developed bioinformatics tools were used for assembly and annotation of transcriptome. A total of 101,141 assembled transcripts were obtained, with coverage size of 22.42 Mb and average length of 221 bp. Guanine-cytosine (GC) content was found to be 44%. Bioinformatics analysis, using non-redundant proteins, gene ontology (GO), enzyme commission (EC) and kyoto encyclopedia of genes and genomes (KEGG) databases, extracted all the known enzymes involved in saponin and flavonoid biosynthesis. Few genes of the alkaloid biosynthesis, along with anticancer and plant defense genes, were also discovered. Additionally, several cytochrome P450 (CYP450) and glycosyltransferase unique sequences were also found. We identified simple sequence repeat motifs in transcripts with an abundance of di-nucleotide simple sequence repeat (SSR; 43.1%) markers. Large scale expression profiling through Reads per Kilobase per Million mapped reads (RPKM) showed major genes involved in different metabolic pathways of the plant. Genes, expressed sequence tags (ESTs) and unique sequences from this study provide an important resource for the scientific community, interested in the molecular genetics and functional genomics of C. borivilianum.


PubMed | Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Type: Journal Article | Journal: PloS one | Year: 2013

A majority of E. coli proteins when overexpressed inhibit its growth, but the reasons behind overexpression toxicity of proteins remain unknown. Understanding the mechanism of overexpression toxicity is important from evolutionary, biotechnological and possibly clinical perspectives. Here we study sequence and functional features of cytosolic proteins of E. coli associated with overexpression toxicity to understand its mechanism. We find that number of positively charged residues is significantly higher in proteins showing overexpression toxicity. Very long proteins also show high overexpression toxicity. Among the functional classes, transcription factors and regulatory proteins are enriched in toxic proteins, while catalytic proteins are depleted. Overexpression toxicity could be predicted with reasonable accuracy using these few properties. The importance of charged residues in overexpression toxicity indicates that nonspecific electrostatic interactions resulting from protein overexpression cause toxicity of these proteins and suggests ways to improve the expression level of native and foreign proteins in E. coli for basic research and biotechnology. These results might also be applicable to other bacterial species.


PubMed | Institute of Genomics and Integrative Biology Council of Scientific and Industrial Research
Type: Journal Article | Journal: Current molecular medicine | Year: 2011

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.

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