Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation

Signal transducer and activator of transcription (Stat) 3 is an oncogene constitutively activated in many cancer systems where it contributes to carcinogenesis. To develop chemical probes that selectively target Stat3, we virtually screened 920,000 small drug-like compounds by docking each into the peptide-binding pocket of the Stat3 SH2 domain, which consists of three sites—the pY-residue binding site, the +3 residue-binding site and a hydrophobic binding site, which served as a selectivity filter. Three compounds satisfied criteria of interaction analysis, competitively inhibited recombinant Stat3 binding to its immobilized pY-peptide ligand and inhibited IL-6-mediated tyrosine phosphorylation of Stat3. These compounds were used in a similarity screen of 2.47 million compounds, which identified 3 more compounds with similar activities. Examination of the 6 active compounds for the ability to inhibit IFN-γ-mediated Stat1 phosphorylation revealed that 5 of 6 were selective for Stat3. Molecular modeling of the SH2 domains of Stat3 and Stat1 bound to compound revealed that compound interaction with the hydrophobic binding site was the basis for selectivity. All 5 selective compounds inhibited nuclear-to-cytoplasmic translocation of Stat3, while 3 of 5 compounds induced apoptosis preferentially of breast cancer cell lines with constitutive Stat3 activation. Thus, virtual ligand screening of compound libraries that targeted the Stat3 pY-peptide binding pocket identified for the first time 3 lead compounds that competitively inhibited Stat3 binding to its pY-peptide ligand; these compounds were selective for Stat3 vs. Stat1 and induced apoptosis preferentially of breast cancer cells lines with constitutively activated Stat3

Biochemical and physiological characterization for nitrogen use efficiency in aromatic rice genotypes

Not AvailableIn a set of 78 aromatic rice genotypes, cluster analysis was performed for yield and its related traits in field under two nitrogen (N) conditions viz., application of N fertilizer (N100) and without application of N fertilizer (N0) during wet season, 2011 and dry season, 2012. Basmati370 and Ranbir basmati were selected as high nitrogen use efficiency (NUE) genotypes and Kolajoha-3 and Ratnasundari as low NUE genotypes for characterization in terms of biochemical, physiological and agronomical aspects of NUE. A total of 32 biochemical, physiological and agronomical characters were measured in the selected four genotypes, growing in field under two N levels i.e., N0 and N100 during wet season 2012. Five efficiency parameters were also studied to determine their NUE. GS activity increased under low N and the increase was more in two high NUE genotypes (41.3%) than that of two low NUE genotypes (5.43%). NR activity increased with application of N fertilizer and low NUE genotypes expressed higher NR activity (8.8% and 2.02% more in N0 and N100 respectively). Chlorophyll content recorded maximum (3.6 mg g−1) in low NUE genotypes under N100 condition, where as the chlorophyll content was minimum (0.43 mg g−1) in high NUE genotypes under N0 condition. Electron transport rate (ETR), quantum yield (ΦPSII) and Fv/Fm were not affected by N levels but there were significant variations in non-photochemical quenching (qN) (15% more in N0) and photochemical quenching (qP) (25% more in N0). Grain yield, total dry matter and N uptake by grain and straw were higher in high NUE genotypes. Higher GS activity, maintenance of sufficient chlorophyll fluorescence and chlorophyll content in case of high NUE genotypes support their higher grain yield and total dry matter content under low N conditions by efficient N uptake, and utilization of nitrogen.Not Availabl

Not Available

Not AvailableNot AvailableNot Availabl