2058 research outputs found
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Novel Gold(I)− and Gold(III)−N-Heterocyclic Carbene Complexes: Synthesis and Evaluation of Their Anticancer Properties
No full textA novel Au(III)−N-heterocyclic carbene organometallic
complex supported by two N-heterocyclic carbene (NHC)
ligands was synthesized from Au(SMe2)Cl and 1-methyl-2-pyridin-2- yl-2H-imidazo[1,5-a]pyridin-4-ylium hexafluorophosphate via a Ag intermediate. X-ray crystallography revealed the first example of a square planar geometry adopted by a Au(III) species stabilized by two NHCs and two chloride ligands. The aforementioned Au(I)− and Au(III)−NHC complexes were found to be more potent than cisplatin against the HCT 116, HepG2, A549, and MCF7 cell lines
Efficacy of Withania somnifera chemotypes NMITLI – 101R, 118R and Withaferin A against experimental visceral leishmaniasis
No full textThe immunoprophylactic and therapeutic potentials of root
extracts of Withania somnifera chemotypes (NMITLI-118,
NMITLI-101) and pure withanolide–withaferin A was investigated against Leishmania donovani infection in hamsters.The naive animals, fed orally with immunostimulatory doses of chemotypes 101R, 118R (10 and 3 mg/kg) and withaferin A (9 and 3 mg/kg) for five consecutive days and challenged with Leishmania parasites on day 6, were euthanized on days 30 and 45 p.c. for the assessment of parasite clearance, real-time analysis of mRNAs of Th1/Th2 cytokines (IFN-c, IL-12, TNF-a, iNOS/IL-4, IL-10 and TGF-b), NO production, reactive oxygen species(ROS) generation, lymphocyte transformation test and antibody responses. By day 45 p.c., there was a significant increase in the mRNA expression of iNOS, IFN-c, IL-12 and TNF-a but decrease in IL-4, IL-10 and TGF-b, an enhanced Leishmania-specific LTT response as well as ROS, NO and antileishmanial IgG2 levels in 101R-treated hamsters followed by 118R- and withaferin A-treated ones, respectively. When these chemotypes were given to L. donovani-infected hamsters at different doses, there was moderate therapeutic efficacy of chemotype 101R (~50%) at 30 mg/kg 9 5 followed by the other two. The results established that the 101R is the most potential chemotype and can be evaluated for combination therapy along with available antileishmanials
Prostaglandin E2 Negatively Regulates the Production of Inflammatory Cytokines/Chemokines and IL-17 in Visceral Leishmaniasis
No full textPersistence of intracellular infection depends on the exploitation of factors that negatively regulate the host immune response. In this study, we elucidated the role of macrophage PGE2, an immunoregulatory lipid, in successful survival of Leishmania donovani, causative agent of the fatal visceral leishmaniasis. PGE2 production was induced during infection and resulted in increased cAMP
level in peritoneal macrophages through G protein–coupled E-series prostanoid (EP) receptors. Among four different EPs (EP1–4), infection upregulated the expression of only EP2, and individual administration of either EP2-specific agonist, butaprost, or 8-Br–cAMP, a cell-permeable cAMP analog, promoted parasite survival. Inhibition of cAMP also induced generation of reactive oxygen species, an antileishmanial effector molecule. Negative modulation of PGE2 signaling reduced infection-induced antiinflammatory
cytokine polarization and enhanced inflammatory chemokines, CCL3 and CCL5. Effect of PGE2 on cytokine and chemokine production was found to be differentially modulated by cAMP-dependent protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). PGE2-induced decreases in TNF-a and CCL5 were mediated specifically by PKA,
whereas administration of brefeldin A, an EPAC inhibitor, could reverse decreased production of CCL3. Apart from modulating inflammatory/anti-inflammatory balance, PGE2 inhibited antileishmanial IL-17 cytokine production in splenocyte culture. Augmented PGE2 production was also found in splenocytes of infected mice, and administration of EP2 antagonist in mice resulted in
reduced liver and spleen parasite burden along with host-favorable T cell response. These results suggest that Leishmania facilitates an immunosuppressive environment in macrophages by PGE2-driven, EP2-mediated cAMP signaling that is differentially regulated by PKA and EPA
Drug Discovery Research in India: Current State and Future Prospects
No full textIndian civilization developed a strong system of traditional medicine and was one of the first nations to develop a synthetic drug. In the postindependence era, Indian pharmaceutical industry developed a strong base for production of generic drugs. Challenges for the future are to give its traditional medicine a strong scientific base and develop research and clinical capability to consistently produce new drugs based on advances in modern biological science
Mitochondrial Genome Variations among Arsenic Exposed Individuals and Potential Correlation with Apoptotic Parameters
No full textExposure to arsenic (As) causes serious health
hazards. Therefore, there is a sustained effort to
