Impact of CYP2C:TG Haplotype on CYP2C19 substrates clearance in vivo, protein content, and in vitro activity

A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.2:c.819+2182G (rs11188059), referred to as “CYP2C:TG,” was recently associated with ultrarapid metabolism of various CYP2C19 substrates. As the underlying mechanism and clinical relevance of this effect remain uncertain, we analyzed existing in vivo and in vitro data to determine the magnitude of the CYP2C:TG haplotype effect. We assessed variability in pharmacokinetics of CYP2C19 substrates, including citalopram, sertraline, voriconazole, omeprazole, pantoprazole, and rabeprazole in 222 healthy volunteers receiving one of these six drugs. We also determined its impact on CYP2C8, CYP2C9, CYP2C18, and CYP2C19 protein abundance in 135 human liver tissue samples, and on CYP2C18/CYP2C19 activity in vitro using N-desmethyl atomoxetine formation. No effects were observed according to CYP2C:TG haplotype or to CYP2C19*1+TG alleles (i.e., CYP2C19 alleles containing the CYP2C:TG haplotype). In contrast, CYP2C19 intermediate (e.g., CYP2C19*1/*2) and poor metabolizers (e.g., CYP2C19*2/*2) showed significantly higher exposure in vivo, lower CYP2C19 protein abundance in human liver microsomes, and lower activity in vitro compared with normal, rapid (i.e., CYP2C19*1/*17), and ultrarapid metabolizers (i.e., CYP2C19*17/*17). Moreover, a tendency toward lower exposure was observed in ultrarapid metabolizers compared with rapid metabolizers and normal metabolizers. Furthermore, when the CYP2C19*17 allele was present, CYP2C18 protein abundance was increased suggesting that genetic variation in CYP2C19 may be relevant to the overall metabolism of certain drugs by regulating not only its expression levels, but also those of CYP2C18. Considering all available data, we conclude that there is insufficient evidence supporting clinical CYP2C:TG testing to inform drug therapyP.S.-C. is financed by Universidad Autónoma de Madrid (FPIUAM, 2021). P.Z. is financed by Universidad Autónoma de Madrid, Margarita Salas contract, grants for the requalification of the Spanish university system. A.R.-L. and E.G.-I. contracts are financed by Programa Investigo (NextGenerationEU funds of the Recovery and Resilience Facility), fellowship numbers 2022-C23.I01.P03. S0020–0000031 and 09-PIN1-00015.6/2022. Human liver tissue samples were obtained through the Liver Tissue Cell Distribution System, Minneapolis, MN, and Pittsburgh, PA, which was funded by NIH Contract #HHSN276201200017C. The proteomics part of the work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) Grant R01.HD08129

Factors associated with the intention to participate in COVID-19 vaccine clinical trials: A cross-sectional study in Peru

Objective: To evaluate the factors associated with the intention to participate in COVID-19 vaccine clinical trials in the Peruvian population. Methods: Cross-sectional study and secondary analysis of a database that involved Peruvian population during September 2020. The Poisson regression model was used to estimate the associated factors. Results: Data from 3231 individuals were analyzed, 44.1% of whom intended to participate in COVID-19 vaccine clinical trials. Factors associated with the outcome were being male (RPa: 1.25; 95% CI: 1.15–1.35), being from the highlands region (RPa: 1.18; 95% CI: 1.09–1.28) or jungle (RPa: 1.30; 95% CI: 1.15–1.47), having a relative that is a healthcare professional (PRa: 1.16; 95% CI: 1.06–1.28), using a medical source of information (PRa: 1.28; 95% CI: 1.17–1.41), and trusting in the possible effectiveness of vaccines (PRa: 1.40; 95% CI: 1.29–1.51). The main reason for not participating in the trial was the possibility of developing side effects (69.80%). Conclusion: There is an urgent need to generate a perception of safety in COVID-19 vaccine clinical trials, to increase the population's intention to participate in these studies, and to provide evidence-based information about the vaccine.Revisión por pare

Multi-omics profiling of mouse gastrulation at single-cell resolution.

