Дисертації з теми "Modèle intestinal in vitro"
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Ponce, de Leon Rodriguez Maria del Carmen. "Développement d’un modèle in vitro d’inflammation intestinale par l’utilisation de lignées cellulaires humaines en co-culture pour l’étude des interactionsavec les micro-constituants alimentaires." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTG009/document.
The intestinal epithelium, main place of the absorption of (micro)-nutrients is also the first body's defense system. An imbalance in homeostasis can lead to an inflammatory reaction associated with defects in the intestinal barrier and immune function as well as malabsorption of nutrients, as seen in IBD (Inflammatory Bowel Diseases), in micronutrient fortification strategies and noncommunicable diseases (obesity). It is therefore important to find ways of action, for example through diet, to prevent or at least reduce the nutritional and pathological consequences of intestinal inflammation, and to understand the mechanisms involved. Among intestinal models, in vitro cell culture models are increasingly used and allow to evaluate the molecular mechanisms in a simple and reproducible way and to reduce animal experimentation.In this context and in order to study the interaction of dietary bioactive compounds with the intestine in state of inflammation, the first objective of this work was the development of an in vitro model of inflamed intestine combining in co-culture two human intestinal cell lines: Caco-2 TC7 (enterocytes) and HT29-MTX (goblet cells) and an immune cell line of macrophages (THP1). Several inflammation markers were evaluated and we were able to show that the tri-culture model responded to an inflammatory stimulus (LPS / IFNγ), by increasing the production of pro-inflammatory cytokines (TNF-α, IL6 and IL8) and enzymes (INOS and COX2) as well as the expression of their genes. In addition, an increase of epithelial permeability via tight junctions (TJs) alteration has also been demonstrated, as well as overproduction of mucus, which are recognized inflammation characteristics.The second objective was to study the interaction of β-cryptoxanthin (BCX), a lipophilic and antioxidant carotenoid of citrus, with the inflamed model. To solubilize BCX, we used two types of micelles (artificial and physiological) and studied markers of inflammation. Although it appears from the preliminary results that BCX micelles show a tendency to decrease the production of some cytokines (IL6 and IL8), the role of micelle constituents (Tween 40 or bile salts / phospholipids) in the phenomenon observed and in the epithelial permeability remains to be therefore clarified
Roy, Isabelle. "Contribution à la mise en place d'un modèle "in vitro" prédictif de l'absorption et du métabolisme intestinal." Paris 5, 1994. http://www.theses.fr/1994PA05P159.
Fleury, Mickaël. "Impact de traitements antibiotiques sur la flore digestive du porcelet : Etude in vivo et développement d'une approche en système de fermentation in vitro." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1B002/document.
In the context of antibiotic resistance, the aim of the current PhD work is to assess the impact of antibiotics on intestinal microbiota of piglets. Two antibiotics i.e. colistin and ceftiofur, for which the main resistances include respectively chromosomal mutations and plasmid genes have been used. Colistin significantly reduced the population of Enterobacteriaceae, but there was no selection of resistant E. coli. The administration of ceftiofur had a limited impact on the bacterial populations that make up the digestive ecosystem but it led to strong selection and dissemination of a plasmid gene encoding an extended-spectrum beta-lactamase. Then, in the framework of regulations to reduce animal testing, an in vitro model of colonic pig named PigutIVM was developed in order to simulate the digestive environment of the piglet and then check the effect of colistin on the microbiota simulated in PigutIVM in vitro. Therefore both the approaches i.e. in vivo and in vitro were compared in order to check the effect of colistin on intestinal microbiota of piglets. This tool was then used to evaluate the impact of a probiotic i.e. Saccharomyces cerevisiae, as alternative to antibiotics. Therefore we assume that this PigutIVM model should be positioned as a relevant predictive tool in the fields of nutritional and pharmacological investigations
Altay, Gizem. "Towards the development of biomimetic in vitro models of intestinal epithelium derived from intestinal organoids." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664864.
El epitelio intestinal es un tejido altamente especializado, organizado en unidades de criptas y vellosidades que son relevantes para sus eficaces funciones de barrera y absorción de nutrientes. En las unidades de criptas residen las células madre intestinales (ISC) proliferativas que se dividen y diferencian mientras migran a lo largo de las vellosidades, las cuales generan el epitelio maduro. En el epitelio maduro, las ISC y las células proliferativas se localizan en las criptas y las células absorbentes y secretoras diferenciadas en las vellosidades. La proliferación, migración y diferenciación de las ISC se rigen por los gradientes químicos espaciales altamente controlados de los factores de nicho de la ISC; Moduladores de la vía de bone morphogenic protein (BMP), wingless/Int (Wnt) y epidermal growth factor (EGF). El modelado experimental de la biología y la fisiología del epitelio intestinal está limitado debido a la falta de plataformas in vitro que recapitulan estos aspectos clave del epitelio del intestino delgado: sus distintas poblaciones celulares, la arquitectura 3D y los gradientes de factores bioquímicos de nicho ISC a lo largo del eje cripta-vellosidad. Aquí, describimos el desarrollo de modelos in vitro de epitelio intestinal obtenidos de criptas derivadas de organoides intestinales. En primer lugar, presentamos un método para obtener monocapas epiteliales intestinales 2D con lumen accesible y función de barrera fisiológica. A continuación, describimos el desarrollo de andamios biomiméticos 3D similares a vellosidades en hidrogeles de diacrilato de polietilenglicol (PEGDA) utilizando un enfoque fotolitográfico simple y rentable. Demostramos que nuestra plataforma de vellosidades sintéticas apoya la formación de monocapas epiteliales de células epiteliales intestinales derivadas de organoides. Finalmente, describimos métodos para crear gradientes espaciotemporales de factores nicho bioquímicos ISC en hidrogeles 3D similares a vellosidades y demostramos que estos gradientes se pueden usar para compartimentar las células epiteliales diferenciadas. La plataforma 3D que recrea las vellosidades intestinalesmejora los modelos actuales al proporcionar a las células las señales topográficas y mecánicas y los gradientes bioquímicos fisiológicamente representativos. Debido a su utilidad, esta plataforma puede encontrar innumerables aplicaciones. Puede ser utilizada para la comprensión de la biología básica del epitelio intestinal. Además, se puede utilizar para cultivar células madre intestinales humanas que permitan la detección de nuevas terapias y el modelado de enfermedades.
Gérémie, Lauriane. "Development of an in-vitro intestinal model featuring peristaltic motion." Thesis, Sorbonne université, 2019. http://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS118.pdf.
My PhD work is part of the organ-on-chip field, and more precisely part of the gut-on-chip field. It is in line with the main objective of this field, which is the development of in-vitro models recapitulating as faithfully as possible the intestinal micro-environment. Through my PhD work I first developed a versatile gut-on-chip platform recapitulating the intestinal 3D architecture as well as its dynamic micro-environment. Therefore, this platform allows us to study the influence of the intestinal dynamic, especially the peristalsis, on cellular behavior in function of the 3D architecture of the scaffold. For this study Caco2 cells have been seeded either on a 2D or a 3D scaffold coated with laminin and submitted to a cyclic stretching (at 0.2 Hz and 10%) for 2, 5, 8, 16, 24 and 48 hours. Our main observation was the cellular reorientation induced by the stretching, therefore we characterized the cell behavior in function of the coating condition, the initial confluency, the stretching time and the scaffold geometry. Interestingly, the strongest cellular response was obtained when the 3D geometry and the stretching was combined illustrating the need of these two stimuli to better mimic the intestinal in vivo conditions
Garcia, Rodriguez Alba. "The applicability of in vitro models of the intestinal barrier for the risk assessment of engineered nanomaterials used as food additives." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/669883.