understand the molecular basis of the risk posed
by the toxicant. It has been reported that apoptotic
changes ensue on exposure to As. To
investigate the molecular basis of such changes,
we sequenced the entire mitochondrial (mt)
genome from PBMC of a subset of these individuals
(As-exposed516 and unexposed518) using
Affymetrix platform. Our analysis revealed that
As exposure does not induce large-scale mt-DNA
variations, but that specific deleterious changes
could induce mt dysfunction. A Glu115Ter mutation
as well as 17 other in silico predicted deleterious
variants were identified exclusively in exposed individuals. The number of variants in mt Complex I in As-exposed individuals was positively correlated with their respective intracellular ROS level. In addition, the extent of potentially damaging variants in As-exposed individuals had significant positive correlation to the degree of
G0/G1 cell cycle arrest. Environ. Mol. Mutagen.55:70–76, 2014
Minor Groove Binding of the Food Colorant Carmoisine to DNA: Spectroscopic and Calorimetric Characterization Studies
No full textThe interaction of the food additive carmoisine with herring testes DNA was studied by multifaceted biophysical
techniques. Carmoisine exhibited hypochromic effects in absorbance, whereas in fluorescence the intensity enhanced upon complexation with DNA. Energy transfer from the DNA base pairs to carmoisine molecules occurred upon complexation. A groove binding model of interaction was envisaged for carmoisine−DNA complexation from 4′,6-diamidino-2-phenylindole (DAPI) and Hoechst displacement studies. The binding of carmoisine stabilized the DNA structure against thermal denaturation. The binding induced moderate conformational perturbations in the B-form structure of DNA. The binding affinity (104 M−1) values, calculated from absorbance and fluorescence data, and calorimetry titrations were in close agreement with each other. The binding was characterized to be exothermic and favored by small negative enthalpic and large positive entropic contributions. Salt-dependent calorimetric studies revealed that the binding reaction was dominated by nonpolyelectrolytic forces. The negative heat capacity value suggested the role of hydrophobic effect in the interactio
Application Of 1,3-Dipolar Cycloaddition Reactions In The Synthesis Of Carbohydratebased Spiro-Heterocycles
No full textThe thesis embodies the results of studies on the ―APPLICATION OF 1,3-DIPOLAR CYCLOADDITION REACTIONS IN THE SYNTHESIS OF CARBOHYDRATE-BASED SPIROHETEROCYCLES‖. Carbohydrate-based heterocyclic scaffolds are a class of exceedingly popular bioactive natural and synthetic chemical entities featuring carbohydrate containing mono or
polynuclear heterocyclic cores in their skeleton, with broad spectrum of antitumor, antimicrobial and antiviral activities. Some of them have proved their efficacy in the treatment of several deadly diseases like influenza (H1N1), HIV, cancer etc. Hence, it is not surprising that engagement of medicinal chemists for the construction and bio-evaluation of diversely modified newer carbohydratebased
heterocyclic libraries having fused, bridged or spiro linkages, has assumed immense attention in recent times and amongst them, carbohydrate-based spiro- and bisspiropyrrolidine skeletons are well documented. Nevertheless, the diversity of pyrrolidine skeleton as well as their biological and pharmaceutical relevance is still motivating academic and industrial researchers to look for new and improved syntheses for pyrrolidine derivatives. Among several available tools for the realization of
this goal, the 1,3-dipolar azomethine ylide cycloaddition reaction on a properly functionalized carbohydrate derived olefin system caught our attention, as it is a simple and easily accessible one-pot three-component reaction procedure, involving a trouble-free [3+2] cycloaddition reaction
Structural characterization of type three secretion system related translocator and regulator proteins from Pseudomonas aeruginosa and Yersinia enterocolitica
No full textGram negative bacteria Yersinia enterocolitica and Pseudomonas aeruginosa employ a TTSS to inject toxins into the host cell cytoplasm. For the translocation of toxic effectors an injectisome is formed with a translocation apparatus at its tip. This translocon comprises of translocator proteins, controlled by their cognate chaperones and regulators. SycB is a class II chaperone of Ysa-Ysp TTSS of Y. enterocolitica biovar 1B. SycB interacts
with annotated transloctor YspC. YspC is a unique translocator both structurally and evolutionarily. Unlike any other minor hydrophobic translocator, it is highly stable and has a rigid tertiary structure. The model of SycB depicts a concave core with 3 TPR regions and a
