2058 research outputs found
Sort by
Signaling pathways and gene-gene network interaction in the pathogenesis of Oral submucous fibrosis: a precancerous condition
No full textA prominent count of world’s population is affected from the oral malignancies and the number is increasing at an alarming rate (90.3 million cases being recorded annually), due to lack of effective control of the malady. These malignancies are almost always preceded by inflammatory
oral lesions such as Leukoplakia (LPK), Erythroplakia (EP), Oral lichen planus (OLP) and Oral submucous Fibrosis (OSF) with malignant transformation rates of 15%,14.3%-50%, 0.4%-5.6% and 3%-19% respectively (Mithani et al. 2007). The WHO monograph on Head and Neck Tumors (2005) used the term “Epithelial precursor lesions” for such pre-malignant lesions. In May 2005, the term “Potentially Malignant disorders” was recommended by workshop coordinated by the WHO Collaborating center for Oral Cancer and Precancer in UK as it conveys that not all disorders described under this term may transform into cancer (Warnakulasuriya et al. 2007). The current study comprises the analysis of genetic alteration involved in OSF which is a major concern especially in south Asian countries. Worldwide estimates of OSF in 1996 indicated 2.5 million people being affected; whereas according to 2002 statistics, 5 million cases were reported from Indian subcontinent alone (Rajalalitha et al. 2005). Though current statistics are not available, but the discrete case studies reporting the prevalence of OSF among younger population makes OSF a major health concern among the south Asian countries. This is supported by the widespread use of areca nut and tobacco, which has been
implicated as principal etiological factors of OSF, in these countries
Entropy driven binding of the alkaloid chelerythrine to polyadenylic acid leads to spontaneous self-assembled structure formation
No full textThe binding thermodynamics and interaction of the putative anticancer alkaloid chelerythrine with polyadenylic acid were investigated by isothermal titration calorimetry, absorption and fluorescence spectroscopy, circular dichroism, differential scanning calorimetry and thermal melting experiments. The equilibrium binding constant was evaluated to be of the order of 107 M�1. Strong positive entropic and favorable enthalpic contributions to the binding were revealed. The binding affinity was enhanced within (10 to 100) mM Na+ concentration. Circular dichroism spectra confirmed that the increase in entropy change was caused by a strong conformational change in the RNA polynucleotide. Absorption and circular dichroism melting studies revealed that chelerythrine binding induced self-assembled duplex structure formation in poly(A) molecules resulting in a cooperative melting profile. This was further confirmed from differential scanning calorimetry data. The intercalation binding of the alkaloid involved strong energy transfer from the polynucleotide bases to the bound alkaloid molecules. The remarkably high entropy driven binding of the alkaloid induced spontaneous self-assembled structure formation in poly(A) and the associated binding affinity is the highest so far reported for a small molecule binding to poly(A)
Synthesis and Evaluation of Technetium-99m-Labeled Bioreductive Pharmacophores Conjugated with Amino Acids and Peptides for Tumor Imaging
No full textDevelopment of molecular imaging agents to target
tumor has become a major trend in nuclear medicine.
With the aim to develop new potential 99mTc-radiopharmaceuticals for targeting tumor, we have synthesized 5-nitroimidazolyl amino acids and RGD-coupled
2-nitroimidazoles. Technetium-99m radiolabeling with
high radiochemical purity (>90%) was achieved for all
the compounds. The radiolabeled complexes exhibited
substantial in vitro stability in saline, serum, and histidine solution (10�2M). Cell binding studies in EAC and
B16F10 cell lines also revealed rapid and comparatively
high cellular internalization. Among all the compounds
studied, the binding of 99mTc(CO)3-5 to B16F10 cells was moderately inhibited by the competitive peptide c[RGDfV], suggesting specificity of the radioligand toward avb3 receptor. However, no significant displacement of bound radioligand was observed when the binding of the 99mTc-labeled complexes to above cells was challenged with excess competitive peptide. Fluorescent microscopy study provided direct evidence of intracellular localization of 5(6)-carboxyfluorescein- labeled 2-nitroimidazolyl-RGD-peptide in avb3-positive B16F10 mouse melanoma cell line. The
ligands caused only 8–13% of hemolysis toward rat
erythrocytes at concentrations as high as 100 lM.