Nano-technological approaches are allowing the development of deliberately engineered nanomaterials (ENMs), presenting promising new applications for many industrial fields. Especially, ENMs possess unique properties and novel uses in food or food packaging materials such as the enhancement of texture, colour, flavour, nutrient stability and food packaging safety. Despite their innovative properties, there is an increasing concern about the possibility that human exposure to TiO2NPs may lead to significant adverse health effects. The International Agency for Research on Cancer (IARC) classified TiO2 as a human carcinogen group 2B because there was enough evidence that nano-TiO2 may cause lung cancer by inhalation. Although oral exposure was also debated by IARC, the final report was inconclusive due to non-existing standardized procedures for nano- TiO2 risk assessment. Due to the potential adverse effects of this ENMs and the lack of information regarding toxicological aspects over the oral exposure, in this Thesis we have carried out in vitro studies on the biological effects of TiO2NPs. For the aforementioned purpose, we set up and characterized, for the first time in our laboratory, an epithelial in vitro model that closely mimics the human small intestine. Thus, in our first study, we defined the best culture conditions for the alreadydescribed model, Caco-2/HT29/Raji-B. From our integrity and permeability findings, we confirmed that the best Caco-2/HT29 cell ratio is 90:10, respectively, as TEER values, paracellular LY permeability and the mucus shed formed correlated well with other studies. We also were able to detect the induction of M-like cells by TEM. Moreover, in order to monitor the proper barrier formation, we proposed a set of genes related to the cell junctional complexes, brush border enzymes, mucus shed components and M-cell markers. Finally, we tested the goodness of our epithelial in vitro model by exposing it to both TiO2NPs and SiO2NPs for 24 h. Our confocal results evidenced the potential adverse effects of TiO2NPs and SiO2NPs on the intestinal epithelium, as NPs internalization and NPs-cell nucleus interaction were observed. Because of the heightened interest in the identification, validation and standardization of the effects associated to exposures to new ENMs, our second study aimed to assess the effects of three different shapes of TiO2NPs (spheres, rods and wires) on the Caco-2/HT29 barrier. Our results demonstrated that the three types of TiO2NPs have the ability to impair the membrane’s integrity, translocate through the mucus shed and internalize in the cells, reaching the nucleus. Taking into account our confocal images results, we hypothesize that due to their shapes, nano-wires are more likely to cross paracellularly, while nano-spheres and nano-rods used intracellular passage to cross the intestinal epithelium. Despite previous evidence that relate the capability of TiO2NPs to produce ROS, we have not detected oxidatively DNA damage. However, and in accordance with the confocal images showing a great amount of NPscell nucleus events, we detected a slight but significant general DNA damage in the barrier’s cells. Finally, the third study was performed under the framework of an international mention carried out in the Biomedical Engineering Department at the Binghamton University (Binghamton, NY, USA). Nutrient absorption is one of the main and most important functions of the small intestine. Thus, to understand and evaluate whether ENPs can trigger physiological potential pathologies, the activity of the intestinal alkaline phosphatase (IAP), aminopeptidase-N (APN) and Na+/K+ ATPase enzymes were measured after exposing the Caco-2/HT29-MTX barrier to TiO2NPs and SiO2NPs for 4 h. Moreover, and in order to further mimic the physiological conditions of a real digestion, the Caco-2/HT29-MTX barrier was exposed to both NPs previously digested and co-cultured with both Escherichia coli and Lactobacillus rhamnosus, as examples of commensal microbiota.
SUNDARAM, TAMIL SELVI. "ESTABLISHING IN VITRO INTESTINAL EPITHELIAL CELL MODELS IN TRANSLATIONAL ANIMAL NUTRITION." Doctoral thesis, Università degli Studi di Milano, 2022. https://hdl.handle.net/2434/944348.
Kratz, Jadel Müller. "Implementação e aplicação do modelo in vitro com células Caco-2 para estudo da permeabilidade intestinal de fármacos." Florianópolis, SC, 2011. http://repositorio.ufsc.br/xmlui/handle/123456789/95611.
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A absorção oral de um fármaco é controlada fundamentalmente por dois fatores: a solubilidade aquosa/dissolução e a permeabilidade intestinal. Portanto, a determinação dessas características ainda nas fases de descoberta e desenvolvimento de fármacos pode prover moléculas com ótimo perfil biofarmacêutico. Nesse sentido, esta tese teve dois objetivos: implementar e validar o modelo de avaliação da permeabilidade in vitro com células Caco-2 no Laboratório de Virologia Aplicada da UFSC, e aplicar esse modelo na determinação da permeabilidade de fármacos e compostos em estudo. Na implementação do modelo Caco-2 foi demonstrada a adequação morfológica das células, através do monitoramento da resistência elétrica transepitelial e da permeabilidade do Lucifer yellow. Através da avaliação da permeabilidade de fármacos marcadores (aciclovir, carbamazepina, hidroclorotiazida, propranolol, vimblastina e verapamil) em experimentos de transporte bi-direcional foi demonstrado que o modelo foi devidamente validado, já que foi estabelecida correlação entre a permeabilidade in vitro e a absorção em humanos. Adicionalmente, uma metodologia por CLAE-UV foi desenvolvida e validada para a determinação concomitante de todos esses fármacos marcadores. Na segunda etapa, avaliou-se o complexo talidomida:hidroxipropil-?-ciclodextrina, desenvolvido e caracterizado no estado sólido por diferentes técnicas, que comprovaram a complexação do fármaco e a redução da sua cristalinidade. Essas alterações culminaram em um leve aumento da solubilidade aparente do fármaco, bem como propiciaram um perfil de dissolução superior, quando comparado ao da talidomida isolada. No entanto, nenhuma alteração na permeabilidade foi detectada. Esses resultados sugerem que esta complexação poderia aumentar a biodisponibilidade oral da talidomida, através do aumento da sua solubilidade nos fluídos gastrointestinais, bem como facilitando a sua dissolução a partir de uma forma farmacêutica sólida. Também foi avaliado o composto anti-herpético galato de pentila, e foi demonstrado que ele apresenta perfis de permeabilidade intestinal e cutânea favoráveis para sua absorção oral e permeação tópica, respectivamente. Assim, após administração oral, sua biodisponibilidade não seria limitada pela permeabilidade intestinal, e no que se refere à administração tópica, ele ficaria restrito às camadas da pele no local de aplicação. Esses dados fornecem informações valiosas para o desenvolvimento de formas farmacêuticas e para a avaliação da atividade antiviral in vivo. Em suma, o modelo com células Caco-2 foi implementado, validado e aplicado satisfatoriamente, o que permitirá a execução de estudos colaborativos, sobretudo com o enfoque do Sistema de Classificação Biofarmacêutica.