flexible N-terminal helix. The N-terminal helix of SycB is essential for its dimerization.However, the dimeric physiological state of SycB dissociates upon interaction with YspC and a 1:1 heterodimeric YspC-SycB complex is formed. SycB attains a molten globule structure with reduction in pH to 5.0, thereby, releasing YspC, which could be a potential signal for activation of TTSS. The first two TPR regions of SycB contain the YspC interaction site. Therefore, the first structural characterization of SycB, YspC, and the structural aspects of YspC-SycB interaction is presented. PcrV is a hydrophilic translocator of P. aeruginosa, regulated by PcrG. The dumbbell shaped model of PcrV depicts two terminal globular domains, and two long helices (7&12) forming the grip of the dumbbell. The PcrG interaction site is localized within helix-7 and helix- 12 of PcrV, with helix-12 being the key mediator of the interaction. The N-terminal globular
domain maintains the physiological state of PcrV. The first intramolecular coiled-coil region of PcrG is responsible for its interaction with PcrV, although the 12 N-terminal residues play an indirect role in the interaction. Also, PcrG could restore the monomeric state of PcrV and
provides structural stability to it. The maintenance of proper state of PcrV prior to translocation is a pre-requisite for formation of functional translocon. Finally, we could propose a model for PcrG-PcrV interaction, where we could show that PcrG sits in a groove formed by helix-7 and helix-12 in between the two globular domains
Generation And Proteomic Profiling Of Transgenic Mentha Overexpressing Glutathione Biosynthesis Pathway Gene/s And Comparative Proteomic Profiling of Arabidopsis Under Altered Glutathione Conditions
No full textGeneration And Proteomic Profiling Of Transgenic Mentha Overexpressing
Glutathione Biosynthesis Pathway Gene/s And Comparative Proteomic Profiling of
Arabidopsis Under Altered Glutathione Conditions
Glutathione (GSH) is a nearly ubiquitous, most abundant non-protein tripeptide thiol
compound found in both prokaryotes and eukaryotes. Recent years have witnessed
considerable progress in understanding GSH synthesis, degradation and transport,
particularly in relation to cellular redox homeostasis and related signalling under optimal and
stress conditions. The role of GSH in plant defence has long been known in addition to its
substantial role in stress tolerance and antioxidant signalling. Function of GSH has been
reported vividly in various types of biotic and abiotic stress tolerance in plants. In the present
study the role of GSH in plant defence has been further explored using two systems. First
deals with the enhancement of GSH content in target plant viz. Mentha arvensis using
transgenic approach. A constitutive overexpression of g-ECS (rate limiting enzyme of GSH
biosynthetic pathway) is performed through Agrobacterium tumefaciens mediated
transformation. The transgenic plants showed an enhancement of total GSH content and
displayed stress tolerant ability against metal toxicity and pathogen stress. A comparative
protein profile between wild type and transgenic plants under non-infected and Alternaria
alternata infected conditions showed differential accumulation of protein species related to
stress and defense, redox regulation, transcription factors and energy and metabolism. Protein
species related to signalling and gene regulation of defence related proteins showed
differential accumulation specifically in infected transgenic plants. Thus it can be postulated
that transgenic plants with enhanced GSH content could be a promising approach for raising
stress tolerant plants. Owing to the limited database information with Mentha, the study was
further continued with Arabidopsis thaliana. Hence in the second part of the study, the role of
GSH was explored using in-vivo feeding of GSH to Col 0 and pad2-1, an A. thaliana mutant
for g-ECS allele with Col 0 as control. Proteins related to stress, defence signalling, redox
related proteins, protein synthesis and degradation, DNA repair proteins were identified as
differentially regulated through comparative proteomics. Likewise genes related to biotic
stress, abiotic stress, redox, signalling, RNA regulation, protein modification, development,
cell organisation, protein synthesis and degradation were identified as differentially expressed
through microarray analysis. The study demonstrated that GSH has a role in defence in target
plant which was further validated in model plant. The bio-informatics analyses of integrated
proteome and transcriptome was further performed to gain an in depth insight into
involvement of GSH in defense signalling network. The interplay between GSH and salicylic
acid (SA) is noted by differential expression of SA-mediated signalling related genes. In
addition, a new insight into the interaction between GSH and ethylene in defence signalling
pathway is observed. The effect of GSH on glucosinolate (GSL) biosynthetic pathways is
also observed which might be an important information linking the GSH to the GSL mediated
defence response. Furthermore, present dataset serves as a resource of altered genes and
protein under changed GSH content in A. thaliana and offers clues for future investigation on
GSH as signalling molecule