Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide

Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 mu M) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading Delta psi m dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.

Tuning the chiro-plasmonic response using high refractive index-dielectric templates

Chiral metamaterials have recently gained attention due to their applicability in developing polarization devices and in the detection of chiral molecules. A common approach towards fabricating plasmonic chiral nanostructures has been decorating metallic nanoparticles on dielectric chiral scaffolds, such as a helix. This resulted in the generation of a large chiro-optical response over a wide range of the electromagnetic spectrum. It has been shown previously that the optical tunability of these chiral metamaterials depends on the geometrical aspects of the overall structure, as well as the nature of the plasmonic constituents. In this study, we have investigated the role of the underlying dielectric scaffold with numerical simulations, and experimentally demonstrated that it is possible to enhance and engineer their chiro-plasmonic response significantly by choosing dielectric scaffolds of appropriate materials.

A novel DNA intercalator, 8-methoxy pyrimido4 `,5 `:4,5]thieno (2,3-b)quinoline-4(3H)-one induces apoptosis in cancer cells, inhibits the tumor progression and enhances lifespan in mice with tumor

Polycyclic aromatic molecules such as ellipticine intercalate into double-stranded DNA and interfere with physiological functions. In the present study, we evaluate the chemotherapeutic potential of MPTQ on animal models and its mode of action. In order to test the antitumor activity, monohydrochloride of MPTQ was orally administered in mice bearing tumor. Results showed a significant inhibition of tumor growth compared to that of untreated controls. More importantly, mean lifespan of tumor bearing animals treated with MPTQ was significantly higher as compared to that of untreated tumor bearing mice suggesting that the treatment affected viability of cancerous cells, but not of normal cells. Consistent with this, we find that administration of MPTQ to normal mice did not cause any major side effects as observed upon hematological and serum profiling. We also found that MPTQ induces cytotoxicity in cancer cell lines, by activating apoptosis both by intrinsic and extrinsic pathways. Thus, MPTQ could be used as a potential cancer therapeutic agent. (c) 2011 Wiley Periodicals, Inc.

Separation index of graphs and stacked 2-spheres

In 1987, Kalai proved that stacked spheres of dimension d >= 3 are characterised by the fact that they attain equality in Barnette's celebrated Lower Bound Theorem. This result does not extend to dimension d = 2. In this article, we give a characterisation of stacked 2-spheres using what we call the separation index. Namely, we show that the separation index of a triangulated 2-sphere is maximal if and only if it is stacked. In addition, we prove that, amongst all n-vertex triangulated 2-spheres, the separation index is minimised by some n-vertex flag sphere for n >= 6. Furthermore, we apply this characterisation of stacked 2-spheres to settle the outstanding 3-dimensional case of the Lutz-Sulanke-Swartz conjecture that ``tight-neighbourly triangulated manifolds are tight''. For dimension d >= 4, the conjecture has already been proved by Effenberger following a result of Novik and Swartz. (C) 2015 Elsevier Inc. All rights reserved.

Epithelial atrophy in oral submucous fibrosis is mediated by copper (II) and arecoline of areca nut

Exposure of oral cavity to areca nut is associated with several pathological conditions including oral submucous fibrosis (OSF). Histopathologically OSF is characterized by epithelial atrophy, chronic inflammation, juxtaepithelial hyalinization, leading to fibrosis of submucosal tissue and affects 0.5% of the population in the Indian subcontinent. As the molecular mechanisms leading to atrophied epithelium and fibrosis are poorly understood, we studied areca nut actions on human keratinocyte and gingival fibroblast cells. Areca nut water extract (ANW) was cytotoxic to epithelial cells and had a pro-proliferative effect on fibroblasts. This opposite effect of ANW on epithelial and fibroblast cells was intriguing but reflects the OSF histopathology such as epithelial atrophy and proliferation of fibroblasts. We demonstrate that the pro-proliferative effects of ANW on fibroblasts are dependent on insulin-like growth factor signalling while the cytotoxic effects on keratinocytes are dependent on the generation of reactive oxygen species. Treatment of keratinocytes with arecoline which is a component of ANW along with copper resulted in enhanced cytotoxicity which becomes comparable to IC50 of ANW. Furthermore, studies using cyclic voltammetry, mass spectrometry and plasmid cleavage assay suggested that the presence of arecoline increases oxidation reduction potential of copper leading to enhanced cleavage of DNA which could generate an apoptotic response. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling assay and Ki-67 index of OSF tissue sections suggested epithelial apoptosis, which could be responsible for the atrophy of OSF epithelium.