Langan, Laura. "Fish intestinal cultures for ecotoxicological studies : in vitro and primary culture models." Thesis, University of Plymouth, 2017. http://hdl.handle.net/10026.1/9486.
Deschamps, Charlotte. "Impact du poids corporel et d'une perturbation antibiotique sur le microbiote intestinal du chien : simulation in vitro et stratégies de restauration." Electronic Thesis or Diss., Université Clermont Auvergne (2021-...), 2023. http://www.theses.fr/2023UCFA0055.
Different dog sizes are associated with variations in digestive physiology, mainly related to the large intestine and its resident microorganisms. This gut microbiota plays a key role in animal health, supporting nutritional, immunological and physiological processes. Nevertheless, diseases or antibiotherapy can disturb microbial equilibrium and induce a perturbated state called dysbiosis. To restore microbiota eubiosis, new restorations strategies have been developed such as pre-, pro- or postbiotics. However, very few studies have evaluated their effects on gut microbiota in the context of antibiotherapy. This joint PhD between the Microbiology, Digestive Environment and Health unit from Université Clermont Auvergne and the two compagnies Lallemand Animal Nutrition and Dômes Pharma, aimed to investigate the impact of body weight and antibiotic disturbance on canine colonic microbiota, as well as the potential of microbial restoration strategies, using in vitro gut models.This thesis started by evaluating the impact of different methods for faecal sample storage (48-h freezing -80°C, 48-h -80°C with glycerol or lyophilization with maltodextrin/trehalose) on the kinetics of microbiota colonization and metabolic activities in the Mucosal Artificial Colon (M-ARCOL). Compared to fresh stools, inoculating with raw frozen stool without cryoprotectant was the best option among those tested. Second, thanks to a large literature review, the M-ARCOL model was adapted to reproduce the main nutritional, physicochemical and microbial parameters specific from small, medium and large size conditions in a new model called Canine M-ARCOL (CANIM-ARCOL), further validated through in vitro-in vivo comparisons. This adaptation allowed to reproduce in vitro the increase in Bacteroidota and Firmicutes abundances and higher main short-chain fatty acid (SCFA) concentrations observed in vivo. Then, we used the CANIM-ARCOL to perform a mechanistic study, which revealed that nutritional and physicochemical parameters are enough to shape microbiota activity according to dog size, but faecal inoculum was necessary to reproduce size-related microbiota composition. The next step was to adapt the CANIM-ARCOL to diseased situation, focusing on antibiotic-induced dysbiosis. In accordance with in vivo data, antibiotherapy induced an increase in Enterobacteriaceae, Streptococcaceae and Lactobacillaceae relative abundances while alpha-diversity and SCFA production decreased. Similar but lower effects were observed in mucus-associated microbiota. Lastly, we evaluated the effect of the live probiotic yeast Saccharomyces boulardii CNCM I-1079 and the heat-inactivated bacteria Lactobacillus helveticus HA-122 on microbiota resistance during antibiotic treatment and resilience afterwards. Of interest, both microbial strategies decreased the Enterobacteriaceae bloom during antibiotherapy and allowed, in the first two days, a quicker recovery of microbiota composition and activity, in both the luminal and mucosal compartments.This PhD work provided pioneering and significant insights into the impact of dog size and antibiotherapy on canine colonic luminal and mucus-associated microbiota composition and activity, filling gaps in knowledge in these fields. This work also contributed to a better understanding of microbiota resilience in response to antibiotic disturbance. In a near future, in accordance with the European 3R's rules aiming to reduce at a maximum animal experiments, our in vitro approaches could be used for mechanistic studies on the interactions between nutrients, feed additives or veterinary products and canine colonic microbiota. Such experiments could be performed under healthy but also disturbed gut microbial situations (including obesity, inflammatory bowel diseases or chronic enteropathies), always considering interindividual variabilities to move towards personalized nutrition and medicine
Dorier, Marie. "Impact du colorant alimentaire E171 et de nanoparticules de dioxyde de titane sur des modèles cellulaires, in vitro, d'épithélium intestinal." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV082/document.
Micro-sized titanium dioxide (TiO2) particles are used for years by industrials for their attractive physical and chemical properties. The use of TiO2 nanoparticles (NPs) is also constantly increasing, because the nanometric size gives new interesting properties to particles which industrials are looking for. In some daily-life products including paints, plastics, paper, medicines and food, micro-sized TiO2 particles are used as a pigment for their opacifying and whitening capacities. The use of TiO2 as a food additive, i.e. E171 in the EU, has been authorized in most countries since the 60ies, without any established acceptable daily intake, because of their low toxicity and intestinal absorption. However, it was recently shown that E171 can contain up to 43% of particles with diameter ranging from 1 to 100 nm, i.e. NPs. Still, E171 is not a nanomaterial as described in the European recommendation of definition because it contains less than 50% of NPs (in number). Food grade TiO2 is present in a wide range of food products while little is known about its toxicological impact to human health. The toxicity of ingested TiO2, either nano- or micro-sized, is increasingly documented, still E171 itself is rarely used in these studies.According to in vivo and in vitro studies, TiO2 particles were proven relatively safe for intestinal cells, no cytotoxicity neither genotoxicity were reported. Nevertheless, particles were often reported to increase reactive oxygen species (ROS) cell content, to impair autophagic processes and modulate gene expression and the content of proteins involved in oxidative stress, endoplasmic reticulum stress and inflammatory response regulation. Interestingly, their reported impact on intestinal cells suggests alteration of almost all the components of the intestinal barrier function, i.e. microbiota, mucus, cell junctions and transporters. This intestinal barrier function is altered in patients suffering from intestinal bowel diseases, these persons are thus possibly more sensitive to mineral particulate in food.The present study aimed at improving knowledge on the toxicity of food-grade TiO2. To this purpose, the impact of E171 was evaluated on in vitro cell models representative of the human intestinal epithelium, i.e. a model of differentiated Caco-2 enterocytes, a model of mucus-secreting epithelium obtained by coculture of Caco-2 and HT29-MTX mucus-secreting cells and a model of the follicle-associated epithelium, which lines Peyer patches, obtained by coculture of Caco-2(C1) and RajiB cells. These cell models were either acutely exposed for 6 h, 24 h and 48 h or chronically exposed for 21 days to E171. In parallel, they were exposed to two model TiO2-NPs, A12 which has the same crystalline structure as E171 and P25, a well-documented TiO2-NPs. Our results show that E171 and TiO2-NPs induced no overt cell mortality but significant oxidative stress, and that they oxidatively damage DNA. They modulate the expression of genes involved in oxidative stress and endoplasmic reticulum stress regulation. They also modulate the expression of genes, as well as the content of proteins from mucus, ABC transporters and inflammatory markers, which are the main players of the intestinal barrier function and presumably increase epithelium sensitivity to xenobiotics. These data suggest that they may be implicated in the development or aggravation of inflammatory bowel diseases
Cinquin, Cécile Françoise. "Développement et validation d'un nouveau modèle de fermentation colique in vitro avec cellules immobilisées." Thesis, Université Laval, 2005. http://www.theses.ulaval.ca/2005/22769/22769.pdf.