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan and is associated with major transcriptional changes1-5. Global epigenetic reprogramming accompanies these changes6-8, but the role of the epigenome in regulating early cell-fate choice remains unresolved, and the coordination between different molecular layers is unclear. Here we describe a single-cell multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and a concomitant increase of accessibility. By contrast, the methylation and accessibility landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or remodelled before cell-fate decisions, providing the molecular framework for a hierarchical emergence of the primary germ layers.CRUK, Wellcome Trust, MRC, BBSRC, EMBL, E

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model.

Abstract Background Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored. Methods Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density. Results Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density. Conclusions Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density

Detección de problemas asociados a la calidad: frutas y hortalizas

El presente documento de la RED TEMÁTICA FRUTURA de CYTED recoge las aportaciones de sus miembros al denominado 1er evento, celebrado en Sao Paulo en septiembre de 2009. El título asignado a dicho primer evento o reunión de los participantes, contiene el tema asignado a la Red Temática, es decir Desarrollo de un sistema integral de la mejora de la calidad y seguridad de las frutas durante la confección, el transporte y la comercialización mediante nuevas tecnologías de inspección y monitorización, y se refiere al análisis de temas actuales respecto de la Detección y caracterización de problemas asociados a la calidad: Los problemas y desafíos asociados con el transporte de fruta fresca para cada país participante, con especial atención a los países tropicales. Bajo este título se organizan unas sesiones técnicas, y visitas y presentaciones técnicas en instituciones de Sao Paulo y el EMBRAPA, que son las siguientes: Visita técnica a la Unidad de Instrumentación Agropecuaria en São Carlos/SP , sita a 300 km de São Paulo), y la visita técnica a la Central de Abastecimiento del Estado de São Paulo - CEAGESP/SP. Las contribuciones aquí recogidas se completaron con los puntos de vista expresados por la industria, en un coloquio de empresas, presidido por el Dr. Fernando Flores, con la participación de industriales, que abordaron sus puntos de vista sobre el tema: Los problemas del transporte de frutas y hortalizas, desde el punto de vista de la industria. De ellas se extrajo algunas conclusiones para tener en cuenta en las siguientes reuniones. La principal de ellas, fue que es fundamental a la hora de aconsejar mejoras en el transporte internacional de frutas contar con dicho punto de vista, lo que se tendrá en cuenta en los eventos siguientes de FRUTURA . Asociando países y contribuciones, se identificaron y describieron varios condicionamientos y problemas que aparecen durante el transporte de productos perecederos, en especial de frutas durante su transporte, y que se asocian a pérdidas de calidad: • Evaluar la problemática del transporte de frutas y hortalizas a mercados ubicados a gran distancia supone entender la fisiología del producto y conocer los cambios que puede sufrir durante la conservación y el transporte. Las pérdidas en el transporte de frutas se basan en condiciones ambientales no apropiadas a las que el producto se ve expuesto, tanto en transporte terrestre como en el aéreo, y se relaciona con instalaciones y equipos de frío\ud insuficientes, e insuficientemente controlados. • La reglamentación de cada uno de los países receptores de fruta y hortalizas frescas afecta enormemente a los intercambios comerciales, y es un aspecto que debe ser estudiado especialmente, y a nivel internacional. Existen por ejemplo regulaciones cuarentenarias frente a plagas que requieren tratamientos específicos con altas exigencias tecnológicas. • Teniendo en cuenta que las condiciones óptimas, en especial de temperatura, son diferentes para cada producto. los amplísimos conocimientos y datos existentes a este respecto han de ser analizados y aplicados apropiadamente en los procesos de transporte. • Se establece el alto potencial de nuevas tecnologías como las RFID (Identificación por Radio Frecuencia) y WSN (Redes inalámbricas de Sensores) que hacen posible la supervisión/monitorización y el control de las condiciones del ambiente y del producto en el interior de contenedores de transporte. • El diseño y uso de envases adecuados al producto, el tipo de transporte, paletización, condiciones de frío y las especies frutícolas debe ser analizado cuidadosamente para grandes distancias. Por otro lado, aumenta de demanda de productos fáciles de preparar, siendo las frutas como manzana, pera y durazno mínimamente procesadas en fresco (MPF) una nueva alternativa para los consumidores. Sin embargo estas frutas MPF presentan una serie de daños durante su procesamiento que reducen su vida útil durante su transporte y comercialización, por lo que presentan exigencias especiales en su envasado, comercialización y almacenaje. • Se añade a la variabilidad y falta de calidad de las frutas en el mercado, las deficiencias en las fechas y condiciones de cosecha, de envasado, de tratamiento y de manejo en origen, y a lo largo de la cadena de distribución. • Debe asumirse en varios países y zonas productivas una falta de conocimientos de los productores, transportistas e intermediarios en la distribución. (Es un objetivo iniciar acciones de formación en este sentido, a través de FRUTURA). • Los problemas en las infraestructuras, se centran en varios aspectos de gran relevancia y en todo caso requieren ser optimizados si se persigue calidad y reducción de pérdidas: situación de las fincas, caminos, distancias, carreteras, puertos, aeropuertos, equipos de transporte (camiones, contenedores). Las capacidades y características de los centros de distribución, tales como los visitados CEAGESP de Sao Paulo y MERCAMADRID que representan un factor de enorme influencia en la comercialización de calidad, procesos y productos. Los artículos, al ser contribuciones de los miembros de los distintos países asociados a FRUTURA aportan datos, de la producción frutícola y de su transporte, específicos para algunos de los países participantes en el proyecto: Uruguay, Argentina, Brasil, Costa Rica y España. Los trabajos aquí recogidos se completan con las presentaciones expuestas en la reunión, y que se encuentran accesibles en la página web de FRUTURA: www.frutura.net. Finalmente, otra contribución relevante de estos trabajos es sus listados de bibliografía, los cuales ofrecen una información de gran valor dentro de los objetivos de FRUTURA

