Showing papers by "Pallu Reddanna published in 2014"

Free Energy Calculations to Estimate Ligand-Binding Affinities in Structure-Based Drug Design

Abstract: Post-genomic era has led to the discovery of several new targets posing challenges for structure-based drug design efforts to identify lead compounds. Multiple computational methodologies exist to predict the high ranking hit/lead compounds. Among them, free energy methods provide the most accurate estimate of predicted binding affinity. Pathway-based Free Energy Perturbation (FEP), Thermodynamic Integration (TI) and Slow Growth (SG) as well as less rigorous end-point methods such as Linear interaction energy (LIE), Molecular Mechanics-Poisson Boltzmann./Generalized Born Surface Area (MM-PBSA/GBSA) and λ-dynamics have been applied to a variety of biologically relevant problems. The recent advances in free energy methods and their applications including the prediction of protein-ligand binding affinity for some of the important drug targets have been elaborated. Results using a recently developed Quantum Mechanics (QM)/Molecular Mechanics (MM) based Free Energy Perturbation (FEP) method, which has the potential to provide a very accurate estimation of binding affinities to date has been discussed. A case study for the optimization of inhibitors for the fructose 1,6- bisphosphatase inhibitors has been described.

Hepatoprotective Effects of Terminalia chebula Fruit Extract against 2-AAF–Induced Hepatic Damage in Albino Mice: Role of MDR1 and COX-2

Abstract: Terminalia chebula extracts were evaluated on 2-acetylaminofluorene (2-AAF)-induced hepatocellular carcinoma in mice. The 25 mg.kg−1 b.w. 2-AAF treatment showed liver aberration and up-regulation of multidrug resistance-1 (MDR1), generation of reactive oxygen species (ROS) and cyclooxygenase-2 (COX-2) expression via phosphorylation of Akt-MAPKs and nuclear translocation of NF-κB. Pre-administration of 50 mg.kg−1 TCE along with 25 mg.kg−1 2-AAF inhibited the expression of MDR1 by preventing ROS generation and COX-2 expression through Akt and MAPK signaling pathway. T. chebula may overcome the 2-AAF-induced oxidative stress and drug resistance in the hepatic tissue of mice and prevent the possible neoplastic transformation leading to hepatocarcinoma.

15-LOX metabolites and angiogenesis: angiostatic effect of 15(S)-HPETE involves induction of apoptosis in adipose endothelial cells

Abstract: Inflammation is critical in the dysregulated growth of adipose tissue and associated vascular dysfunctions. 15-Lipoxygenase metabolites, important mediators of inflammation in adipose tissue during obese conditions, may contribute to codependence of inflammation and angiogenesis in adipose tissue. We have already reported the pro-angiogenic effect of 15(S)-HETE in adipose tissue. The present study was designed to understand the effect of 15(S)-HPETE, precursor of 15(S)-HETE, on angiogenesis in adipose tissue. Results showed that 15(S)-HPETE exerts an anti-angiogenic effect in adipose tissue. This was evidenced from decreased endothelial sprouting in adipose tissue explants, inhibition of angiogenic phenotype in adipose endothelial cells, decreased production of CD31 and VEGF in endothelial cells treated with 15(S)-HPETE. Further studies to examine the molecular mechanism of anti-angiogenic effect of 15(S)-HPETE showed that it inhibited cell survival signaling molecule Akt and anti-apoptotic Bcl-2 and also activated caspase-3 in adipose endothelial cells. These observations indicate that 15(S)-HPETE exerts its angiostatic effect in adipose tissue by inducing apoptosis of endothelial cells.

Draft Genome Sequence of the Field Isolate Brucella melitensis Strain Bm IND1 from India

Abstract: Brucella spp. are facultative intracellular bacterial pathogens causing the zoonotic disease brucellosis. Here, we report the draft genome sequence of the Brucella melitensis strain from India designated Bm IND1, isolated from stomach contents of an aborted goat fetus.

The Pasteur's Dictum: Nitrogen Promotes Growth and Oxygen Reduces the Need for Sugar.

Abstract: In our previous article (1), we presented a unifying principle in the hypotheses of Pasteur, Warburg, and Crabtree that “an inverse relation exists between glucose uptake and respiration.” Warburg’s hypothesis laid emphasis on glucose metabolism and damaged respiration (mitochondria) for growth of cells in cancer (2). Pasteur recognized that yeast can grow only if ammonium tartrate (nitrogen source) is available, whether oxygen is available or not (3) and ammonium is transformed into a “complex albuminoid” (protein) material. Growth is faster in the presence of oxygen and for producing one unit of mass, yeast requires only 1/15th of glucose when compared to that in the absence of oxygen (4–10 parts as against 60–80 parts). Since the ratio of ATP produced per one glucose molecule in glycolysis/oxidative phosphorylation (OXPHOS) is 1:15, the energy consumed per unit of growth of yeast remains same (60X1 and 4X15 ATP). We call this: “the Pasteur’s dictum,” which is different from the “Pasteur effect” introduced by Warburg. Lagunas et al. (4) in early 80s reported that Pasteur effect is observed only in resting cells in the absence of nitrogen, but not in growing cells. Warburg’s hypothesis relies on energetics of glucose metabolism and damaged respiration but ignores Pasteur’s demonstration of nitrogen as the primary requirement for triggering growth. It also ignores the anabolic functions of mitochondria (5, 6) and the role of glutamine, another key nutrient avidly consumed by actively proliferating cells (7, 8). We present in this article, a hypothesis that activation of complexes of mechanistic target of rapamycin (mTORC1 and C2) by amino acids (nitrogen source) is the molecular explanation of the “Pasteur’s dictum.” Amino acids activate both mTORC1 and C2 independent of insulin or growth factor signaling (IIS). Amino acids are also required for activation of mTORC1 in IIS dependent pathway.