The intestinal microbiota is a complex ecosystem playing a key role in human health. The intestinal microbiota establishment occurred during the first year of life. To stimulate bifidobacteria and lactobacilli in formula fed infants, infant formula could be supplemented with probiotics or prebiotics, food ingredient able to improve human health. This supplementation could provide to them a better protection against gastro-intestinal disorders, infections and allergic risks. In vivo studies are difficult to carry out in infants due to accessibility and ethic problems, then in vitro studies become important. Continuous fermentation systems display the closest conditions to those encountered in vivo. Different fermentation systems have been proposed, all are using free-cell cultures whereas in vivo bacteria are present in colon at planktonic and sessile states. To our knowledge only one in vitro model has been proposed to simulate infant colonic fermentation. The aim of this study was to develop a new in vitro system with immobilized cells to simulate infant colonic ecosystem. First a feasibility study was done, we showed that a complex fecal microflora could be immobilized and the inoculum bacterial diversity was conserved in the ecosystem established in the fermentation system. The bacterial composition and metabolic activities of the microbiota reached an equilibrium specific to the fermentation conditions tested. These equilibriums were closed to those detected in vivo in infant colon. Then a three-stage chemostat using immobilized fecal bacteria was developed and validate to simulate simultaneously, proximal, transverse and distal infant colon conditions. This last in vitro colonic fermentation model was used to compared the effect of a well-known prebiotic (fructooligosaccharide) with an exopolysaccharide produced by L. rhamnosus RW-9595M on the infant colonic microbiota. The fructooligosaccharide used beneficially influenced the bacterial ecosystem whereas exopolysaccharide substrate did not seem to be metabolized by infant colonic microbiota. The main advantage of this system with immobilized cells is the great stability of the bacterial composition and metabolic activities of the microflora established in the model. For this, the in vitro colonic fermentation system with immobilized cells is a very efficient tool, easy to operate and reliable.
Vila, Vecilla Laura. "Desarrollo de un modelo in vitro de barrera intestinal para la evaluación del riesgo de los nanomateriales." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/398242.
The field of nanotechnology is increasing every day. For this reason, the social concern about the possible effects of their products (nanomaterials; NMs) in living organisms is also growing. Since the main routes of exposure to NMs are dermal contact, inhalation, and ingestion, the intestinal barrier is very important due to the presence of NMs in food and food packaging, in addition to its presence in many other daily products. In this context, the objective of this Thesis is to develop an intestinal model formed by Caco-2 cells in order to assess the risk of NMs. Caco-2 cells are from colon adenocarcinoma and have the capacity to differentiate into enterocytes of the small intestine. Under the framework of the NANoREG’s project, the results have shown that we have successfully developed a robust protocol to obtain stable and reproducible in vitro intestinal barrier composed of these differentiated Caco-2 cells. Using sub-toxic concentrations of TiO2NPs, ZnONPs, SiO2NPs, CeO2NPs, AgNPS and MWCNT for 24 hours, we have performed different types of analysis: a) assessment of the integrity and permeability of the monolayer, b) cellular internalization, c) translocation of NMs, d) evaluation of genotoxic damage, d) assessment of the integrity of the monolayer through changes in mRNA expression. The results after exposure to sub-toxic concentrations showed no alteration in the integrity or the permeability of the monolayer. Furthermore, internalization of AgNPS was observed in both the cytoplasm and nucleus while TiO2NPs and CeO2NPs found sedimented on the apical membrane of cells. The ability to evaluate the translocation of NMs through the cell barrier proved to be very limited. TEM-EDX, confocal microscopy, and ICP-MS showed limited translocation of TiO2NPs, ZnONPs, and CeO2NPS. In the evaluation of genotoxic damage by comet assay, it was observed that only AgNPS are capable of producing oxidative DNA damage and only at the highest concentration tested (50 μg/mL). In assessing mRNA expression of genes of cellular transporters (SI and SLC15A1) and cell-cell adhesion (OCCLUDIN and CLAUDIN2), results showed a lot of variability between replicates and no significant changes were found in any of them after exposure to AgNPS. Besides the European project and in order to assess the risk of exposure to NMs in the long term, Caco-2 cells in their undifferentiated state were exposed for 6 weeks to sub-toxic concentrations of AgNPS evaluating its transformation capacity. These cells were subjected to a period of adaptation in which the cells decreased the rate of division due to exposure until regaining it at the end of the treatment. After 6 weeks of exposure, the Caco-2 cells expressed some features of the transformed cells: a) increased the proliferation rate, b) acquired the ability to grow in soft agar, and promoted the growth of other tumour cells (HCT116) in soft-agar, c) increased the secretion of MMPs, and d) increased their migratory capacity. However, exposure didn’t show changes in the expression of genes involved in EMT, cell adhesion, cytoskeleton or tumour suppressors. Despite this, the overall results indicate that the AgNPS are not safe in terms of carcinogenesis.
Costa, Tie Bezerra. "Efeito da privação da glutamina sobre as células secretoras do epitélio intestinal em um modelo in vitro de enteroide." reponame:Repositório Institucional da UFC, 2012. http://www.repositorio.ufc.br/handle/riufc/10626.
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The intestinal epithelium is formed and sustained by a population of stem cells capable of generating different cell lines while maintaining pluripotent and self-renewal capacity. Glutamine is a conditional essential amino acid important for the maintenance of the intestinal epithelium. However, few studies to date have explored the role of glutamine in the fine regulation of the intestinal crypt cell turnover. In order to evaluate the role of glutamine in the crypt cell turnover, an in vitro enteroid model was used, where stem cells are capable of generating an epithelium containing the main intestinal secretory cell lines (Paneth, goblet, and enteroendocrine cells) and absorptive enterocytes as well, while forming a villus-crypt like structure. This model was used to test the effect of 24h of glutamine deprivation (standard media with 2mM glutamine vs glutamine-free media) on epithelial turnover by counting EdU- labeled cells/total number per section and cell apoptosis by counting cleavage-caspase 3- labeled cells/total number per section. In order to assess crypt secretory function, Paneth and goblet crypt cell ratios (target secretory cell/total cell number per crypt) were measured. The number of Paneth and goblet cells was measured with the aid of confocal microscopy and lysozyme and mucin-2 immunostainning. In addition, Paneth and globet cell product transcripts (lysozyme and mucin, respectively) were measured using quantitative Real-time PCR. In order to assess the potential immunomodulatory role of glutamine, innate immune element transcripts, Toll like receptor and their accessory protein MD-2, and cytokines, as follows: TNF-α, IL-1β and CXCL-1, were measured. Glutamine deprivation reduced the number of EdU positive cell ratio as compared with the enteroid under the standard media (p=0.006). No significant differences regarding Paneth and goblet cell ratios were seen between groups following glutamine deprivation. Glutamine deprivation significantly decreased lysozyme transcripts as compared with the enteroid under the standard media (p=0.007), but not for mucin-2 transcripts, related to goblet cell function. Decreased TNF-α and MD-2 transcription (p=0.005 and p=0.016, respectively) were found following glutamine deprivation. Altogether, our findings reinforce the glutamine positive role on the intestinal epithelial turnover and furthermore suggest an important glutamine regulatory effect over Paneth cells and the innate immune system. The enteroid model provides an important tool the dissect the mechanisms of glutamine protection and shed light for future studies.