From ancient herbs to modern drugs : In search of alternatives for cancer therapy

Breast cancer is the major cause of deaths related to cancer for women worldwide. Although much is known about this malignancy, extensive research is still needed to gain complete understanding of the complexity of the disease. The inter and intra tumor heterogeneity is an important trait of breast cancer. The intratumor heterogeneity is reflected in sub-populations of cancer cells that appear to have different levels of aggressiveness. The most aggressive population termed the cancer stem cell (CSC) population is believed to play a critical role in cancer recurrence and resistance to conventional chemotherapy and CSCs seem to be the responsible for relapse and cancer death. Sesquiterpene lactones (SLs) and methoxyflavones, plant-derived molecules usually found in Asteraceae family plant extracts, have been reported to have anti-inflammatory and anti-cancer activities. This thesis describes the biological activity of natural and synthetized SLs and natural flavones on CSCs and non-CSCs in breast cancer cell lines.Damsin is a natural SL and it was used for the chemical synthesis of damsin derivatives. Here the toxicity of damsin and the damsin derivatives have been investigated in three breast cancer cell lines and one normal-like cell line. In all, 46 compounds were evaluated in dose-response testing to obtain IC50 values that were used to deduce structure activity relationships. Selected SLs were studied further to gain insight into cellular and molecular mechanisms. The studied SLs inhibited cell proliferation and cell migration and remarkably also reduced the CSC population of a breast cancer cell line. The damsin derivatives were more toxic to cancer cells than to normal cells. On the molecular level, the results point to interference of the function of the transcription factor NF-κΒ, being the molecular initiating event. SLs are known to bind to a cysteine in the DNA binding site of NF-κΒ. Our data implicate that it is not only DNA binding of NF-κΒ that is prevented by SL treatment but also the binding of other proteins that have a role in the function of NF-κΒ. The toxicity of three natural methoxyflavones was evaluated revealing that small differences in chemical structure can have a large impact on toxicity. Only one of the methoxyflavones showed anti-proliferative activity in breast cancer cell lines which may be caused by the induction of DNA strand breaks. In contrast to the SLs, treatment with the methoxyflavones did not reduce the CSC population

