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Regio- and Stereoselective Synthesis of a Library of Bioactive Dispiro-Oxindolo/Acenaphthoquino Andrographolides via 1,3- Dipolar Cycloaddition Reaction Under Microwave Irradiation
No full textDispiro-pyrrolidino/pyrrolizidino fused oxindoles/acenaphthoquinones have
been derived from andrographolide via azomethine ylide cycloaddition to the conjugated
double-bond under microwave (MW) irradiation. The reactions are chemo-, stereo-, and
regioselective in nature. Change in amino acid from sarcosine/N-benzyl glycine to L-proline
changes the regiochemistry. A representative library of 40 compounds along with in vitro
anticancer evaluation is reported
Status of Sialic Acids and Their Role on Pseudomonas Aeruginosa in Host-Pathogen Interaction
No full text“Sialic acids are not only the most interesting molecules in the world, but also the most important”, said by Eric Sixmister set the exhilarating theme of the field of sialoglycobiology and challenges encountered by glycobiologists working with this molecule (Vimr, 1994). Sialic acids (Sias) are nine carbon acidic sugars typically found as the terminal residue of cell surface sugar chains as well as on secreted glycoproteins and in the extracellular matrix (Varki et al.,2009). The monosaccharide sialic acid is metabolically derived from two „primary‟ Sias; Nacetylneuraminic
acid and 2-keto-3- deoxynomonic acid. N-acetylneuraminic acid(Neu5Ac) is the most common sialic acid in humans. The molecular structure is shown in Figure 1-1. In other mammals Nglycolylneuraminic acid (Neu5Gc) which is
resulted due to hydroxylation of Neu5Ac, is also abundant. The enzyme that mediates the hydroxylation reaction contains a specific mutation in humans, which results in the lack of Neu5Gc in normal healthy individuals
Wnt/B-Catenin Pathway Is Regulated by PITX2 Homeodomain Protein and Thus Contributes to the Proliferation of Human Ovarian Adenocarcinoma Cell, SKOV-3
No full textWnt pathway and homeodomain proteins are associated with cancer, but their interaction in ovarian cancer
cells has not been studied.PITX2 itself and through inducing Wnt ligands activates the canonical Wnt pathway and cell proliferation. Downregulation
of Frizzled receptors limits further Wnt activation.PITX2 enhances proliferation of SKOV-3 cells by inducing canonical Wnt signaling. This study will help understand the mechanism of proliferation in ovarian cancer cells
115 kDa serine protease confers sustained protection to visceral leishmaniasis caused by Leishmania donovani via IFN-�Y induced down-regulation of TNF-� mediated MMP-9 activity
No full textVisceral leishmaniasis caused by the intracellular parasite Leishmania donovani is a major public health
problem in the developing world. The emergence of increasing number of L. donovani strains resistance
to antimonial drugs recommended worldwide requires the intervention of effective vaccine strategy for
treatment of VL. In the present study L. donovani culture derived, soluble, secretory serine protease (pSP)
has been shown to be vaccine target of VL. Protection from VL could be achieved by the use of safer
vaccine which generally requires an adjuvant for induction of strong Th1 response. To assess the safety,
immunogenicity and efficacy of pSP as vaccine candidate in mouse model we used IL-12 as adjuvant.
BALB/c mice immunized with pSP+IL-12 were protected significantly from challenged infection even after
four months by reducing the parasite load in liver and spleen and suppressed the development of the
disease along with an increase in IgG2a antibody level in serum, enhanced delayed type hypersensitivity
and strong T-cell proliferation. Groups receiving pSP+IL-12 had an augmented pSP antigen specific Th1
cytokines like IFN-� and TNF-� response with concomitant decrease of Th2 cytokines IL-4 and IL-10 after
vaccination. In this study the vaccine efficacy of pSP was further assessed for its prophylactic potential by
enumerating matrix metalloprotease-9 (MMP-9) profile which has been implicated in various diseases.
MMP-9 associated with different microbial infections is controlled by their natural inhibitors (TIMPS) and
by some cytokines. In this study pSP was found to regulate excessive inflammation by modulating the
balance between MMP-9 and TIMP-1 expression. This modulatory effect has also been demonstrated by
IFN-� mediated down regulation of TNF-� induced MMP-9 expression in activated murine macrophages.
This is the first report where a secretory L. donovani serine protease (pSP) adjuvanted with IL-12 could
also act as protective imunogen by modifying cytokine mediated MMP-9 expression in experimental VL.
These findings elucidate the mechanisms of regulation of MMP-9 following infection of L. donovani in
vaccinated animals and thus pave the way for developing new immunotherapeutic interventions for VL
Mahanine, A DNA Minor Groove Binding Agent Exerts Cellular Cytotoxicity with Involvement of C‑7-OH and −NH Functional Groups
No full textMahanine, a carbazole alkaloid is a potent anticancer molecule. To recognize the structure−activity correlation, mahanine was chemically modified. Antiproliferative activity of these derivatives was determined in 19 cancer cell line from seven different origins. Mahanine showed enhanced apoptosis compared to dehydroxy-mahanine-treated cells, indicating significant contribution of the C-7-OH group. O-Methylated-mahanine and N-methylated dehydroxy-mahanine-treated cells exhibited apoptosis only at higher concentrations, suggesting additional contribution of 9-NH group. Using biophysical techniques, we demonstrated that mahanine interacts with DNA through strong association with phosphate backbone compared to otherderivatives but is unable to induce any conformational change in DNA, hence suggestingthe possibility of being a minor groove binder. This was corroborated by molecular modeling and isothermal titration calorimetry studies. Taken together, the results of the current study represent the first evidence of involvement of C-7-OH and 9-NH group of mahanine for its cytotoxicity and its minor groove binding ability with DN
Structural characterization of Type III Secretion System Structural characterization of Type III Secretion Systemrelated translocator and effector from Pseudomonas aeruginosa. .