O epitélio intestinal é formado e mantido por uma população de células-tronco capaz de gerar diferentes linhagens celulares, mantendo a pluripotência e a capacidade de auto-renovação. A glutamina é um aminoácido essencial condicional importante para a manutenção do epitélio do intestino. No entanto, poucos estudos têm explorado o papel da glutamina na regulação fina do turnover celular da cripta intestinal. Com o propósito de avaliar o papel da glutamina n o turnover de células da cripta, foi utilizado um modelo in vitro de enteroide, onde as células-tronco são capazes de gerar um epitélio contendo as principais linhagens de células secretoras intestinais (célula de Paneth, célula caliciforme e célula enteroendócrina), além dos enterócitos absortivos, com a formação de uma estrutura tipo vilosidade-cripta. Este modelo foi usado para testar o efeito de 24 horas de privação de glutamina (meio padrão com glutamina a 2 mM vs meio livre de glutamina) no turnover epitelial através da contagem de células marcadas por Edu/número total por secção e ainda na apoptose celular, através da contagem de células marcadas para caspase 3-clivada/número total por secção. A fim de avaliar a função secretora das criptas, as razões das células de Paneth e caliciformes por cripta (célula alvo/número total de células secretoras por cripta) foram medidas. O número de células de Paneth e caliciformes foi obtido com o auxílio da microscopia confocal e imunomarcação para lisozima e mucina-2. Além disso, os transcritos dos produtos das células de Paneth e caliciformes (lisozima e mucina, respectivamente) foram analisados utilizando o método de PCR quantitativo em tempo real. Com intuito de avaliar o potencial papel imunomodulador da glutamina, transcritos de elementos da imunidade inata, receptor de tipo Toll e sua proteína acessória MD-2, e citocinas, a saber: TNF-α, IL-1β e CXCL-1, foram medidos. A privação de glutamina reduziu o número de células Edu positivas, em comparação com o enteroide sob meio padrão (p=0,006). Não houve diferença significativa em relação às razões das células de Paneth e células caliciformes entre os grupos após privação de glutamina. A privação da glutamina diminuiu significativamente os transcritos de lisozima, em comparação com o enteroide sob meio padrão (p = 0,007), mas não para mucina-2, transcrição relacionada com a função das células caliciformes. Uma transcrição reduzida para TNF- α e MD-2 (p=0,005 e p=0,016, respectivamente) foi observada após a privação de glutamina. Ao todo, nossos achados reforçam o papel positivo da glutamina sobre o turnover do epitélio intestinal e, além disso, sugerem um importante efeito regulador da glutamina sobre as células de Paneth e resposta imune inata. O modelo enteroide fornece uma ferramenta importante para dissecar os mecanismos de proteção pela glutamina e guiar estudos futuros.
Alves, Luis Antonio de Oliveira. "ExpressÃo e regulaÃÃo da quinase celular intestinal (ICK) em modelo de desnutriÃÃo in vivo e in vitro." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=12743.
Malnutrition can affect the intestinal architecture, causing mucosal atrophy and compromising epithelial turnover. Although the gut is able to compensatorily respond to malnutrition, the molecular mechanisms by which the gut responds to protein deprivation are not completely understood. The intestinal cell kinase (ICK) is a highly conserved serine/threonine protein and a novel component of the signaling pathways that regulate cell proliferation in the intestinal crypt. In order to evaluate the role of the intestinal compensatory response to protein deprivation mediated by ICK, the activation of molecular pathways related to cell proliferation and survival were measured in C57BL/6J mice subjected to low protein diet (containing 2% protein) for five days and received standard chow-fed controls. We analyzed the intestinal canonical Wnt/β-catenin pathway, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and protein kinase B (PKB/Akt) by immunoblotting. We also measured the expression of intestinal stem cells markers (LGR-5 and Bmi1). We also conducted an in vitro study using human ileocecal adenocarcinoma cells (HCT-8) starved with low serum (0-1%) to evaluate the ICK response with or without gut trophic factors, such as glutamine (2 mM), alanyl-glutamine (10 and 50mM), and zinc (10 and 50μM), casein and bovine serum albumin (BSA) at a concentration of 0.25 or 0.5% in the medium, respectively. We also assessed ICK mRNA transcript by q-PCR after protein deprivation. In order to evaluate the effect of this kinase on cell proliferation and apoptosis, the ICK gene was silenced using interference RNA in HCT-8 cells. Cell viability was measured by trypan blue exclusion. Furthermore, caspase 3 and 9, cleaved PARP, analyzed by western blot, and annexin V, measured by flow cytometry, were used to assess apoptosis. In order to measure ICK effect on cell proliferation, we analyzed Wnt/β-catenin and cyclin D1 pathways by western blot. We identified a significant and transient increase in ICK intestinal levels following low-protein induced malnutrition, concomitant with the activation of molecular pathways related to proliferation and survival, as well as increased expression of intestinal stem cell markers. This work also documented that the protein deprivation, induced by low serum concentration, increased the expression of ICK in HCT-8 cells, an effect that was reversed by BSA in the medium. This reverse effect was not seen with other compounds such as glutamine, alanyl-glutamine or zinc. Despite the increase in ICK expression after protein deprivation, no significant difference in its transcripts was found, when compared with controls. The silencing of the ICK gene significantly decreased Wnt/β-catenin and cyclin D1 signaling activation in HCT-8 cells with increased apoptosis by a caspase dependent mechanism. Our results suggest that the increased ICK expression in response to protein deprivation is a protective mechanism that limits cell apoptosis and supports epithelial cell proliferation following malnutrition. Keywords: Malnutrition. Protein deprivation. Intestinal cell kinase. β
Alves, Luis Antonio de Oliveira. "Expressão e regulação da quinase celular intestinal (ICK) em modelo de desnutrição in vivo e in vitro." reponame:Repositório Institucional da UFC, 2014. http://www.repositorio.ufc.br/handle/riufc/15323.
