Effect of DNA repair deficiencies on the cytotoxicity of resveratrol

Numerous preclinical studies have shown that the naturally-occurring polyphenol resveratrol may produce health-beneficial effects in a variety of disorders, including cancer, diabetes, Alzheimer, and cardiovascular diseases. Resveratrol has entered clinical trials for the prevention and treatment of several of these disorders. This polyphenol is also available in the market as a dietary supplement. Experimental data have shown, however, that resveratrol induces DNA damage in a variety of cells. Here we review such evidence and evaluate the cytotoxicity of resveratrol (MTT assay) in cells deficient in several major DNA repair pathways (i.e., homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, and Fanconi anemia repair). Cells deficient in base excision repair (EM9), nucleotide excision repair (UV4 and UV5) and Fanconi Anemia (KO40) were slightly hypersensitive to resveratrol-induced cytotoxicity with respect to their parental cells (AA8). Our results suggest that these pathways may participate in the repair of the DNA damage induced by resveratrol and that deficiencies in these pathways may confer hypersensitivity to the genotoxic activity of this dietary constituen

Proyecto de desarrollo aplicación web cooperativa para impulso del sector de la economía popular y solidaria

Recomendado.com is a technological app oriented to meet the needs of contact between non-corporative service providers (first phase construction services) as: artisans, sole proprietorships, subsistence businesses and other actors of the popular economy and solidarity with the final consumer –users-, providing the user greater security and information to contract these services through cell phone and web apps...Recomendado.com es una aplicación tecnológica orientada a satisfacer las necesidades de contacto entre oferentes de servicios (primera fase: servicios de construcción) no corporativos como: artesanos, negocios unipersonales, negocios de subsistencias y demás actores de la economía popular y solidaria con el consumidor final -usuarios-, brindando al usuario mayor seguridad e información para contratar estos servicios a través de aplicaciones celular y web..

A hydroalcoholic extract from the leaves of Nerium oleander inhibits glycolysis and induces selective killing of lung cancer cells

Recent evidence suggests that cardiac glycosides might be used for the treatment of cancer. The ornamental shrub Nerium oleander has been used in traditional medicine for treating several disorders including cancer, and extracts from the leaves of this plant have already entered phase I clinical trials. In this communication, we have prepared a hydroalcoholic extract from the leaves of Nerium oleander (containing 4.75 ± 0.32 % of cardenolides) and have assessed its cytotoxic activity in A549 lung cancer cells vs. MRC5 nonmalignant lung fibroblasts. The results showed that the cytotoxicity of the Nerium oleander extract against the cancer cell line was significantly higher than that against the nonmalignant cell line, with a potency and selectivity similar to those of the anticancer drug cisplatin. Pretreatment of A549 cells with the antioxidants N-acetylcysteine and catalase slightly prevented the cytotoxicity of the extract, therefore suggesting that the formation of reactive oxygen species participates in its cytotoxic activity but does not play a major role. Nerium oleander extract-induced cytotoxicity and DNA damage (gamma-H2AX focus formation) were slightly higher in cells lacking BRCA2 (deficient in homologous recombination repair) than in parental cells; this indicates that the induction of DNA damage may also play a role in the cytotoxicity of the extract. Nerium oleander extract induced a marked inhibition of glycolysis (glucose consumption and lactate production) in A549 cells, comparable to that of the glycolysis inhibitor dichloroacetate (currently in clinical development for cancer therapy). Because platinum compounds are widely used in the treatment of lung cancer, we tested the cytotoxicity of several combinations of cisplatin with the extract and found a moderate synergism when Nerium oleander extract was administered after cisplatin but a moderate antagonism when it was added before cisplatin. Our results suggest that extracts from Nerium oleander might induce anticancer effects in patients with lung cancer and support their possible advancement into phase II clinical trials for the treatment of this type of cancer

Ajustes de distribuciones probabilísticas para la variable temperatura media multianual para el departamento de Boyacá (Colombia)

This paper presents a study on the selection of the best probabilistic distribution for multi-year average temperature variable in the department of Boyacá (Colombia) as the basis for future estimates and projections of the variable under uncertainty arises. Normal, Gamma, Weibull and lognormal distributions were selected to fit the data. To find which best fits the data criteria information based in maximum likelihood, Akaike (Akaike Information Criterion) and Bayesian (Bayesian Information Criteron) were used. The results are shown in both tabular and graphical form, as well as a map of the probabilistic distribution functions most representative in the study area. As a result we obtain that the Weibull distribution is the best fits in general.En este trabajo se presenta un estudio acerca de la selección de la mejor distribución probabilística para la variable media multianual de la temperatura en el departamento de Boyacá (Colombia), como base para futuras estimaciones y proyecciones de la variable en condiciones de incertidumbre. Se seleccionaron las distribuciones Normal, Gamma, Weibull y LogNormal para ajustar los datos; y para encontrar cual distribución ajusta mejor los datos se utilizaron los criterios de información basados en la máxima verosimilitud de Akaike (Akaike Information Criterion) y Bayesiano (Bayesian Information Criteron). Se muestran los resultados tanto en forma tabular como gráfica, así como un plano de las funciones de distribución probabilísticas más representativas en el área de estudio. Como resultado se obtiene que en general la distribución que mejor se ajusta es la Weibull

Managing large amounts of data generated by a Smart City internet of things deployment

