A novel approach towards therapeutic optimization of diclofenac

Con objeto de obtener compuestos con menor toxicidad gástrica que el diclofenaco, se sintetizaron yevaluaron cinco ésteres derivados aminoetílicos N,N-sustituidos derivados del diclofenaco. Estos ésteresse diseñaron para satisfacer el requisito estructural de disponer de una actividad anticolinérgica intactaantes de la separación. Además de bloquear el grupo carboxilo ácido mediante esterificación, estaactividad se incorporó a los ésteres sintetizados, con el beneficio adicional esperado de la reducción dela secreción de ácido gástrico y la consecuente eliminación de la irritación local mediante un mecanismodual. En este estudio se describen la síntesis, la cinética de la hidrólisis y la actividad biológica de estosésteres. Todos los derivados de éster permanecieron estables en tampones de pH 2,0 y 7,4 durante unperíodo de tiempo suficiente, lo que aseguró su absorción en estado intacto y la eliminación de lairritación gástrica local producida por el fármaco principal. Se observó una rápida hidrólisis enzimáticade todos los derivados en un 80% de suero humano combinado. Se descubrió que los ésteres sintetizadosposeían la actividad anticolinérgica propuesta. Se mantuvo la actividad antiinflamatoria en la mayoría delos compuestos y se logró una significativa reducción del potencial ulcerogénico en comparación con eldiclofenaco.In an effort for obtaining compounds with lower gastric toxicity than diclofenac, five different N,Ndisubstitutedaminoethylester derivatives of diclofenac were synthesized and evaluated. These esterswere designed so as to satisfy the structural requirement for them to possess the anticholinergic activityin intact form before cleavage. Besides blocking the acidic carboxyl group by esterification this activitywas incorporated into the synthesized esters with an expected additional benefit of having reduced gastricacid secretion and thereby abolishing the local irritation by a dual mechanism. This report describes thesynthesis, hydrolysis kinetics and the biological activity of these esters. All the ester derivatives werefound to be stable in buffers (pH 2.0 and 7.4) for sufficient time period, assuring them to be absorbedintact and to successfully overcome the local gastric irritation of the parent drug. A fast enzymatichydrolysis was observed for all the derivatives in 80% pooled human serum. The synthesized esters werefound to possess the proposed anticholinergic activity. The anti-inflammatory activity for most of thecompounds was retained with a significant reduction in the ulcerogenic potential compared to diclofenac

Una nueva aproximación a la optimización terapéutica del diclofenaco

In an effort for obtaining compounds with lower gastric toxicity than diclofenac, five different N,Ndisubstitutedaminoethylester derivatives of diclofenac were synthesized and evaluated. These esterswere designed so as to satisfy the structural requirement for them to possess the anticholinergic activityin intact form before cleavage. Besides blocking the acidic carboxyl group by esterification this activitywas incorporated into the synthesized esters with an expected additional benefit of having reduced gastricacid secretion and thereby abolishing the local irritation by a dual mechanism. This report describes thesynthesis, hydrolysis kinetics and the biological activity of these esters. All the ester derivatives werefound to be stable in buffers (pH 2.0 and 7.4) for sufficient time period, assuring them to be absorbedintact and to successfully overcome the local gastric irritation of the parent drug. A fast enzymatichydrolysis was observed for all the derivatives in 80% pooled human serum. The synthesized esters werefound to possess the proposed anticholinergic activity. The anti-inflammatory activity for most of thecompounds was retained with a significant reduction in the ulcerogenic potential compared to diclofenac.Con objeto de obtener compuestos con menor toxicidad gástrica que el diclofenaco, se sintetizaron yevaluaron cinco ésteres derivados aminoetílicos N,N-sustituidos derivados del diclofenaco. Estos ésteresse diseñaron para satisfacer el requisito estructural de disponer de una actividad anticolinérgica intactaantes de la separación. Además de bloquear el grupo carboxilo ácido mediante esterificación, estaactividad se incorporó a los ésteres sintetizados, con el beneficio adicional esperado de la reducción dela secreción de ácido gástrico y la consecuente eliminación de la irritación local mediante un mecanismodual. En este estudio se describen la síntesis, la cinética de la hidrólisis y la actividad biológica de estosésteres. Todos los derivados de éster permanecieron estables en tampones de pH 2,0 y 7,4 durante unperíodo de tiempo suficiente, lo que aseguró su absorción en estado intacto y la eliminación de lairritación gástrica local producida por el fármaco principal. Se observó una rápida hidrólisis enzimáticade todos los derivados en un 80% de suero humano combinado. Se descubrió que los ésteres sintetizadosposeían la actividad anticolinérgica propuesta. Se mantuvo la actividad antiinflamatoria en la mayoría delos compuestos y se logró una significativa reducción del potencial ulcerogénico en comparación con eldiclofenaco