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Malnutrition can affect the intestinal architecture, causing mucosal atrophy and compromising epithelial turnover. Although the gut is able to compensatorily respond to malnutrition, the molecular mechanisms by which the gut responds to protein deprivation are not completely understood. The intestinal cell kinase (ICK) is a highly conserved serine/threonine protein and a novel component of the signaling pathways that regulate cell proliferation in the intestinal crypt. In order to evaluate the role of the intestinal compensatory response to protein deprivation mediated by ICK, the activation of molecular pathways related to cell proliferation and survival were measured in C57BL/6J mice subjected to low protein diet (containing 2% protein) for five days and received standard chow-fed controls. We analyzed the intestinal canonical Wnt/β-catenin pathway, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and protein kinase B (PKB/Akt) by immunoblotting. We also measured the expression of intestinal stem cells markers (LGR-5 and Bmi1). We also conducted an in vitro study using human ileocecal adenocarcinoma cells (HCT-8) starved with low serum (0-1%) to evaluate the ICK response with or without gut trophic factors, such as glutamine (2 mM), alanyl-glutamine (10 and 50mM), and zinc (10 and 50μM), casein and bovine serum albumin (BSA) at a concentration of 0.25 or 0.5% in the medium, respectively. We also assessed ICK mRNA transcript by q-PCR after protein deprivation. In order to evaluate the effect of this kinase on cell proliferation and apoptosis, the ICK gene was silenced using interference RNA in HCT-8 cells. Cell viability was measured by trypan blue exclusion. Furthermore, caspase 3 and 9, cleaved PARP, analyzed by western blot, and annexin V, measured by flow cytometry, were used to assess apoptosis. In order to measure ICK effect on cell proliferation, we analyzed Wnt/β-catenin and cyclin D1 pathways by western blot. We identified a significant and transient increase in ICK intestinal levels following low-protein induced malnutrition, concomitant with the activation of molecular pathways related to proliferation and survival, as well as increased expression of intestinal stem cell markers. This work also documented that the protein deprivation, induced by low serum concentration, increased the expression of ICK in HCT-8 cells, an effect that was reversed by BSA in the medium. This reverse effect was not seen with other compounds such as glutamine, alanyl-glutamine or zinc. Despite the increase in ICK expression after protein deprivation, no significant difference in its transcripts was found, when compared with controls. The silencing of the ICK gene significantly decreased Wnt/β-catenin and cyclin D1 signaling activation in HCT-8 cells with increased apoptosis by a caspase dependent mechanism. Our results suggest that the increased ICK expression in response to protein deprivation is a protective mechanism that limits cell apoptosis and supports epithelial cell proliferation following malnutrition. Keywords: Malnutrition. Protein deprivation. Intestinal cell kinase. β
A desnutrição pode afetar a arquitetura intestinal, causando atrofia da mucosa e comprometendo o turnover epitelial. Embora o intestino seja capaz de responder compensatoriamente à desnutrição, os mecanismos moleculares pelos quais o intestino responde à privação proteica não estão completamente esclarecidos. A quinase celular intestinal (ICK) é uma proteína altamente conservada do tipo serina/treonina e um novo componente das vias de sinalização que regulam a proliferação celular na cripta intestinal. Para avaliar o papel da resposta intestinal compensatória à privação proteica, regulada pela ICK, foi medida a ativação de vias moleculares relacionadas à proliferação e sobrevivência celulares, como a via canônica Wnt/β-catenina, a via da proteína alvo da rapamicina em mamíferos (mTOR), vias da proteína-quinase ativada por mitógeno (MAPK) e da proteína quinase B (PKB/Akt), bem como a expressão de marcadores para células-tronco intestinais (LgR-5 e Bmi1) por imunoblotting num modelo in vivo em camundongos fêmeas C57BL/6J submetidas à uma dieta hipoproteica (contendo 2% de proteína) por cinco dias e controles nutridos recebendo dieta padrão. Também foi realizado um estudo in vitro utilizando células HCT-8 de adenocarcinoma ileocecal humano desafiadas com meio padrão com restrição de soro fetal bovino (0-1%) para avaliar a resposta da ICK na presença ou não de fatores tróficos intestinais como glutamina (2mM), alanil-glutamina (10 e 50 mM) e zinco (10 e 50μM), além de caseína e albumina sérica bovina (BSA) na concentração de 0,25 e 0,5% no meio, respectivamente. A análise de RNAm foi feita para avaliar o transcrito de ICK por q-PCR, após privação proteica. No intuito de avaliar o efeito dessa quinase sobre a proliferação celular e apoptose, foi realizado o silenciamento do gene da ICK com uso de RNA de interferência em células HCT-8. A viabilidade celular foi avaliada com base na exclusão do azul de tripan. Posteriormente, foram realizados testes de western blot para caspase 3 e 9, PARP-clivada, além de anexina V por citometria de fluxo para avaliar apoptose, assim como western blot para via Wnt/β-catenina e ciclina D1 no intuito de medir os mecanismos relacionados à proliferação celular. Dessa forma, foi identificado um aumento significativo e transitório nos níveis intestinais de ICK na desnutrição induzida pela ração hipoproteica, concomitante com a ativação de vias moleculares relacionadas à proliferação e sobrevivência, bem como o aumento da expressão de marcadores para células-tronco intestinais. Esse trabalho também documentou que a privação proteica, induzida por baixa concentração de soro, aumenta a expressão de ICK em células HCT-8, efeito que foi revertido pela adição de BSA no meio. O mesmo resultado, não foi observado com outros compostos como glutamina, alanil-glutamina e zinco. Apesar do aumento da expressão da ICK após privação proteica, não houve diferença significativa da sua transcrição quando comparado com os controles. O silenciamento do gene de ICK reduziu significativamente a sinalização da via Wnt-β-catenina e ciclina D1 em células HCT-8 com aumento da apoptose por um mecanismo dependente de caspases. Os resultados sugerem que o aumento da expressão de ICK em resposta à privação proteica é um mecanismo de proteção que limita a apoptose e suporta a proliferação celular epitelial na desnutrição.
Cornu, Raphaël. "Nanoparticules et santé : de grandes promesses thérapeutiques, mais pour quel risque ?" Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE018.
Nanoparticles are defined as spherical structures with a maximum diameter of 100 nanometers. The application fields of nanoparticles including food and pharmaceutical industries are extremely broad. Human can be exposed daily to nanoparticles through various administration routes (oral, intravenous, pulmonary and cutaneous). Due to their size at the nanoscale, nanoparticles have unique physicochemical, inducing strong interactions with the biological environment. These features were widely exploited for the conception of nanomedicines for the diagnosis and the therapy. However, issues relative to their biological toxicity were addressed in the same time. This thesis work aims to investigate the potential toxicity of nanoparticles. Toxicological evaluation was performed using cell models adapted for the systemic and the oral routes. Mechanisms involved in the nanotoxicity were studied to identify toxicity factors. The first part of the work focused on the in vitro and in vivo hepatic toxicity of PLGA and silica nanoparticles. PLGA nanoparticles are used as drug carriers while silica nanoparticles play the role of anticaking agent in food industry and of pharmaceutical excipients. Their effects on the liver function and especially on the cytochrome P450 activity were investigated. The second part of the work consisted to study the impact of silica nanoparticles on the intestinal barrier, especially on the paracellular permeability and the integrity of the barrier. By emphasizing interspecies differences or the protective role of mucus, this project demonstrated that the choice of toxicological tools was crucial for a predictive nanotoxicity evaluation. Size, surface properties and composition were identified as major toxicity factors
Roos, Karin Hester. "Effects of plant extracts and phytoconstituents on the intestinal transport of indinavir / K.H. Roos." Thesis, North-West University, 2012. http://hdl.handle.net/10394/9692.
Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.
Cleusix, Valentine. "Study of the effects of Lactobacillus reuteri and reuterin on the human intestinal microbiota using in vitro models /." Zürich : ETH, 2006. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=16976.
Schweinlin, Matthias Oliver [Verfasser], Heike [Gutachter] Walles, Stefan [Gutachter] Störk, and Beate [Gutachter] Niesler. "Development of advanced human intestinal in vitro models / Matthias Oliver Schweinlin ; Gutachter: Heike Walles, Stefan Störk, Beate Niesler." Würzburg : Universität Würzburg, 2017. http://d-nb.info/1123505942/34.
Gérard-Champod, Marie. "Caractérisation et modélisation in vitro de l'écosystème jéjuno-iléal du veau de boucherie." Phd thesis, Université Blaise Pascal - Clermont-Ferrand II, 2009. http://tel.archives-ouvertes.fr/tel-00726333.
