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Recent Advances in Pharmaceutical Sciences VIII

This E-book is the eighth volume of a series that compiles contributions from different areas of the multidisciplinary field of Pharmaceutical Sciences. The E-book consists of 7 chapters that cover the areas of organic chemistry, health and environmental management, plant physiology, food science, toxicology, botany, parasitology, physiology, biochemistry and molecular biology, microbiology, and pharmacology

Assessment of Developmental Delay in the Zebrafish embryo Teratogenicity Assay

In this study we analyzed some aspects of the assessment of developmental delay in the zebrafish embryotoxicity/teratogenicity test and explored the suitability of acetylcholinesterase (AChE) activity as a biochemical marker and as a higher throughput alternative to morphological endpoints such as head-trunk angle, tail length and morphological score. Embryos were exposed from 4 to 52 h post-fertilization (hpf) to a selection of known embryotoxic/teratogen compounds (valproic acid, retinoic acid, caffeine, sodium salicylate, glucose, hydroxyurea, methoxyacetic acid, boric acid and paraoxon-methyl) over a concentration range. They were evaluated for AChE activity, head-trunk angle, tail length and several qualitative parameters integrated in a morphological score. In general, the different patterns of the concentration-response curves allowed distinguishing between chemicals that produced growth retardation (valproic and methoxyacetic acid) and chemicals that produced non-growth-delay related malformations. An acceptable correlation between the morphological score, AChE activity and head-trunk angle as markers of developmental delay was observed, being AChE activity particularly sensitive to detect delay in the absence of malformations

Evaluation of anti-inflammatory activity of food compounds using zebrafish

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/128014The principal aim of this work was to optimize and apply a zebrafish experimental model for the screening of anti-inflammatory substances present in the Mediterranean diet. The zebrafish is an organism widely used in various fields of experimental biology. The inflammation is easily inducible, reproducible and visualized in their early stages of development. Specifically, the migration of neutrophils to the injured caudal fin, one of the first steps of the inflammatory response, is quantitatively measured by image analysis. The anti-inflammatory effect of natural compounds can be evaluated as a decrease of migration. Adverse effects triggered by inflammation are mainly mediated by reactive oxygen species. The anti-oxidant activity of compounds was evaluated in zebrafish embryo measuring their protective effect against tert-butyl hydroperoxide toxicity. Several phenolic compounds have been assayed. Our results showed that the compounds with the greatest decrease on neutrophil migration were chlorogenic acid and cyanidin. The activity of these two polyphenols was quite similar to that observed with anti-inflammatory drugs (indomethacin, piroxicam) and NADPH oxidase inhibitor compounds (dibenzoidolium, apocynin). The anti-inflammatory and the anti-oxidant activity of the assayed polyphenols did not show a clear correlation

Zebrafish as a model for developmental toxicity assessment

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/67430The zebrafish embryo has emerged as promising alternative model for traditional in vivo developmental toxicological screening due to their advantageous characteristics as their small size and transparency. In this paper, we reviewed the applicability of the zebrafish embryo model in some relevant areas to human t oxicology as developmental toxicity, cardiovascular toxicity and neurotoxicity (behavioral assessment). Despite the promising results, further optimization and testing of more substances as well as a harmonized methodology is needed to streamline the metho ds and make the assay conducive to medium - throughput

Cardiovascular effects of PCB 126 (3,3',4,4',5-pentachlorobiphenyl) in zebrafish embryos and impact of co-exposure to redox modulating chemicals

The developing cardiovascular system of zebrafish is a sensitive target for many environmental pollutants, including dioxin-like compounds and pesticides. Some polychlorinated biphenyls (PCBs) can compromise the cardiovascular endothelial function by activating oxidative stress-sensitive signaling pathways. Therefore, we exposed zebrafish embryos to PCB126 or to several redox-modulating chemicals to study their ability to modulate the dysmorphogenesis produced by PCB126. PCB126 produced a concentration-dependent induction of pericardial edema and circulatory failure, and a concentration-dependent reduction of cardiac output and body length at 80 hours post fertilization (hpf). Among several modulators tested, the effects of PCB126 could be both positively and negatively modulated by different compounds; co-treatment with -tocopherol (vitamin E liposoluble) prevented the adverse effects of PCB126 in pericardial edema, whereas co-treatment with sodium nitroprusside (a vasodilator compound) significantly worsened PCB126 effects. Gene expression analysis showed an up-regulation of cyp1a, hsp70, and gstp1, indicative of PCB126 interaction with the aryl hydrocarbon receptor (AhR), while the transcription of antioxidant genes (sod1, sod2; cat and gpx1a) was not affected. Further studies are necessary to understand the role of oxidative stress in the developmental toxicity of low concentrations of PCB126 (25 nM). Our results give insights into the use of zebrafish embryos for exploring mechanisms underlying the oxidative potential of environmental pollutants