Effect of potassium application on yield and quality of green gram (Vigna radiata L.) on coarse textured soils of southern Haryana

59-63Crops need large quantity of potassium for enhancing their yield as well as quality. Pulses are important crops grown in India but their productivity is low. Among production inputs, recommendations for N and P fertilizers are made in most states with no K application resulting in imbalanced nutrient supply and lower crop yields.To quantify optimum dose for green gram ( Vigna radiata L.), a series of field experiments were conducted at Regional Research Station, CCS HAU, Bawal, Haryana, to assess the response of green gram to fertilizer potassium on coarse textured (Typic Haplustepts) soils of southern Haryana. After completion of research trials, crop was tested on farmer’s field through demonstrations and on farm trials (OFTs) to evaluate the response and adoptability of green gram as per the fertilizer potassium doses concluded in research experiment. Five levels of fertilizer potassium (0, 10, 20, 30 and 40 kg K2O ha-1) were evaluated for the response of green gram in randomized block design replicated thrice. The results of research trials revealed that the yield, protein content and growth parameters of green gram increased significantly with the application of fertilizer potassium @20 kg K2O ha-1. Significantly higher yield of green gram was recorded (5.87, 16.29, 19.23 and 22.36 %) due to application of 10, 20, 30 and 40 kg K2O ha-1, respectively over control. The total K uptake by green gram increased significantly with the incremental doses of potassium application which helped to prevent the depletion of available soil K and build-up its content in the soil. The mean K use efficiency varied from 38.30 to 54.15 and maximum (54.15 %) was recorded with the application of 20 kg K2O ha-1. The benefit cost ratio was also increased with the application of potassium and reflected in terms of additional returns per rupee (Rs. 10.94, 15.63, 12.17 and 10.72) invested on application of K @ 10, 20, 30 and 40 kg K2O ha-1, respectively. The farmer’s field trial results with 0 and 20 kg K2O ha-1 revealed that application of 20 kg K2O ha-1 increased the yield of green gram by 10.87% over control

Cytochrome c Reduction by H2S Potentiates Sulfide Signaling.

This is the author accepted manuscript. The final version is available from American Chemical Society via the DOI in this record.Hydrogen sulfide (H2S) is an endogenously produced gas that is toxic at high concentrations. It is eliminated by a dedicated mitochondrial sulfide oxidation pathway, which connects to the electron transfer chain at the level of complex III. Direct reduction of cytochrome c (Cyt C) by H2S has been reported previously but not characterized. In this study, we demonstrate that reduction of ferric Cyt C by H2S exhibits hysteretic behavior, which suggests the involvement of reactive sulfur species in the reduction process and is consistent with a reaction stoichiometry of 1.5 mol of Cyt C reduced/mol of H2S oxidized. H2S increases O2 consumption by human cells (HT29 and HepG2) treated with the complex III inhibitor antimycin A, which is consistent with the entry of sulfide-derived electrons at the level of complex IV. Cyt C-dependent H2S oxidation stimulated protein persulfidation in vitro, while silencing of Cyt C expression decreased mitochondrial protein persulfidation in a cell culture. Cyt C released during apoptosis was correlated with persulfidation of procaspase 9 and with loss of its activity. These results reveal a potential role for the electron transfer chain in general, and Cyt C in particular, for potentiating sulfide-based signaling.This work was supported by the French State in the frame of the “Investments for the future” Programme IdEx Bordeaux, reference ANR-10-IDEX-03-02, and by an ATIP-AVENIR grant (to M.R.F.), the National Institutes of Health (GM112455 to R.B. and R01GM113030 to M.D.P.), the Medical Research Council, UK (MR/M022706/1 to M.W.), the National Science Foundation (DGE-1309047 to A.K.S.), and the Brian Ridge Scholarship (R.T.). The authors are grateful to M.-F. Giraud for the help with purification of mitochondria

Differential distribution of a SINE element in the Entamoeba histolytica and Entamoeba dispar genomes: Role of the LINE-encoded endonuclease

