QSAR models of human data can enrich or replace LLNA testing for human skin sensitization

An example of structural transformation of human skin sensitizers into various non-sensitizers based on interpretation of QSAR models

Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions

Doxorubicin (DOX) is an important tumor chemotherapeutic agent, acting mainly by genotoxic action. This work focus on cell processes that help cell survival, after DOX-induced DNA damage. in fact, cells deficient for XPA or DNA polymerase eta (pol eta, XPV) proteins (involved in distinct DNA repair pathways) are highly DOX-sensitive. Moreover, LY294002, an inhibitor of PIKK kinases, showed a synergistic killing effect in cells deficient in these proteins, with a strong induction of G2/M cell cycle arrest. Taken together, these results indicate that XPA and pol eta proteins participate in cell resistance to DOX-treatment, and kinase inhibitors can selectively enhance its killing effects, probably reducing the cell ability to recover from breaks induced in DNA. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)USP-COFECUB (São Paulo, Brazil)Univ São Paulo, Dept Microbiol, Inst Biomed Sci, São Paulo, BrazilUniv Paris Sud, Inst Gustave Roussy, Ctr Natl Rech Sci, UMR8200, Villejuif, FranceFed Univ São Paulo UNIFESP, Dept Biol Sci, Diadema, SP, BrazilUniv Fed Rio Grande do Sul, Ctr Biotechnol, Dept Biophys, Porto Alegre, RS, BrazilFed Univ Hlth Sci Porto Alegre UFCSPA, Dept Basic Hlth Sci, Porto Alegre, RS, BrazilFed Univ São Paulo UNIFESP, Dept Biol Sci, Diadema, SP, BrazilWeb of Scienc

Predicting chemically-induced skin reactions. Part I: QSAR models of skin sensitization and their application to identify potentially hazardous compounds

Repetitive exposure to a chemical agent can induce an immune reaction in inherently susceptible individuals that leads to skin sensitization. Although many chemicals have been reported as skin sensitizers, there have been very few rigorously validated QSAR models with defined applicability domains (AD) that were developed using a large group of chemically diverse compounds. In this study, we have aimed to compile, curate, and integrate the largest publicly available dataset related to chemically-induced skin sensitization, use this data to generate rigorously validated and QSAR models for skin sensitization, and employ these models as a virtual screening tool for identifying putative sensitizers among environmental chemicals. We followed best practices for model building and validation implemented with our predictive QSAR workflow using random forest modeling technique in combination with SiRMS and Dragon descriptors. The Correct Classification Rate (CCR) for QSAR models discriminating sensitizers from non-sensitizers were 71–88% when evaluated on several external validation sets, within a broad AD, with positive (for sensitizers) and negative (for non-sensitizers) predicted rates of 85% and 79% respectively. When compared to the skin sensitization module included in the OECD QSAR toolbox as well as to the skin sensitization model in publicly available VEGA software, our models showed a significantly higher prediction accuracy for the same sets of external compounds as evaluated by Positive Predicted Rate, Negative Predicted Rate, and CCR. These models were applied to identify putative chemical hazards in the ScoreCard database of possible skin or sense organ toxicants as primary candidates for experimental validation

Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization

Skin permeability is widely considered to be mechanistically implicated in chemically-induced skin sensitization. Although many chemicals have been identified as skin sensitizers, there have been very few reports analyzing the relationships between molecular structure and skin permeability of sensitizers and non-sensitizers. The goals of this study were to: (i) compile, curate, and integrate the largest publicly available dataset of chemicals studied for their skin permeability; (ii) develop and rigorously validate QSAR models to predict skin permeability; and (iii) explore the complex relationships between skin sensitization and skin permeability. Based on the largest publicly available dataset compiled in this study, we found no overall correlation between skin permeability and skin sensitization. In addition, cross-species correlation coefficient between human and rodent permeability data was found to be as low as R2=0.44. Human skin permeability models based on the random forest method have been developed and validated using OECD-compliant QSAR modeling workflow. Their external accuracy was high (Q2ext = 0.73 for 63% of external compounds inside the applicability domain). The extended analysis using both experimentally-measured and QSAR-imputed data still confirmed the absence of any overall concordance between skin permeability and skin sensitization. This observation suggests that chemical modifications that affect skin permeability should not be presumed a priori to modulate the sensitization potential of chemicals. The models reported herein as well as those developed in the companion paper on skin sensitization suggest that it may be possible to rationally design compounds with the desired high skin permeability but low sensitization potential

PLA films loaded with green tea and rosemary polyphenolic extracts as an active packaging for almond and beef