Imaging and biodistribution studies were performed in
Swiss albino mice bearing induced tumor. 99mTc-1 and
99mTc(CO)3-5 demonstrated a very favorable in vivo
profile. Selective uptake and retention in tumor with
encouraging tumor/muscle and tumor/blood ratio and
significant cellular uptake of fluorescence-labeled-2-nitroimidazolyl RGD indicate the great potentiality of the
pharmacophore for further evaluation as potential
molecular imaging agent in cancer diagnosis
mRNA Targeting to Endoplasmic Reticulum Precedes Ago Protein Interaction and MicroRNA (miRNA)-mediated Translation Repression in Mammalian Cells
No full textMicroRNA (miRNA) binds to the 3�-UTR of its target mRNAs
to repress protein synthesis. Extensive research was done to
understand the mechanism of miRNA-mediated repression in
animal cells. Considering the progress in understanding the
mechanism, information about the subcellular sites of
miRNA-mediated repression is surprisingly limited. In this
study, using an inducible expression system for an miRNA
target message, we have delineated how a targetmRNApasses
through polysome association and Ago2 interaction steps on
rough endoplasmic reticulum (ER) before the miRNA-mediated
repression sets in. From this study, de novo formed target
mRNA localization to the ER-bound polysomes manifested as
the earliest event, which is followed by Ago2 micro-ribonucleoprotein binding, and translation repression of target message. Compartmentalization of this process to rough ER membrane ensures enrichment of miRNA-targeted messages and micro-ribonucleoprotein components on ER upon reaching a steady stat
Sonication Assisted Three Phase Partitioning for the Extraction of Palmitic Acid and Elaidic Acid from Cassia sophera Linn.
No full textUltrasound assisted three phase partitioning (UATPP) has been explored for the extraction of palmitic acid (PA) and elaidic acid(EA) from Cassia sophera Linn. seed powder, and the process were optimized. Ultrasound was applied with TPP to improve the yield with operating frequencies of 25 and 40 kHz and at a power 200W. The yield of PA and EA was 0.25 ± 0.005% and 0.26 ± 0.006%,respectively, with TPP. The yield was found 0.31 ± 0.002% and 0.32 ± 0.016%, with UATPP at 40 kHz and 180 W power. UATPP was found to be an effective techniqu
Invasion of ovarian cancer cells is induced by PITX2-mediated activation of TGF-β and Activin-A
Get PDFBackground:Most ovarian cancers are highly invasive in nature and the high burden of metastatic disease make them a leading cause of mortality among all gynaecological malignancies. The homeodomain transcription factor, PITX2 is associated with cancer in different tissues. Our previous studies demonstrated increased PITX2 expression in human ovarian tumours. Growing evidence linking activation of TGF-β pathway by homeodomain proteins prompted us to look for the possible involvement of this signalling pathway in PITX2-mediated progression of ovarian cancer.
Methods: The status of TGF-β signalling in human ovarian tissues was assessed by immunohistochemistry. The
expression level of TGFB/INHBA and other invasion-associated genes was measured by quantitative-PCR (Q-PCR)
and Western Blot after transfection/treatments with clones/reagents in normal/cancer cells. The physiological
effect of PITX2 on invasion/motility was checked by matrigel invasion and wound healing assay. The PITX2- and
activin-induced epithelial-mesenchymal transition (EMT) was evaluated by Q-PCR of respective markers and confocal/phase-contrast imaging of cells.
Results: Human ovarian tumours showed enhanced TGF-β signalling. Our study uncovers the PITX2-induced
expression of TGFB1/2/3 as well as INHBA genes (p < 0.01) followed by SMAD2/3-dependent TGF-β signalling
pathway. PITX2-induced TGF-β pathway regulated the expression of invasion-associated genes, SNAI1, CDH1
and MMP9 (p < 0.01) that accounted for enhanced motility/invasion of ovarian cancers. Snail and MMP9 acted
as important mediators of PITX2-induced invasiveness of ovarian cancer cells. PITX2 over-expression resulted in
loss of epithelial markers (p < 0.01) and gain of mesenchymal markers (p < 0.01) that contributed significantly to ovarian oncogenesis. PITX2-induced INHBA expression (p < 0.01) contributed to EMT in both normal and ovarian cancer cells.
