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ItemBetanin a betacyanin pigment purified from fruits of Opuntia ficus-indica induces apoptosis in human chronic myeloid leukemia Cell line-K562( 2007-11-05)Betalains are water-soluble nitrogenous vacuolar pigments present in flowers and fruits of many caryophyllales with potent antioxidant properties. In the present study the antiproliferative effects of betanin, a principle betacyanin pigment, isolated from the fruits of Opuntia ficus-indica, was evaluated on human chronic myeloid leukemia cell line (K562). The results show dose and time dependent decrease in the proliferation of K562 cells treated with betanin with an IC50 of 40 μM. Further studies involving scanning and transmission electron microscopy revealed the apoptotic characteristics such as chromatin condensation, cell shrinkage and membrane blebbing. Agarose electrophoresis of genomic DNA of cells treated with betanin showed fragmentation pattern typical for apoptotic cells. Flow cytometric analysis of cells treated with 40 μM betanin showed 28.4% of cells in sub G0/G1 phase. Betanin treatment to the cells also induced the release of cytochrome c into the cytosol, poly (ADP) ribose polymerase (PARP) cleavage, down regulation Bcl-2, and reduction in the membrane potentials. Confocal microscopic studies on the cells treated with betanin suggest the entry of betanin into the cells. These studies thus demonstrate that betanin induces apoptosis in K562 cells through the intrinsic pathway and is mediated by the release of cytochrome c from mitochondria into the cytosol, and PARP cleavage. The antiproliferative effects of betanin add further value to the nutritional characteristics of the fruits of O. ficus-indica. © 2007 Elsevier GmbH. All rights reserved.
ItemComputer aided drug design approaches to develop cyclooxygenase based novel anti-inflammatory and anti-cancer drugs( 2007-12-01)Cylooxygenases (COXs), the enzymes involved in the formation of prostaglandins from polyunsaturated fatty acids such as arachidonic acid, exist in two forms-the constitutive COX-1 that is cytoprotective and responsible for the production of prostaglandins and COX-2 which is induced by cytokines, mitogens and endotoxins in inflammatory cells and responsible for the increased levels of prostaglandins during inflammation. As a result COX-2 has become the natural target for the development of anti-inflammatory and anti-cancer drugs. While the conventional NSAIDs with gastric side effects inhibit both COX-1 and COX-2, the newly developed drugs for inflammation with no gastric side effects selectively block the COX-2 enzyme. NSAIDs, nonselective non-aspirin NSAIDs and COX-2 selective inhibitors, are being widely used for various arthritis and pain syndromes. Selective inhibitors of COX-2, however, convey a small but definite risk of myocardial infarction and stroke; the extent of which varies depending on the COX-2 specificity. In view of the, gastric side effects of conventional NSAIDs and the recent market withdrawal of rofecoxib and valdecoxib due to their adverse cardiovascular side effects there is need to develop alternative anti-inflammatory agents with reduced gastric and cardiovascular problems. The present study reviews various Computer Aided Drug Design (CADD) approaches to develop Cyclooxygenase based anti-inflammatory and anti-cancer drugs. © 2007 Bentham Science Publishers Ltd.
ItemSynthesis of methyl [6-(2-amino-1,3-thiazol-4-yl)-3-oxo-1,4-benzoxazin-2-yl] acetates as possible cox-2 / 5-lox inhibitors( 2008-01-01)A series of methyl [6-(2-aminothiazol-4-yl)-3-oxo-1,4-benzoxazin-2-yl]acetates (3-5) have been synthesized and tested for COX-2 (Cyclooxygenase) / 5-LOX (Lipoxygenase) inhibitory activity. Some of the compounds exhibited notable 5-LOX inhibitory activity. © 2008, by Walter de Gruyter GmbH & Co. All rights reserved.
ItemSynthesis of methyl-(3-oxo-2h-[1,4]-benzoxa /thiazin-6-yl)-pyrazole-5-carboxylates & isoxazole-3-carboxylates as possible cox-2 / 5-lox inhibitors( 2008-01-01)A series of Methyl-(3-oxo-2H-[1,4]benzoxa/thiazin-6-yl)pyrazole-5-carboxylates (5 & 6) and isoxazole-3-carboxylates (7 & 8) have been synthesized and tested for their COX-2 / 5-LOX inhibitory activities. © 2008, by Walter de Gruyter GmbH & Co. All rights reserved.
ItemHomology modeling of 5-lipoxygenase and hints for better inhibitor design( 2008-01-30)Lipoxygenases (LOXs) are a group of enzymes involved in the oxygenation of polyunsaturated fatty acids. Among these 5-lipoxygenase (5-LOX) is the key enzyme leading to the formation of pharmacologically important leukotrienes and lipoxins, the mediators of inflammatory and allergic disorders. In view of close functional similarity to mammalian lipoxygenase, potato 5-LOX is used extensively. In this study, the homology modeling technique has been used to construct the structure of potato 5-LOX. The amino acid sequence identity between the target protein and sequence of template protein 1NO3 (soybean LOX-3) searched from NCBI protein BLAST was 63%. Based on the template structure, the protein model was constructed by using the Homology program in InsightII. The protein model was briefly refined by energy minimization steps and validated using Profile-3D, ERRAT and PROCHECK. The results showed that 99.3% of the amino acids were in allowed regions of Ramachandran plot, suggesting that the model is accurate and its stereochemical quality good. Like all LOXs, 5-LOX also has a two-domain structure, the small N-terminal β-barrel domain and a larger catalytic domain containing a single atom of non-heme iron coordinating with His525, His530, His716 and Ile864. Asn720 is present in the fifth coordination position of iron. The sixth coordination position faces the open cavity occupied here by the ligands which are docked. Our model of the enzyme is further validated by examining the interactions of earlier reported inhibitors and by energy minimization studies which were carried out using molecular mechanics calculations. Four ligands, nordihydroguaiaretic acid (NDGA) having IC50 of 1.5 μM and analogs of benzyl propargyl ethers having IC50 values of 760 μM, 45 μM, and no inhibition respectively were selected for our docking and energy minimization studies. Our results correlated well with the experimental data reported earlier, which proved the quality of the model. This model generated can be further used for the design and development of more potent 5-LOX inhibitors. © Springer Science+Business Media B.V. 2008.