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Development Of Inhibitors Of DNA Topoisomerase(s) Of Leishmania Donovani With Potent Antileishmanial Activities And Study On The Mechanism Of Drug Resistance
No full textIt is a unicellular, protozoan parasite, which exists as motile promastigotes in the sandfly gut and is transmitted into the human host where it transforms into sessile amastigotes that manifests a dreadful clinical symptom called Leishmaniasis. It was discovered at the turn
of the 19th century, viz. by Cunningham, Leishman, Donovan, Borovsky, Wright and Vianna (Gardener et al., 1977). But the name Leishmania donovani was given by Ross in 1903.
Form and Structure In the sandfly midgut, Leishmania exists as an elongated, flagellated, motile promastigote
form. These are usually 12 m (Figure 1) and sometimes as short as 5 m in size. The kinetoplast is anterior in position and free flagellum measures upto 15 m in length. Very small, unattached promastigotes found in the proboscis of sandflies are believed to be the infective form introduced into the mammals (Sacks and Perkins, 1984).
Upon entry into host macrophage, it internalizes in the macrophage and transforms into round shaped, nonflagellated,
non-motile amastigotes in 12-24 hrs (Bachinger, 1987; Alexander and Vickermann, 1975). Amastigotes are spherical in shape (Figure 2), only about 2.5-5 m in diameter and are contained within a parasitophagus vacuole within a macrophage. There is a prominent nucleus and kinetoplast,
the cytoplasm is vacuolated and contains lysosomes. The outer membrane has a polysaccharide component but there is no surface coat. Amastigotes of different species of Leishmania in mammalian hosts are reported to be
morphologically identical. Although the general configuration of amastigote is similar, size has been shown to vary between species (Scorza et al.,1979). Figure 2 shows different forms of Leishmania forms present in sand-fly gut and mammalian host. Metacyclic promastigotes
are the infective stage of Leishmania parasites
Vibrio cholerae O395 Outer Membrane Vesicles Modulate Intestinal Epithelial Cells in a NOD1 Protein-dependent Manner and Induce Dendritic Cell-mediated Th2/Th17 Cell Responses
No full textVibrio cholerae, the etiologic agent of cholera, secretes outer membrane vesicles (OMVs) that are internalized
into host cells. OMVs activate an inflammatory response in intestinal epithelial cells (ECs) via a NOD1-dependent pathway thatactivates dendritic cells (DCs) and promotes T cell polarization toward Th2/Th17 responses.
OMVs stimulate EC-DC cross-talk in generating an inflammatory response.Findings are important for the development of efficient vaccine strategies with OMV
Vibrio cholerae O395 Outer Membrane Vesicles Modulate Intestinal Epithelial Cells in a NOD1 Protein-dependent Manner and Induce Dendritic Cell-mediated Th2/Th17 Cell Responses
No full textVibrio cholerae, the etiologic agent of cholera, secretes outer membrane vesicles (OMVs) that are internalized
into host cells. OMVs activate an inflammatory response in intestinal epithelial cells (ECs) via a NOD1-dependent pathway thatbactivates dendritic cells (DCs) and promotes T cell polarization toward Th2/Th17 responses.
OMVs stimulate EC-DC cross-talk in generating an inflammatory response.Findings are important for the development of efficient vaccine strategies with OMV
Host Cell Contact Induces Fur-dependent Expression of Virulence Factors CagA and VacA in Helicobacter pylori
No full textHelicobacter pylori, a gram negative bacterium, colonizes the stomach in a majority of the world population. The two major virulence factors of H. pylori VacA and CagA, thought to be associated with chronic inflammation and disease, have been extensively studied, but the regulation of the
expression of these virulence genes in H. pylori remains poorly understood
Study Of Protein-Protein And Protein-Nucleic Acid Interaction In Regulation Of Gene Expression
No full textA complex network of protein-protein and protein-nucleic acid interaction lies at the root of all steps leading to regulation of gene expression such as transcription,
translation etc. Studying the structural basis behind these interactions and how these interactions regulate the gene expression has been the central theme of our work. We
have tried to get insights in two separate but related areas. In the first case we have tried to understand the basis of protein-DNA interaction which is occurring at the
initial step of prokaryotic transcription initiation, that is, the formation of a closed complex between promoter and RNA polymerase. The other area is in a eukaryotic
system where we have used a chemical genetic approach to intervene into certain protein-protein interactions which are crucial components in signaling cascades
leading to cellular events like growth, proliferation or apoptosis and cell death. By introducing some designed peptide mimic we have tried to see whether we can alter
the gene expression level so as to counter the diseased state with abnormal cell proliferation. a) Probing the mode of DNA-Protein interaction in the first step of prokaryotic
transcription initiation Even in prokaryotes, initiation of transcription is a multistep process- In contrast to the open complex, our understanding of the closed complex is relatively limited because of its transient nature. The mode of recognition of the promoter DNA by RNA polymerase holoenzyme during this very first step of formation of the closed complex has been the objective of our work here. Previous reports indicated that the sub-region 2.4 of σ70, a promoter specificity determining subunit of RNA polymerase
holoenzyme, contacts nucleotide sequences in the -10 region of promoter DNA. We have tried to find the differences in the binding constants for the initial closed complex formation for a series of mutants in the -10 region of promoters and sub region 2.4 of σ70 using the quantitative technique of fluorescence anisotropy. This was done to find out whether any specific base-amino acid interaction actually occurs between the RNA polymerase holoenzyme and duplex promoter or is it the overall shape that is recognized during formation of the closed complex.