Costa, Tie Bezerra. "Efeito da privaÃÃo da glutamina sobre as cÃlulas secretoras do epitÃlio intestinal em um modelo in vitro de enteroide." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=13454.
O epitÃlio intestinal à formado e mantido por uma populaÃÃo de cÃlulas-tronco capaz de gerar diferentes linhagens celulares, mantendo a pluripotÃncia e a capacidade de auto-renovaÃÃo. A glutamina à um aminoÃcido essencial condicional importante para a manutenÃÃo do epitÃlio do intestino. No entanto, poucos estudos tÃm explorado o papel da glutamina na regulaÃÃo fina do turnover celular da cripta intestinal. Com o propÃsito de avaliar o papel da glutamina n o turnover de cÃlulas da cripta, foi utilizado um modelo in vitro de enteroide, onde as cÃlulas-tronco sÃo capazes de gerar um epitÃlio contendo as principais linhagens de cÃlulas secretoras intestinais (cÃlula de Paneth, cÃlula caliciforme e cÃlula enteroendÃcrina), alÃm dos enterÃcitos absortivos, com a formaÃÃo de uma estrutura tipo vilosidade-cripta. Este modelo foi usado para testar o efeito de 24 horas de privaÃÃo de glutamina (meio padrÃo com glutamina a 2 mM vs meio livre de glutamina) no turnover epitelial atravÃs da contagem de cÃlulas marcadas por Edu/nÃmero total por secÃÃo e ainda na apoptose celular, atravÃs da contagem de cÃlulas marcadas para caspase 3-clivada/nÃmero total por secÃÃo. A fim de avaliar a funÃÃo secretora das criptas, as razÃes das cÃlulas de Paneth e caliciformes por cripta (cÃlula alvo/nÃmero total de cÃlulas secretoras por cripta) foram medidas. O nÃmero de cÃlulas de Paneth e caliciformes foi obtido com o auxÃlio da microscopia confocal e imunomarcaÃÃo para lisozima e mucina-2. AlÃm disso, os transcritos dos produtos das cÃlulas de Paneth e caliciformes (lisozima e mucina, respectivamente) foram analisados utilizando o mÃtodo de PCR quantitativo em tempo real. Com intuito de avaliar o potencial papel imunomodulador da glutamina, transcritos de elementos da imunidade inata, receptor de tipo Toll e sua proteÃna acessÃria MD-2, e citocinas, a saber: TNF-α, IL-1β e CXCL-1, foram medidos. A privaÃÃo de glutamina reduziu o nÃmero de cÃlulas Edu positivas, em comparaÃÃo com o enteroide sob meio padrÃo (p=0,006). NÃo houve diferenÃa significativa em relaÃÃo Ãs razÃes das cÃlulas de Paneth e cÃlulas caliciformes entre os grupos apÃs privaÃÃo de glutamina. A privaÃÃo da glutamina diminuiu significativamente os transcritos de lisozima, em comparaÃÃo com o enteroide sob meio padrÃo (p = 0,007), mas nÃo para mucina-2, transcriÃÃo relacionada com a funÃÃo das cÃlulas caliciformes. Uma transcriÃÃo reduzida para TNF- α e MD-2 (p=0,005 e p=0,016, respectivamente) foi observada apÃs a privaÃÃo de glutamina. Ao todo, nossos achados reforÃam o papel positivo da glutamina sobre o turnover do epitÃlio intestinal e, alÃm disso, sugerem um importante efeito regulador da glutamina sobre as cÃlulas de Paneth e resposta imune inata. O modelo enteroide fornece uma ferramenta importante para dissecar os mecanismos de proteÃÃo pela glutamina e guiar estudos futuros.
The intestinal epithelium is formed and sustained by a population of stem cells capable of generating different cell lines while maintaining pluripotent and self-renewal capacity. Glutamine is a conditional essential amino acid important for the maintenance of the intestinal epithelium. However, few studies to date have explored the role of glutamine in the fine regulation of the intestinal crypt cell turnover. In order to evaluate the role of glutamine in the crypt cell turnover, an in vitro enteroid model was used, where stem cells are capable of generating an epithelium containing the main intestinal secretory cell lines (Paneth, goblet, and enteroendocrine cells) and absorptive enterocytes as well, while forming a villus-crypt like structure. This model was used to test the effect of 24h of glutamine deprivation (standard media with 2mM glutamine vs glutamine-free media) on epithelial turnover by counting EdU- labeled cells/total number per section and cell apoptosis by counting cleavage-caspase 3- labeled cells/total number per section. In order to assess crypt secretory function, Paneth and goblet crypt cell ratios (target secretory cell/total cell number per crypt) were measured. The number of Paneth and goblet cells was measured with the aid of confocal microscopy and lysozyme and mucin-2 immunostainning. In addition, Paneth and globet cell product transcripts (lysozyme and mucin, respectively) were measured using quantitative Real-time PCR. In order to assess the potential immunomodulatory role of glutamine, innate immune element transcripts, Toll like receptor and their accessory protein MD-2, and cytokines, as follows: TNF-α, IL-1β and CXCL-1, were measured. Glutamine deprivation reduced the number of EdU positive cell ratio as compared with the enteroid under the standard media (p=0.006). No significant differences regarding Paneth and goblet cell ratios were seen between groups following glutamine deprivation. Glutamine deprivation significantly decreased lysozyme transcripts as compared with the enteroid under the standard media (p=0.007), but not for mucin-2 transcripts, related to goblet cell function. Decreased TNF-α and MD-2 transcription (p=0.005 and p=0.016, respectively) were found following glutamine deprivation. Altogether, our findings reinforce the glutamine positive role on the intestinal epithelial turnover and furthermore suggest an important glutamine regulatory effect over Paneth cells and the innate immune system. The enteroid model provides an important tool the dissect the mechanisms of glutamine protection and shed light for future studies.
Batista, Lobo Samira. "Development of 'In vitro' intestinal models to study the pharmacology of drugs affecting the gastrointestinal tract in normal and diseased conditions. Development of a cell culture model for intestinal pharmacology." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4295.
Le, Bacquer Olivier. "Effets trophiques de la glutamine : études in vivo chez le nouveau-né prématuré et in vitro sur un modèle d'entérocytes humains en culture." Nantes, 2002. http://www.theses.fr/2002NANT18VS.
Animal and human studies suggest that glutamine supply may enhance whole body protein synthesis stimulation and improve gut trophicity during critical illness. The mechanisms of these effects remain unclear. This work combines an in vivo study in very-low-birth-weight infants with two in vitro studies using the Caco-2 cell line as a model of human enterocytes in culture. Our results show that 1) in parenterally fed preterm, a 24h glutamine supplementation decreases whole body protein synthesis, but may have an acute protein-sparing effect, as it suppresses protein breakdown and oxidation; 2) we also demonstrate that glutamine deprivation impairs protein synthesis in a model of enterocytes. Finally, 3) apical nutrient deprivation, a model of fasting, impairs protein synthesis, depletes glutathione pool, and increases transepithelial permeability. Most of these parameters are restored by glutamine supplementation, probably through glutamine utilization as a source of energy. Taken together, these findings suggest that glutamine may improve protein accretion in preterm infants through an anti-catabolic effect, and regulate gut barrier function by stimulating intestinal protein synthesis
Vila, Giraut Anna. "Hydrogel co-networks of gelatin methacryloyl and poly(ethylene glycol)diacrylate sustain 3D functional in vitro models of intestinal mucosa." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/670921.