The Smart City concept is being developed from a lot of different axes encompassing multiple areas of social and technical sciences. However, something that is common to all these approaches is the central role that the capacity of sharing information has. Hence, Information and Communication Technologies (ICT) are seen as key enablers for the transformation of urban regions into Smart Cities. Two of these technologies, namely Internet of Things and Big Data, have a predominant position among them. The capacity to "sense the city" and access all this information and provide added-value services based on knowledge derived from it are critical to achieving the Smart City vision. This paper reports on the specification and implementation of a software platform enabling the management and exposure of the large amount of information that is continuously generated by the IoT deployment in the city of Santander.This work has been partially funded by the research project SmartSantander, under FP7- ICT-2009-5 of the 7th Framework Programme of the European Community. The authors would also like to express their gratitude to the Spanish government for the funding in the following project: "Connectivity as a Service: Access for the Internet of the Future", COSAIF (TEC2012-38574-C02-01)

Large-scale mobile sensing enabled internet-of-things testbed for smart city services

Smart cities are one of the key application domains for the Internet-of-Things paradigm. Extending the Web into the physical realm of a city, by means of the widespread deployment of spatially distributed Internet-addressable devices with sensing and/or actuation capabilities, allows improving efficiency of city services. Vehicles moving around the city become excellent probes when the objective is to gather information across the city in a cost effective manner. Public transportation fleets, taxis, or vehicles such as waste collection trucks cover most of the urban areas with a limited number of vehicles. This paper presents the deployment of a large scale Internet-of-Things testbed that has been carried out in the city of Santander. It extends previous descriptions by providing a specification of one of the unique features of the testbed, namely, the devices that have been installed on 140 buses, taxis, and vans that every day drive around the city. Besides the physical characteristics of the devices installed and the lessons learnt during the deployment, the paper introduces the three mobile sensing network strategies used for distributing the data gathered. Finally, the paper sketches some of smart city services which might be provided using the information coming from the mobile IoT devices.This work has been partially funded by Research Project SmartSantander, under FP7-ICT-2009-5 of the 7th Framework Programme of the European Community. The authors would like to acknowledge the collaboration with the rest of partners within the consortium leading to the results presented in this paper.The authors would also like to express their gratitude to the Spanish government for the funding in the following project: “Connectivity as a Service: Access for the Internet of the Future,” COSAIF (TEC2012-38574-C02- 01)

Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid

Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee

Evaluating the cancer therapeutic potential of cardiac glycosides

Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na(+)/K(+)-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studie

Alkamides Activate Jasmonic Acid Biosynthesis and Signaling Pathways and Confer Resistance to Botrytis cinerea in Arabidopsis thaliana

Alkamides are fatty acid amides of wide distribution in plants, structurally related to N-acyl-L-homoserine lactones (AHLs) from Gram-negative bacteria and to N- acylethanolamines (NAEs) from plants and mammals. Global analysis of gene expression changes in Arabidopsis thaliana in response to N-isobutyl decanamide, the most highly active alkamide identified to date, revealed an overrepresentation of defense-responsive transcriptional networks. In particular, genes encoding enzymes for jasmonic acid (JA) biosynthesis increased their expression, which occurred in parallel with JA, nitric oxide (NO) and H2O2 accumulation. The activity of the alkamide to confer resistance against the necrotizing fungus Botrytis cinerea was tested by inoculating Arabidopsis detached leaves with conidiospores and evaluating disease symptoms and fungal proliferation. N-isobutyl decanamide application significantly reduced necrosis caused by the pathogen and inhibited fungal proliferation. Arabidopsis mutants jar1 and coi1 altered in JA signaling and a MAP kinase mutant (mpk6), unlike salicylic acid- (SA) related mutant eds16/sid2-1, were unable to defend from fungal attack even when N-isobutyl decanamide was supplied, indicating that alkamides could modulate some necrotrophic-associated defense responses through JA-dependent and MPK6-regulated signaling pathways. Our results suggest a role of alkamides in plant immunity induction

The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2'-deoxycytidine lesions

Decitabine (5-aza-2′-deoxycytidine, 5-azadC) is used in the treatment of Myelodysplatic syndrome (MDS) and Acute Myeloid Leukemia (AML). Its mechanism of action is thought to involve reactivation of genes implicated in differentiation and transformation, as well as induction of DNA damage by trapping DNA methyltranferases (DNMT) to DNA. We demonstrate for the first time that base excision repair (BER) recognizes 5-azadC-induced lesions in DNA and mediates repair. We find that BER (XRCC1) deficient cells are sensitive to 5-azadC and display an increased amount of DNA single- and double-strand breaks. The XRCC1 protein co-localizes with DNMT1 foci after 5-azadC treatment, suggesting a novel and specific role of XRCC1 in the repair of trapped DNMT1. 5-azadC-induced DNMT foci persist in XRCC1 defective cells, demonstrating a role for XRCC1 in repair of 5-azadC-induced DNA lesions. Poly (ADP-ribose) polymerase (PARP) inhibition prevents XRCC1 relocation to DNA damage sites, disrupts XRCC1–DNMT1 co-localization and thereby efficient BER. In a panel of AML cell lines, combining 5-azadC and Olaparib cause synthetic lethality. These data suggest that PARP inhibitors can be used in combination with 5-azadC to improve treatment of MDS and AML