Conclusions: Overall, our findings suggest a significant contributory role of PITX2 in promoting invasive
behaviour of ovarian cancer cells through up-regulation of TGFB/INHBA. We have also identified the previously unknown involvement of activin-A in promoting EMT. Our work provides novel mechanistic insights into the invasive behavior of ovarian cancer cells. The extension of this study have the potential for therapeutic applications in future
Di-oxime based selective fluorescent probe for arsenate and arsenite ions in a purely aqueous medium with living cell imaging applications and H-bonding induced microstructure formation
No full textA 2-hydroxy-5-methyl-benzene-1,3-dicarboxaldehyde di-oxime
based turn-on blue emission fluorescent probe was found to
recognize both AsO2− and H2AsO4 − in a purely aqueous medium in intra and extra-cellular conditions. Self-organization of the ligand in the absence and presence of AsO2 − and H2AsO4 − was investigated by DLS, optical microscopy, optical fluorescence microscopy
and FE-SEM method
Ellagic Acid, a Dietary Polyphenol, Inhibits Tautomerase Activity of Human Macrophage Migration Inhibitory Factor and Its Pro-inflammatory Responses in Human Peripheral Blood Mononuclear Cells
No full textEllagic acid (EA), a phenolic lactone, inhibited tautomerase activity of human macrophage migration inhibitory factor (MIF) noncompetitively (Ki = 1.97 ± 0.7 μM). The binding of EA to MIF was determined by following the quenching of tryptophan fluorescence. We synthesized several EA derivatives, and their structure−activity relationship studies indicated that the planar conjugated lactone moiety of EA was essential for MIF inhibition. MIF induces nuclear translocation of NF-κB and chemotaxis of peripheral blood mononuclear cells (PBMCs) to promote inflammation. We were interested in evaluating the
effect of EA on nuclear translocation of NF-κB and chemotactic activity in human PBMCs in the presence of MIF. The results showed that EA inhibited MIF-induced NF-κB nuclear translocation in PBMCs, as evident from confocal immunofluorescence microscopic data. EA also inhibited MIF-mediated chemotaxis of PBMCs. Thus, we report MIF-inhibitory activity of EA and inhibition of MIF-mediated proinflammatory responses in PBMCs by EA
Association of MMP7-181A-G Promoter Polymorphism with Gastric Cancer Risk
No full textElevated expression of matrix metalloproteinase7 (MMP7)
has been demonstrated to play a pivotal role in cancer invasion.The�181A3G(rs11568818) polymorphism in theMMP7promoter modulates gene expression and possibly affects cancer progression. Here, we evaluated the impact of�181A3G polymorphism on MMP7 promoter activity and its association with gastric cancer risk in eastern Indian case-control cohorts (n �520). The GG genotype as compared with the AA genotype was predisposed (p � 0.02; odds ratio � 1.9, 95% confidence interval1.1–3.3) to gastric cancer risk. Stratification analysis showed that tobacco addiction enhanced gastric cancer risk in GG subjects when compared with AA subjects (p � 0.03, odds ratio � 2.46, and 95% confidence interval � 1.07–5.68). Metaanalysis
revealed that tobacco enhanced the risk for cancer more
markedly in AG and GG carriers. Activity and expression of
MMP7 were significantly higher in GG than in AA carriers. In
support, MMP7 promoter-reporter assays showed greater transcriptional activity toward A to G transition under basal/nicotine- induced/cAMP-response element-binding protein (CREB) overexpressed conditions in gastric adenocarcinoma cells. Moreover, nicotine (a major component of tobacco) treatment significantly up-regulated MMP7 expression due to enhanced CREB phosphorylation followed by its nuclear translocation in gastric adenocarcinoma cells. Furthermore, chromatin immunoprecipitation experiments revealed higher binding of phosphorylated CREB with the �181G than the �181A allele. Altogether, specific binding of phosphorylated CREB to the G allele-carrying promoter enhances MMP7 gene expression that is further augmented by nicotine due to increased CREB phosphorylation and thereby increases the risk for gastric cancer
Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validated in silico modeling techniques and molecular dynamics simulation
No full textInhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) enzyme are useful for the treatment of various diseases
including cancer. Comparative in silico studies were performed on different ligand-based (2D-QSAR, Kernel-based
partial least square (KPLS) analysis, Pharmacophore Search Engine (PHASE) pharmacophore mapping), and structurebased
(molecular docking, MM-GBSA analyses, Gaussian-based 3D-QSAR analyses on docked poses) modeling techniques to explore the structure–activity relationship of a diverse set of PARP-1 inhibitors. Two-dimensional (2D)-QSAR
highlighted the importance of charge topological index (JGI7), fractional polar surface area (JursFPSA3), and connectivity index (CIC2) along with different molecular fragments. Favorable and unfavorable fingerprints were demonstrated in KPLS analysis, whereas important pharmacophore features (one acceptor, one donor, and two ring aromatic) along with favorable and unfavorable field effects were demonstrated in PHASE-based pharmacophore model. MM-GBSA analyses revealed significance of different polar, non-polar, and solvation energies. Docking-based alignment of ligands was used to perform Gaussian-based 3D-QSAR study that further demonstrated importance of different field effects. Overall, it was found that polar interactions (hydrogen bonding, bridged hydrogen bonding, and pi–cation) play major roles for higher activity. Steric groups increase the total contact surface area but it should have higher fractional polar surface area
to adjust solvation energy. Structure-based pharmacophore mapping spotted the positive ionizable feature of ligands as
the most important feature for discriminating highly active compounds from inactives. Molecular dynamics simulation,
conducted on highly active ligands, described the dynamic behaviors of the protein complexes and supported the interpretations obtained from other modeling analyses. The current study may be useful for designing PARP-1 inhibitors