No full textPseudomonas aeruginosa, a Gram-negative pathogen utilizes a specialized set of Type III Secretion System (T3SS) translocator and effector proteins to establish virulence in the host
cell. An understanding of these pathogenic factors that play a key role in the establishment
and maintenance of bacterial pathogenicity are thus, of immense importance, and are likely
the interest of study of several research groups.
The T3SS encoding “translocator operon” of P. aeruginosa consists of a major translocator
protein PopB, minor translocator protein PopD and their cognate chaperone Pcpresent a comprehensive study of PopB structure, its interaction with PcrH and their
associated pH-based structural and functional changes. The pH-dependent studies indicate that PcrH not only provides structural support to the ordered molten globule PopB in
complex but also undergoes conformational change to assist PopB to pass through.SPR studies determine the terminal domains of PopB to be involved in hydrophobic
interaction with PcrH as well as maintain the oligomerisation of translocator comple
Synthesis and in Vitro Study of Antibacterial, Antifungal Activities of some Novel Bisquinolines
No full textEfficient syntheses of a series of novel bisquinolines
have been accomplished from8-hydroxy quinolines under
phase transfer catalyzed conditions using tetrabutylamoniumbromide
as phase transfer catalyst. In vitro antibacterial and antifungal
study of the synthesized analogues revealed six of them to
show significant antibacterial and four to show significant antifungal
activity. Among them 3c and 6c show most significant
antibacterial activities with minimum inhibitory concentration
value 32 lg/mL against four bacterial strains. Ultra structural
studies of the microbes treated with 6c demonstrated deformation
of cell wall and cell agglomeration. The bisquinolines
exhibiting bacteriostatic or fungistatic activity may be developed
as newer antimicrobial agents
IL-15 activated human peripheral blood dendritic cell kill allogeneic and xenogeneic endothelial cells via apoptosis
No full textIL-15 is a pleotropic cytokine, which plays an important role in natural killer (NK) cell activity, T cell proliferation,
and T cell cytotoxic activity. Dendritic cells (DCs) are the major antigen presenting cells in the
immune system and presumed to play an important role in immune recognition of allo and xenotransplantation.
We showed that IL-15 activated human peripheral blood DC is cytotoxic to human and porcine
aortic endothelial cells. Unlike DCs, CD14+ monocytes show no cytotoxicity against the endothelial
cells. This cytotoxic potential of IL-15 activated DC against endothelial cells is dose dependent and
increases significantly upon treatment of endothelial cells with inflammatory cytokines like TNF-a or
IFN-c. The cytotoxic potential of IL-15 activated DC is associated with apoptosis of endothelial cells, as
indicated by the increased Annexin V staining, caspase activation and loss of mitochondrial membrane
potential. Further it was observed that DC mediated cytotoxicity against endothelial cell is mediated
via granzyme B possibly secreted by the activated DCs
miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression
No full textThe spindle assembly checkpoint (SAC) is a ‘wait-anaphase’ mechanism that has evolved in eukaryotic cells in response to the
stochastic nature of chromosome–spindle attachments. In the recent past, different aspects of the SAC regulation have been
described. However, the role of microRNAs in the SAC is vaguely understood. We report here that Mad1, a core SAC protein, is
repressed by human miR-125b. Mad1 serves as an adaptor protein for Mad2 – which functions to inhibit anaphase entry till the
chromosomal defects in metaphase are corrected. We show that exogenous expression of miR-125b, through downregulation of
Mad1, delays cells at metaphase. As a result of this delay, cells proceed towards apoptotic death, which follows from elevated
chromosomal abnormalities upon ectopic expression of miR-125b. Moreover, expressions of Mad1 and miR-125b are inversely
correlated in a variety of cancer cell lines, as well as in primary head and neck tumour tissues. We conclude that increased
expression of miR-125b inhibits cell proliferation by suppressing Mad1 and activating the SAC transiently. We hypothesize an
optimum Mad1 level and thus, a properly scheduled SAC is maintained partly by miR-125
Computational screening for new inhibitors of M. tuberculosis mycolyltransferases antigen 85 group of proteins as potential drug targets
No full textThe group of antigen 85 proteins of Mycobacterium tuberculosis is responsible for converting trehalose monomycolate to
trehalose dimycolate, which contributes to cell wall stability. Here, we have used a serial enrichment approach to identify
new potential inhibitors by searching the libraries of compounds using both 2D atom pair descriptors and binary fingerprints
followed by molecular docking. Three different docking softwares AutoDock, GOLD, and LigandFit were used for
docking calculations. In addition, we applied the criteria of selecting compounds with binding efficiency close to the starting
known inhibitor and showing potential to form hydrogen bonds with the active site amino acid residues. The starting
inhibitor was ethyl-3-phenoxybenzyl-butylphosphonate, which had IC50 value of 2.0 μM in mycolyltransferase inhibition
assay. Our search from more than 34 million compounds from public libraries yielded 49 compounds. Subsequently, selection
was restricted to compounds conforming to the Lipinski rule of five and exhibiting hydrogen bonding to any of the
amino acid residues in the active site pocket of all three proteins of antigen 85A, 85B, and 85C. Finally, we selected those
ligands which were ranked top in the table with other known decoys in all the docking results. The compound NIH415032
from tuberculosis antimicrobial acquisition and coordinating facility was further examined using molecular dynamics simulations
for 10 ns. These results showed that the binding is stable, although some of the hydrogen bond atom pairs varied
through the course of simulation. The NIH415032 has antitubercular properties with IC90 at 20 μg/ml (53.023 μM). These
results will be helpful to the medicinal chemists for developing new antitubercular molecules for testin