A novel benzimidazole derivative binds to the DNA minor groove and induces apoptosis in leukemic cells

DNA minor groove binders are an important class of chemotherapeutic agents. These small molecule inhibitors interfere with various cellular processes like DNA replication and transcription. Several benzimidazole derivatives showed affinity towards the DNA minor groove. In this study we show the synthesis and biological studies of a novel benzimidazole derivative (MH1), that inhibits topoisomerase II activity and in vitro transcription. UV-visible and fluorescence spectroscopic methods in conjunction with Hoechst displacement assay demonstrate that MH1 binds to DNA at the minor groove. Cytotoxic studies showed that leukemic cells are more sensitive to MH1 compared to cancer cells of epithelial origin. Further, we find that MH1 treatment leads to cell cycle arrest at G2/M, at early time points in Molt4 cells. Finally multiple cellular assays demonstrate that MH1 treatment leads to reduction in MMP, induction of apoptosis by activating CASPASE 9 and CASPASE 3. Thus our study shows MH1, a novel DNA minor groove binder, induces cytotoxicity efficiently in leukemic cells by activating the intrinsic pathway of apoptosis.

Diffractive Optical Analysis for Refractive Index Sensing using Transparent Phase Gratings

We report the implementation of a micro-patterned, glass-based photonic sensing element that is capable of label-free biosensing. The diffractive optical analyzer is based on the differential response of diffracted orders to bulk as well as surface refractive index changes. The differential read-out suppresses signal drifts and enables time-resolved determination of refractive index changes in the sample cell. A remarkable feature of this device is that under appropriate conditions, the measurement sensitivity of the sensor can be enhanced by more than two orders of magnitude due to interference between multiply reflected diffracted orders. A noise-equivalent limit of detection (LoD) of 6 x 10(-7) was achieved with this technique with scope for further improvement.

A novel index for identification of weak nodes for reactive compensation to improve voltage stability

In this study, a new reactive power loss index (RPLI) is proposed for identification of weak buses in the system. This index is further used for determining the optimal locations for placement of reactive compensation devices in the power system for additional voltage support. The new index is computed from the reactive power support and loss allocation algorithm using Y-bus method for the system under intact condition and as well as critical/severe network contingencies cases. Fuzzy logic approach is used to select the important and critical/severe line contingencies from the contingency list. The inherent characteristics of the reactive power in system operation is properly addressed while determining the reactive power loss allocation to load buses. The proposed index is tested on sample 10-bus equivalent system and 72-bus practical equivalent system of Indian southern region power grid. The validation of the weak buses identification from the proposed index with that from other existing methods in the literature is carried out to demonstrate the effectiveness of the proposed index. Simulation results show that the identification of weak buses in the system from the new RPLI is completely non-iterative, thus requires minimal computational efforts as compared with other existing methods in the literature.

Use of polydispersity index as control parameter to study melting/freezing of Lennard-Jones system: Comparison among predictions of bifurcation theory with Lindemann criterion, inherent structure analysis and Hansen-Verlet rule