Modulation and Protection Effects of Antioxidant Compounds against Oxidant Induced Developmental Toxicity in Zebrafish

The antioxidant effect of compounds is regularly evaluated by in vitro assays that do not have the capability to predict in vivo protective activity or to determine their underlying mechanisms of action. The aim of this study was to develop an experimental system to evaluate the in vivo protective effects of different antioxidant compounds, based on the zebrafish embryo test. Zebrafish embryos were exposed to tert-butyl hydroperoxide (tBOOH), tetrachlorohydroquinone (TCHQ) and lipopolysaccharides from Escherichia coli (LPS), chemicals that are known inducers of oxidative stress in zebrafish. The developmental toxic effects (lethality or dysmorphogenesis) induced by these chemicals were modulated with n-acetyl l-cysteine and Nω-nitro l-arginine methyl ester hydrochloride, dimethyl maleate and dl-buthionine sulfoximine in order to validate the oxidant mechanism of oxidative stress inducers. The oxidant effects of tBOOH, TCHQ, and LPS were confirmed by the determination of significant differences in the comparison between the concentration-response curves of the oxidative stress inducers and of the modulators of antioxidant status. This concept was also applied to the study of the effects of well-known antioxidants, such as vitamin E, quercetin, and lipoic acid. Our results confirm the zebrafish model as an in vivo useful tool to test the protective effects of antioxidant compounds

Developmental effects and genotoxicity of ten water disinfection by-products in zebrafish

Disinfection by-products are contaminants produced during drinking water disinfection. Several DBPs have been implicated in a variety of toxic effects, mainly carcinogenic and genotoxic effects. Moreover, DBPs exposure has also been associated with an increased risk of developmental effects. In this study, the developmental toxicity and genotoxicity of 10 DBPs (4 trihalomethanes [THMs], 5 haloacetic acids [HAAs] and sodium bromate) in the zebrafish embryo model were evaluated. Embryos exposed for 72 hours were observed for different endpoints such as growth, hatching success, malformations and lethality. THMs exposure resulted in adverse developmental effects and a significant reduced tail length. Two HAAs, tribromoacetic acid and dichloroacetic acid, along with sodium bromate were found to cause a significant increase in malformation rate. Chloroform,chlorodibromomethane and sodium bromate produced a weak induction of DNA damage to whole embryos. However, developmental effects occurred at a range of concentrations (20 100 μg/mL)several orders of magnitude above the levels that can be attained in fetal blood in humans exposed to chlorinated water. In conclusion, the teratogenic and genotoxic activity observed by some DBPs in zebrafish reinforce the view that there is a weak capacity of disinfection products to cause developmental effects at environmentally relevant concentrations

La enseñanza de la Toxicología en Farmacia: los seminarios como herramienta para la evaluación continuada

Con la finalidad de adaptarnos al EEES, desarrollamos una herramienta que nos permitiera realizar un proceso de evaluación continua de la asignatura troncal de Toxicología. En el presente trabajo presentamos los resultados de este modelo en el que utilizamos los seminarios como elementos básicos de este proceso. Describimos cómo se estructuran y desarrollan estos seminarios, así como el modelo de evaluación de los mismos. Los seminarios fueron evaluados con una puntuación máxima del 30 % sobre la nota final de la signatura, y la participación en los mismos con un máximo del 10 %. Algunos de estos seminarios incorporaban evaluaciones realizadas antes del desarrollo de los mismos, que denominábamos «pre», y otras justo al final del desarrollo de los mismos, que denominábamos «post». Esta herramienta de evaluación continua se ha mostrado muy eficaz en lo que respecta al grado de participación y preparación de los alumnos. Además, ha supuesto un cambio significativo en el grado de implicación de los profesores, y una mejora de la comunicación alumno-profesor

Farmacología y toxicología en I+D+i: adquisición de competencias a través de un ejemplo de desarrollo de un fármaco

The implementation of the subject Pharmacology and Toxicology in R+D+i in the Pharmacy Degree, has led to the launch of a new methodological approach and teaching performance with the aim of developing the generic skills of the University of Barcelona (e.g., self-learning, team-working). An additional objective was students' integration of knowledge from different subjects in the degree which form the basis of the preclinical and clinical development of a drug. For this purpose, the teaching strategy used in the development of the subject was based on: 1) re-developing the content that students had been taught previously or were being taught in the same semester as a part of other subjects, and framing them in the environment of the pharmaceutical industry, 2) introducing new and previously unseen contents to do with drug development and toxicology, 3) developing a battery of activities to be undertaken by teams of students relating to the R+D+i of a particular drug. During the development of these activities, students have to acquire generic skills in addition to the subject-specific skills. The results obtained from the student survey give us grounds for satisfaction and allow us to consider that we have reached the goal of improving students' learning in Pharmacology and Toxicology applied to drug development in the pharmaceutical world today