<p>Abstract</p> <p>Background</p> <p><it>Entamoeba histolytica </it>and <it>Entamoeba dispar </it>are closely related protistan parasites but while <it>E. histolytica </it>can be invasive, <it>E. dispar </it>is completely non pathogenic. Transposable elements constitute a significant portion of the genome in these species; there being three families of LINEs and SINEs. These elements can profoundly influence the expression of neighboring genes. Thus their genomic location can have important phenotypic consequences. A genome-wide comparison of the location of these elements in the <it>E. histolytica </it>and <it>E. dispar </it>genomes has not been carried out. It is also not known whether the retrotransposition machinery works similarly in both species. The present study was undertaken to address these issues.</p> <p>Results</p> <p>Here we extracted all genomic occurrences of full-length copies of EhSINE1 in the <it>E. histolytica </it>genome and matched them with the homologous regions in <it>E. dispar</it>, and vice versa, wherever it was possible to establish synteny. We found that only about 20% of syntenic sites were occupied by SINE1 in both species. We checked whether the different genomic location in the two species was due to differences in the activity of the LINE-encoded endonuclease which is required for nicking the target site. We found that the endonucleases of both species were essentially very similar, both in their kinetic properties and in their substrate sequence specificity. Hence the differential distribution of SINEs in these species is not likely to be influenced by the endonuclease. Further we found that the physical properties of the DNA sequences adjoining the insertion sites were similar in both species.</p> <p>Conclusions</p> <p>Our data shows that the basic retrotransposition machinery is conserved in these sibling species. SINEs may indeed have occupied all of the insertion sites in the genome of the common ancestor of <it>E. histolytica </it>and <it>E. dispar </it>but these may have been subsequently lost from some locations. Alternatively, SINE expansion took place after the divergence of the two species. The absence of SINE1 in 80% of syntenic loci could affect the phenotype of the two species, including their pathogenic properties, which needs to be explored.</p

Compliance with the smoke-free public places legislation in Nepal: A cross-sectional study from Biratnagar Metropolitan City

Background Smoke-free legislation banning tobacco smoking in public places was implemented across Nepal in 2014 with the ambition to reduce the impact of second-hand smoking. As part of a comprehensive policy package on tobacco control, the implementation of the legislation has seen a marked reduction in tobacco consumption. Yet there remains uncertainty about the level of compliance with smoke-free public places. Objectives This study assesses the compliance with smoke-free laws in public places and the factors associated with active smoking in public places in Biratnagar Metropolitan City, Nepal. Methods A cross-sectional study was conducted in the Biratnagar metropolitan city in Province 1 of Nepal from July to December 2019. A total of 725 public places within the metropolitan city were surveyed using a structured survey tool. Active smoking was the primary outcome of the study which was defined as smoking by any person during the data collection time at the designated public place. Results The overall compliance with smoke-free legislation was 56.4%. The highest compliance (75.0%) was observed in Government office buildings. The lowest compliance was observed in eateries, entertainment, and shopping venues (26.3%). There was a statistically significant association between active smoking and the presence of ‘no smoking’ notices appended at the entrance and the odds of active smoking in eateries, entertainment, hospitality, shopping venues, transportations and transits was higher compared to education and health care institutions. None of the ‘no smoking’ notices displayed fully adhered to the contents as prescribed by the law. Conclusion As more than half of the public places complied with the requirements of the legislation, there was satisfactory overall compliance with the smoke-free public places law in this study. The public venues (eateries, shopping venues and transportations) that are more frequently visited and have a high turnover of the public have lower compliance with the legislation. The content of the message in the ‘no smoking’ notices needs close attention to adhere to the legal requirements

Policy of foreign direct investment liberalisation in India: implications for retail sector

This study has analysed the impact of liberalisation of Indian economy and FDI policy on the retail sector since its implementation in the 1990s. It also further analyses sub-categories by investigating its impact on the unorganised retail sector and the flow of FDI in single-brand retail and multi-brand retail sectors. A comprehensive and critical review of the existing evidence on the subject was carried out, and descriptive statistical analysis of data from 1991 to 2013 was performed which leads to conclude that the policy of FDI liberalisation has proved to provide diversification and sustainable development to the Indian economy and specifically retail sector which is considered to be one of the significant pillars of economy. Furthermore, for continuous growth of the economy, it seems vital to encourage more investment in other sectors by liberalising the restrictive policies

Enhanced UV photosensitivity from rapid thermal annealed vertically aligned ZnO nanowires

We report on the major improvement in UV photosensitivity and faster photoresponse from vertically aligned ZnO nanowires (NWs) by means of rapid thermal annealing (RTA). The ZnO NWs were grown by vapor-liquid-solid method and subsequently RTA treated at 700°C and 800°C for 120 s. The UV photosensitivity (photo-to-dark current ratio) is 4.5 × 103 for the as-grown NWs and after RTA treatment it is enhanced by a factor of five. The photocurrent (PC) spectra of the as-grown and RTA-treated NWs show a strong peak in the UV region and two other relatively weak peaks in the visible region. The photoresponse measurement shows a bi-exponential growth and bi-exponential decay of the PC from as-grown as well as RTA-treated ZnO NWs. The growth and decay time constants are reduced after the RTA treatment indicating a faster photoresponse. The dark current-voltage characteristics clearly show the presence of surface defects-related trap centers on the as-grown ZnO NWs and after RTA treatment it is significantly reduced. The RTA processing diminishes the surface defect-related trap centers and modifies the surface of the ZnO NWs, resulting in enhanced PC and faster photoresponse. These results demonstrated the effectiveness of RTA processing for achieving improved photosensitivity of ZnO NWs