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Hegde M.,Indian Institute of Science | Karki S.S.,KLE University | Thomas E.,Indian Institute of Science | Kumar S.,KLE University | And 5 more authors.
PLoS ONE | Year: 2012

Background: Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(49-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1,3,4]thiadiazole).Results: We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 mM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models.Conclusion: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.Materials and Methods: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. © 2012 Hegde et al.

Somasagara R.R.,Indian Institute of Science | Hegde M.,Indian Institute of Science | Chiruvella K.K.,Indian Institute of Science | Musini A.,Indian Institute of Science | And 2 more authors.
PLoS ONE | Year: 2012

Background: The consumption of berry fruits, including strawberries, has been suggested to have beneficial effects against oxidative stress mediated diseases. Berries contain multiple phenolic compounds and secondary metabolites that contribute to their biological properties. Methodology/Principal Findings: Current study investigates the anticancer activity of the methanolic extract of strawberry (MESB) fruits in leukaemia (CEM) and breast cancer (T47D) cell lines ex vivo, and its cancer therapeutic and chemopreventive potential in mice models. Results of MTT, trypan blue and LDH assays suggested that MESB can induce cytotoxicity in cancer cells, irrespective of origin, in a concentration- and time-dependent manner. Treatment of mice bearing breast adenocarcinoma with MESB blocked the proliferation of tumor cells in a time-dependent manner and resulted in extended life span. Histological and immunohistochemical studies suggest that MESB treatment affected tumor cell proliferation by activating apoptosis and did not result in any side effects. Finally, we show that MESB can induce intrinsic pathway of apoptosis by activating p73 in breast cancer cells, when tumor suppressor gene p53 is mutated. Conclusions/Significance: The present study reveals that strawberry fruits possess both cancer preventive and therapeutic values and we discuss the mechanism by which it is achieved. © 2012 Somasagara et al.

Bateman A.,Wellcome Trust Sanger Institute | Agrawal S.,Institute of Bioinformatics and Applied Biotechnology IBAB | Agrawal S.,BioCOS Life science Private Ltd | Birney E.,European Bioinformatics Institute | And 28 more authors.
RNA | Year: 2011

During the last decade there has been a great increase in the number of noncoding RNA genes identified, including new classes such as microRNAs and piRNAs. There is also a large growth in the amount of experimental characterization of these RNA components. Despite this growth in information, it is still difficult for researchers to access RNA data, because key data resources for noncoding RNAs have not yet been created. The most pressing omission is the lack of a comprehensive RNA sequence database, much like UniProt, which provides a comprehensive set of protein knowledge. In this article we propose the creation of a new open public resource that we term RNAcentral, which will contain a comprehensive collection of RNA sequences and fill an important gap in the provision of biomedical databases. We envision RNA researchers from all over the world joining a federated RNAcentral network, contributing specialized knowledge and databases. RNAcentral would centralize key data that are currently held across a variety of databases, allowing researchers instant access to a single, unified resource. This resource would facilitate the next generation of RNA research and help drive further discoveries, including those that improve food production and human and animal health. We encourage additional RNA database resources and research groups to join this effort. We aim to obtain international network funding to further this endeavor.

Acharya K.K.,Institute of Bioinformatics and Applied Biotechnology IBAB | Acharya K.K.,Shodhaka Life science Pvt. Ltd. | Chandrashekar D.S.,Institute of Bioinformatics and Applied Biotechnology IBAB | Chitturi N.,Institute of Bioinformatics and Applied Biotechnology IBAB | And 8 more authors.
BMC Genomics | Year: 2010

Background: In the recent years, there has been a rise in gene expression profiling reports. Unfortunately, it has not been possible to make maximum use of available gene expression data. Many databases and programs can be used to derive the possible expression patterns of mammalian genes, based on existing data. However, these available resources have limitations. For example, it is not possible to obtain a list of genes that are expressed in certain conditions. To overcome such limitations, we have taken up a new strategy to predict gene expression patterns using available information, for one tissue at a time.Results: The first step of this approach involved manual collection of maximum data derived from large-scale (genome-wide) gene expression studies, pertaining to mammalian testis. These data have been compiled into a Mammalian Gene Expression Testis-database (MGEx-Tdb). This process resulted in a richer collection of gene expression data compared to other databases/resources, for multiple testicular conditions. The gene-lists collected this way in turn were exploited to derive a 'consensus' expression status for each gene, across studies. The expression information obtained from the newly developed database mostly agreed with results from multiple small-scale studies on selected genes. A comparative analysis showed that MGEx-Tdb can retrieve the gene expression information more efficiently than other commonly used databases. It has the ability to provide a clear expression status (transcribed or dormant) for most genes, in the testis tissue, under several specific physiological/experimental conditions and/or cell-types.Conclusions: Manual compilation of gene expression data, which can be a painstaking process, followed by a consensus expression status determination for specific locations and conditions, can be a reliable way of making use of the existing data to predict gene expression patterns. MGEx-Tdb provides expression information for 14 different combinations of specific locations and conditions in humans (25,158 genes), 79 in mice (22,919 genes) and 23 in rats (14,108 genes). It is also the first system that can predict expression of genes with a 'reliability-score', which is calculated based on the extent of agreements and contradictions across gene-sets/studies. This new platform is publicly available at the following web address: http://resource.ibab.ac.in/MGEx-Tdb/. © 2010 Acharya et al; licensee BioMed Central Ltd.

Pathak B.R.,National Health Research Institute | Breed A.A.,National Health Research Institute | Apte S.,National Health Research Institute | Acharya K.,Institute of Bioinformatics and Applied Biotechnology IBAB | And 2 more authors.
Molecular and Cellular Biochemistry | Year: 2016

Cysteine-rich secretory protein 3 (CRISP-3) is upregulated in prostate cancer as compared to the normal prostate tissue. Higher expression of CRISP-3 has been linked to poor prognosis and hence it has been thought to act as a prognostic marker for prostate cancer. It is proposed to have a role in innate immunity but its role in prostate cancer is still unknown. In order to understand its function, its expression was stably knocked down in LNCaP cells. CRISP-3 knockdown did not affect cell viability but resulted in reduced invasiveness. Global gene expression changes upon CRISP-3 knockdown were identified by microarray analysis. Microarray data were quantitatively validated by evaluating the expression of seven candidate genes in three independent stable clones. Functional annotation of the differentially expressed genes identified cell adhesion, cell motility, and ion transport to be affected among other biological processes. Prostate-specific antigen (PSA, also known as Kallikrein 3) was the top most downregulated gene whose expression was also validated at protein level. Interestingly, expression of Annexin A1 (ANXA1), a known anti-inflammatory protein, was upregulated upon CRISP-3 knockdown. Re-introduction of CRISP-3 into the knockdown clone reversed the effect on invasiveness and also led to increased PSA expression. These results suggest that overexpression of CRISP-3 in prostate tumor may maintain higher PSA expression and lower ANXA1 expression. Our data also indicate that poor prognosis associated with higher CRISP-3 expression could be due to its role in cell invasion. © 2015, Springer Science+Business Media New York.

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