Funding Information: This paper was carried out under the MobFOOD Project ( POCI-01-0247-FEDER-024524 and LISBOA-01-0247-FEDER-024524 ), funded by POCI ( Operational Programme “Competitiveness and Internationalization ”) and POR Lisboa ( Lisbon Regional Operational Programme ), through ANI, and by the Programa de Cooperación Interreg V-A España–Portugal (POCTEP) 2014-2020 (project 0377_IBERPHENOL_6_E ). Cássia H. Barbosa is grateful for her Ph.D. Grant 2021.08154 . BD funded by Foundation for Science and Technology (FCT), Portugal. The authors also would like to thank Talho Girassol, LDA, for kindly supplying the beef meat samples and to Dr. Sidney Tomé for his contribute for the statistical analysis. Funding Information: This paper was carried out under the MobFOOD Project (POCI-01-0247-FEDER-024524 and LISBOA-01-0247-FEDER-024524), funded by POCI (Operational Programme “Competitiveness and Internationalization”) and POR Lisboa (Lisbon Regional Operational Programme), through ANI, and by the Programa de Cooperación Interreg V-A España–Portugal (POCTEP) 2014-2020 (project 0377_IBERPHENOL_6_E). Cássia H. Barbosa is grateful for her Ph.D. Grant 2021.08154. BD funded by Foundation for Science and Technology (FCT), Portugal. The authors also would like to thank Talho Girassol, LDA, for kindly supplying the beef meat samples and to Dr. Sidney Tomé for his contribute for the statistical analysis. Publisher Copyright: © 2023 The AuthorsIn the present study, RE presented higher antioxidant capacity and higher content of total phenolic compounds than GTE. While the main phenolic compounds identified in RE were carnosic acid, carnosol and rosmarinic acid, in GTE catechins, rutin and gallic acid were the main identifies compounds. Extracts were incorporated into PLA active films, followed by the evaluation of its properties. The potential of the active PLA films to extend foods shelf-life was tested in almonds and beef. PLA/4GTE presented the highest water vapor permeability and opacity, while PLA/4RE presented the highest O2 permeability. PLA/2 GTE and PLA/4GTE presented the highest total content in phenolic compounds at the end of 10 days (at 40 °C). Regarding the almond packaged with the active films, PLA with RE films were the most effective in the reduction of oxidation, allowing to obtain the lowest lipid oxidation products, at the end of 60 days of storage at room temperature. In addition, active PLA films inhibited the formation of MDA content in beef stored for 11 days. This study shows that these PLA active packages can contribute for delaying lipid oxidation in foodstuffs with high fat content.publishersversionpublishe

Alarms about structural alerts

Integrative approach for safety assessment of new chemicals by combining structural alerts and QSAR models

QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni.

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure-activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents

Stock de carbono en especies arbóreas del espinal entrerriano

El objetivo fue estimar el stock de carbono (C) en la biomasa arbórea de los bosques nativos del Espinal y valorar el servicio ecosistémico que prestan como secuestradores de C ante escenarios de cambio climático. El estudio se desarrolló en el área de bosques nativos de Entre Ríos. Se cuantificó la biomasa arbórea aérea y la fracción de C por componente (fuste, ramas ≥5cm de diámetro y <5cm) de las especies dominantes (Prosopis affinis, Vachellia caven y P.nigra). Se obtuvieron para cada especie, modelos alométricos de alta precisión y factores de expansión de la biomasa, que constituyen herramientas de utilidad para estimar el C almacenado en estos ecosistemas. Los bosques nativos del Espinal entrerriano almacenan en promedio en su biomasa arbórea aérea, un stock de 43,99±10,43 tC/ha, que representan 161,44 t CO2/ha capturados de la atmósfera. Se estimó una tasa promedio de captura y fijación de C de 0,75±0,17 tC/ha/año. Este valor indica que en promedio, 1 ha de bosque nativo secuestra 2,75 t CO2/año. La información generada permite valorar el servicio ambiental que brindan los bosques nativos del Espinal entrerriano como sumidero de C en un escenario de cambio climático, siendo prioritaria su protección contra la deforestación y degradación.Fil: Sione, Silvana Maria Jose. Provincia de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Universidad Autónoma de Entre Ríos. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones Científicas y Transferencia de Tecnología a la Producción; Argentina. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Ledesma, Silvia Gabriela. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias. Departamento de Ciencias de la Tierra; ArgentinaFil: Rosenberger, Leandro Javier. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Oszust, José Daniel. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias. Departamento de Ciencias de la Tierra; ArgentinaFil: Maciel, Gabriel Omar. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Wilson, Marcelo Germán. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Entre Ríos. Estación Experimental Agropecuaria Paraná; ArgentinaFil: Andrade Castañeda, H.. Universidad del Tolima; ColombiaFil: Sasal, Maria Carolina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Entre Ríos. Estación Experimental Agropecuaria Paraná; Argentin