Enfermedades presentes en la alimentación casera y procesada en perros

Objective: To analyze the relationship between different types of canine pet food and degenerative diseases. Method: systematic reviews. Result and conclusion: The birth of gastrointestinal food allergies is a key warning property to verify any possible cause of this infectious agent. The consequences of inadequate nutrition on animal health are frequent, in several investigations Veterinarians recommend implementing healthy habits to improve and control the health of their pets.Objetivo: analizar la relación entre los diferentes tipos de alimentos para mascotas caninas y las enfermedades degenerativas. Método: Revisiones sistemáticas. Resultado y conclusión: El nacimiento de alergias alimentarias gastrointestinales es una propiedad clave de advertencia para verificar toda posible causa de este agente infeccioso. Las consecuencias de una inadecuada alimentación en la salud animal son frecuentes, en varias investigaciones Veterinarios recomiendan implementar hábitos saludables para mejorar y poder controlar la salud de sus mascotas

Gastroprotective effect of the etanolic extract of dry leaves of dracontium loretense “jergon sacha”in albinas rats hotlzman strain

El estudio tuvo como objetivo evaluar el efecto gastroprotector del extracto etanólico de las hojas de Dracontium loretense “Jergón sacha” en ratas albinas en las dosis de 250, 500 y 1000. Los resultados demostraron efecto gastroprotector en dosis de 500 y 1000 mg/kg del peso corporal, estadísticamente significativas en comparación a los resultados obtenidos con el omeprazol. Para concluir se evidenció que el extracto etanólico de las hojas de Dracontium loretense “Jergón sacha”, presentó efecto gastroprotector en 79.45% Y 87.50% respectivamente, como porcentaje de inhibición ante el daño ulcerativo producidoThe objective of the study was to evaluate the gastroprotective effect of the ethanolic extract of the leaves of Dracontium loretense "Jergón sacha" in albino rats at doses of 250, 500 and 1000. The results showed a gastroprotective effect at doses of 500 and 1000 mg/kg of body weight, statistically significant in comparison to the results obtained with omeprazole. To conclude, it was evidenced that the ethanolic extract of the leaves of Dracontium loretense "Jergón sacha", presented gastroprotective effect in 79.45% and 87.50% respectively, as a percentage of inhibition against the ulcerative damage produced by the ulce

Gastroprotective effect of the etanolic extract of dry leaves of dracontium loretense “jergon sacha”in albinas rats hotlzman strain

El estudio tuvo como objetivo evaluar el efecto gastroprotector del extracto etanólico de las hojas de Dracontium loretense “Jergón sacha” en ratas albinas en las dosis de 250, 500 y 1000. Los resultados demostraron efecto gastroprotector en dosis de 500 y 1000 mg/kg del peso corporal, estadísticamente significativas en comparación a los resultados obtenidos con el omeprazol. Para concluir se evidenció que el extracto etanólico de las hojas de Dracontium loretense “Jergón sacha”, presentó efecto gastroprotector en 79.45% Y 87.50% respectivamente, como porcentaje de inhibición ante el daño ulcerativo producidoThe objective of the study was to evaluate the gastroprotective effect of the ethanolic extract of the leaves of Dracontium loretense "Jergón sacha" in albino rats at doses of 250, 500 and 1000. The results showed a gastroprotective effect at doses of 500 and 1000 mg/kg of body weight, statistically significant in comparison to the results obtained with omeprazole. To conclude, it was evidenced that the ethanolic extract of the leaves of Dracontium loretense "Jergón sacha", presented gastroprotective effect in 79.45% and 87.50% respectively, as a percentage of inhibition against the ulcerative damage produced by the ulce