Using polydispersity index as an additional order parameter we investigate freezing/melting transition of Lennard-Jones polydisperse systems (with Gaussian polydispersity in size), especially to gain insight into the origin of the terminal polydispersity. The average inherent structure (IS) energy and root mean square displacement (RMSD) of the solid before melting both exhibit quite similar polydispersity dependence including a discontinuity at solid-liquid transition point. Lindemann ratio, obtained from RMSD, is found to be dependent on temperature. At a given number density, there exists a value of polydispersity index (delta (P)) above which no crystalline solid is stable. This transition value of polydispersity(termed as transition polydispersity, delta (P) ) is found to depend strongly on temperature, a feature missed in hard sphere model systems. Additionally, for a particular temperature when number density is increased, delta (P) shifts to higher values. This temperature and number density dependent value of delta (P) saturates surprisingly to a value which is found to be nearly the same for all temperatures, known as terminal polydispersity (delta (TP)). This value (delta (TP) similar to 0.11) is in excellent agreement with the experimental value of 0.12, but differs from hard sphere transition where this limiting value is only 0.048. Terminal polydispersity (delta (TP)) thus has a quasiuniversal character. Interestingly, the bifurcation diagram obtained from non-linear integral equation theories of freezing seems to provide an explanation of the existence of unique terminal polydispersity in polydisperse systems. Global bond orientational order parameter is calculated to obtain further insights into mechanism for melting.

Evaluation of the Index-Flood Approach Related Regional Frequency Analysis Procedures

Index-flood related regional frequency analysis (RFA) procedures are in use by hydrologists to estimate design quantiles of hydrological extreme events at data sparse/ungauged locations in river basins. There is a dearth of attempts to establish which among those procedures is better for RFA in the L-moment framework. This paper evaluates the performance of the conventional index flood (CIF), the logarithmic index flood (LIF), and two variants of the population index flood (PIF) procedures in estimating flood quantiles for ungauged locations by Monte Carlo simulation experiments and a case study on watersheds in Indiana in the U.S. To evaluate the PIF procedure, L-moment formulations are developed for implementing the procedure in situations where the regional frequency distribution (RFD) is the generalized logistic (GLO), generalized Pareto (GPA), generalized normal (GNO) or Pearson type III (PE3), as those formulations are unavailable. Results indicate that one of the variants of the PIF procedure, which utilizes the regional information on the first two L-moments is more effective than the CIF and LIF procedures. The improvement in quantile estimation using the variant of PIF procedure as compared with the CIF procedure is significant when the RFD is a generalized extreme value, GLO, GNO, or PE3, and marginal when it is GPA. (C) 2015 American Society of Civil Engineers.

Electromagnetic analysis of novel class of multiple core/multiple clad step index single mode optical fiber by analytical means

General propagation properties and universal curves are given for double clad single mode fibers with inner cladding index higher or lower than the outer cladding index, using the parameter: inner cladding/core radii ratio. Mode cut-off conditions are also examined for the cases. It is shown that dispersion properties largely differ from the single clad single mode fiber case, leading to large new possibilities for extension of single mode operation for large wavelength tange. Paper demonstrates that how substantially we can extend the single mode operation range by using the raised inner cladding fiber. Throughout we have applied our own computations technique to find out the eigenvalue for a given modes. Detail derivations with all trivial mathematics for eigenmode equation are derived for each case. Paper also demonstrates that there is not much use of using depressed inner cladding fiber. We have also concluded that using the large inner cladding/inner core radius we can significantly increase the single mode operation range for the large wavelength region. (C) 2015 Elsevier GmbH. All rights reserved.

Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis

Naturally occurring compounds are considered as attractive candidates for cancer treatment and prevention. Quercetin and ellagic acid are naturally occurring flavonoids abundantly seen in several fruits and vegetables. In the present study, we evaluate and compare antitumor efficacies of quercetin and ellagic acid in animal models and cancer cell lines in a comprehensive manner. We found that quercetin induced cytotoxicity in leukemic cells in a dose-dependent manner, while ellagic acid showed only limited toxicity. Besides leukemic cells, quercetin also induced cytotoxicity in breast cancer cells, however, its effect on normal cells was limited or none. Further, quercetin caused S phase arrest during cell cycle progression in tested cancer cells. Quercetin induced tumor regression in mice at a concentration 3-fold lower than ellagic acid. Importantly, administration of quercetin lead to -5 fold increase in the life span in tumor bearing mice compared to that of untreated controls. Further, we found that quercetin interacts with DNA directly, and could be one of the mechanisms for inducing apoptosis in both, cancer cell lines and tumor tissues by activating the intrinsic pathway. Thus, our data suggests that quercetin can be further explored for its potential to be used in cancer therapeutics and combination therapy.