b) Interrupting protein-protein interactions with synthetic peptide mimics Protein-protein interaction networks play a key role in a large number of cellular processes. The underlying cause of many diseases is found in defective proteinprotein interactions and the resulting deregulated signaling. Inhibition of proteinprotein interactions that rebalance the dysregulated pathway is thus crucial to combat
the disease processes. Here in this work we have tried to intervene into two specific protein-protein interactions viz p53-mdm2 and ras-sos interactions, each of which has
been crucial components of signaling cascades regulating cell proliferation. Since both these interactions are reported to occur involving a helix, one from the p53 Nterminal domain and the other from Sos respectively, we have designed peptide mimics with enhanced helicity by inserting unnatural amino acids like Aib and manipulating some charged residues at non-interacting positions. One more reason behind using amino acids like Aib has been to increase the peptide stability within the cell. By varied manipulations we have found one peptide mimic with potent inhibitory property in each case. Their effects and IC50 value in cancer cell lines like A549 and SKmel5 look promising for further development
Characterization of the Aqueous Extractof the Root of Aristolochia Indica: Evaluation of its Traditional use as an Antidote for Snake Bites
No full textEthnopharmacological relevance: The aqueous extract of the roots of Aristolochia indica is used as a decoction for the ailment of a number of diseases including snake bite treatment. Though the alcoholic extract of the different parts of the plant are well studied,information on the aqueous extract is limited. We have estimated aristolochic acid,different enzymes,enzyme inhibitors and anti-snake venom potency of its root extract. potency of its root extract . Reverse phase–HPLC was used to quantify aristo lochic acid.Zymography,DQ- gelatin assay and atomic force microscopy were done to demonstrate gelatinase and collagenase activities of the extract
Facile Synthesis of [1,2,3]-Triazole-Fused Isoindolines, Tetrahydroisoquinolines, Benzoazepines and Benzoazocines by Palladium-Copper Catalysed Heterocyclisation
No full textAn elegant method for the synthesis of 1,2,3-triazoles
fused with five-, six-, seven- and eight-membered benzoheterocycles,
including isoindoline, tetrahydroisoquinoline, benzoazepine
and benzoazocine, has been developed via palladium-copper catalysed
reactions in one-pot. The broad scope of this reaction was illustrated
by effecting bis-heteroannulations, synthesis of uracil
derivatives of biological interest, and employment of acetylene gas
as an inexpensive substrate. The reactions are experimentally simple
and utilise easily accessible substrates of different types
Activation of protein kinase CK2 attenuates FOXO3a functioning in a PML-dependent manner: implications in human prostate cancer
No full textProtein kinase CK2 (also known as Caseine Kinase II) is an ubiquitous Ser/Thr protein kinase present in both the nucleus and
cytoplasm of cells, targeting several key enzymes, growth factor receptors, transcription factors and cytoskeletal proteins. It is
not only a key player in regulating cellular growth and proliferation, but also behaves as a potent suppressor of apoptosis. CK2
has been frequently found to be deregulated (mostly hyperactivated) in all cancers, prostate cancer being prominent of them. In
the recent past, tumor suppressor PML (promyelocytic leukemia) has been shown to be a target of phosphorylation by CK2. This
phosphorylation promotes the ubiquitin-mediated proteasomal degradation of PML thereby effectively curbing its role as a tumor suppressor. Among many others, PML has also been established to mediate its tumor suppressive role by mitigating the inactivation of active AKT (pAKT) inside the nucleus by assembling a dephosphorylating platform for nuclear pAKT. One of the immediate consequences, of this inactivation is the stabilization of FOXO3a, another well-established tumor suppressor, inside the nucleus and its downstream activities. Here, we propose a novel signaling axis apexed by deregulated CK2, dismantling theassociation of PML and PHLPP2 (we also report PHLPP2 to be a novel interacting partner of PML inside the nucleus), ultimately leading to the inactivation and nuclear exclusion of FOXO3a, thereby downregulating p21/p27/Bim in which degradation of PML and the concomitant stabilization of pAKT plays a cardinal par
Biophysical studies of mutated K562 DNA (erythroleukemic cells) binding to adriamycin and daunomycin reveal that mutations induce structural changes influencing binding behavior
No full textK562 cells are erythroleukemic cells derived from a chronic myeloid leukemia patient in blast crisis. Comparison of the
genome from K562 cells and normal human genome has been very useful strategy, in uncovering eight genes, implicated
in acute myeloid leukemia (AML). These genes carry mutations in K562 genome and the role of these mutations in the
progression and treatment of AML is still not known. Consequences of these mutations on drug DNA binding are also
not known exactly. In the present study, mutation induced structural changes in K562 genome, compared to normal genome,
are identified by Fourier transform infra red (FTIR) and circular dichroism (CD) spectroscopy. These structural
changes in native K562 DNA favor stronger binding with binding constants 2.0�108 and 1.9�109M�1 with antileukemic
drugs adriamycin and daunomycin (DNM), respectively, compared to normal DNA. On binding, these drugs disrupt
the native B form structure of normal DNA to a greater extent, compared to A-like structure of K562 DNA. Fluorescence and absorption studies reveal higher intercalation as well as mixed groove binding of these drugs with K562 DNA compared to normal DNA. Among the drugs, DNM has higher affinity for K562 DN