En l’intestí prim trobem la mucosa, la capa més externa de la paret intestinal, formada per dos compartiments, la lamina propia i l’epiteli, en els quals resideixen diferents tipus cel·lulars. La interacció entre els dos compartiments és essencial pel funcionament correcte del intestí. Actualment, els models intestinals in vitro es basen en el cultiu de línies cel·lulars epitelials sobre membranes dures i de plàstic, els quals no representen correctament ni la complexitat ni la organització cel·lular trobada en el intestí prim, ja que manquen de la lamina propria. Conseqüentment, els resultats obtinguts utilitzant aquests models són significativament poc fisiològics i no comparables amb els trobats en condicions in vivo (alts valors de resistència elèctrica transepitelial, subestimació dels valors d’absorció de molècules a través de la ruta paracel·lular i alteració en la expressió enzims digestius). Per reduir les distàncies entre els models intestinals in vitro i l’intestí, s’han de desenvolupar plataformes que modelitzin: (I) les propietats fisicoquímiques i mecàniques de la matriu extracel·lular, (II) els dos compartiments de la mucosa intestinal, i si pogués ser (III) l’arquitectura tridimensional. Per aconseguir aquests requeriments, en aquesta tesi s’utilitzen hidrogels formats per polímers naturals (gelatina metacrilada (GelMA)) co-polimeritzats amb polímers sintètics (poly(ethylene glycol) diacrylate (PEGDA)) com a substrat per imitar els dos compartiments intestinals. Per reproduir la lamina propria, els polímers de GelMA i PEGDA es dissolen juntament amb el fotoiniciador. Tot seguit, les cèl·lules residents de la lamina propria (fibroblasts, miofibroblasts o macròfags) es barregen amb la solució de pre-polimer, s’aboca a les piscines de PDMS, s’exposa a llum ultraviolada, i s’obté l’hidrogel amb les cèl·lules en el seu interior. Finalment, les cèl·lules epitelials es sembren a la superfície del hidrogel. En aquesta tesi, s’ha obtingut un hidrogel amb propietats fisicoquímiques i mecàniques similars a la matriu extracel·lular del intestí humà, i que permeten el cultiu cel·lular fins a 21 dies, imitant els dos compartiments. A més, la el co-cultiu de cèl·lules residents de la lamina propria juntament amb les cèl·lules epitelials, ens ha permès obtenir un model 3D de la mucosa intestinal in vitro amb propietats fisiològiques més semblants a la del intestí prim.
Maares, Maria Henrietta [Verfasser], Hajo [Akademischer Betreuer] Haase, Hajo [Gutachter] Haase, and Anna [Gutachter] Kipp. "Investigations on zinc resorption using in vitro intestinal models / Maria Henrietta Maares ; Gutachter: Hajo Haase, Anna Kipp ; Betreuer: Hajo Haase." Berlin : Technische Universität Berlin, 2019. http://d-nb.info/1186130229/34.
Leonard, Fransisca [Verfasser], and Claus-Michael [Akademischer Betreuer] Lehr. "Novel cell based in vitro models to study nanoparticle interaction with the inflamed intestinal mucosa / Fransisca Leonard. Betreuer: Claus-Michael Lehr." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2013. http://d-nb.info/1052781454/34.
THOREUX, KARINE. "Vieillissement de l'appareil digestif et nutrition. Modeles in vitro et in vivo de vieillissement intestinal, impact des laits fermentes sur la trophicite digestive." Paris 7, 1997. http://www.theses.fr/1997PA077303.
Neuhoff, Sibylle. "Refined in vitro Models for Prediction of Intestinal Drug Transport : Role of pH and Extracellular Additives in the Caco-2 Cell Model." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis: Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5814.
Balandras, Frédérique. "Étude in vitro de la sensibilité de l'[alpha]-casozépine, décapeptide à activité benzodiazépine mimétique, à diverses protéases et peptidases du tractus gastro-intestinal. Étude comportementale chez le rat Wistar de l'activité anxiolytique des fragments F97 et F95 libérés par la pepsine." Thesis, Vandoeuvre-les-Nancy, INPL, 2008. http://www.theses.fr/2008INPL047N/document.
[alpha]-Casozepine, a tryptic decapeptide from bovine [alpha]s1-casein, have in vitro an affinity for the benzodiazepine site of the central receptor GABAA (Lecouvey et al., 1997; Miclo et al., 2001). Some results display the anxiolytic potential of this peptide alone or within its hydrolysat, in vivo, in intra peritoneal administration and per os in Wistar rats (Guesdon et al., 2006; Miclo et al., 2001; Violle et al., 2007) and in human in oral administration (Kim et al., 2007; Messaoudi et al., 2005). To determine the sensitivity of [alpha]-casozepine in various proteolytic attacks, kinetics of gastric, pancreatic and intestinal hydrolyses, were realized in vitro with enzymes and following enzymatic systems; pepsin, trypsin, [alpha]-chymotrypsin, CorolasePPTm, brush border membranar vesicles rats enterocytes and enterocytes epithelium reconstituted by the Caco-2 cell line. For each of the conditions of studied hydrolysis, all the peptides fragments released were separated by liquid chromatography high-performance in inverted phase and characterized by mass spectrometry. These analyses underline the partial resistance of [alpha]-casozepine in some enzymes and enzymatic systems. [alpha]-Casozepine pepsic hydrolysis release in particular two peptide fragments: 91YLGYLEQ97 and 91YLGYL95, named F97 and F95 who turn out to be more resistant than [alpha]-casozepine in some used enzymes. So to allow a better understanding of the relation between structure of [alpha]-casozepine and the benzodiazepine mimetic function obtained in vivo, these peptides truncated in their carboxy-terminal party were tested in vivo with Wistar rat in intra peritoneal injection. They turn out to be also holders of anxiolytic activity. However no transfer of [alpha]-casozepine and fragments F97 and F95 was observed through the enterocyte epithelium reconstituted by the cellular model Caco-2 and this in spite of the various conditions of cultures and tested analyses
Belliard, Anne-Marie. "Influence de l'IL2, de l'INFγ et du TNFα sur l'activité, l'expression et la localisation de la P-glycoprotéine intestinale dans un modèle in vitro : les cellules Caco-2 en culture". Paris 11, 2003. http://www.theses.fr/2003PA114819.
The P-glycoprotein (Pgp), a drug efflux pump, is expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotic substrates. In inflammatory bowel disease, a dysregulation in the production of IL2, IFNg and TNFa, and an alteration of Pgp expression and activity have been reported. The aim of our study was to investigate the effects of each cytokine on Pgp activity, expression and localization in Caco-2 cells model. IL2 and TNFa induced both a diminution of MDR1 mRNA by semi-quantitative RT-PCR and a significant decrease of Pgp activity with a normal localisation of Pgp by confocal laser scanning microscopy. In contrast, IFNg induced up-regulation of both mRNA MDR1 and Pgp protein expression without incidence on Pgp activity but a delocalization of Pgp was observed in apical plasma membrane
Amamou, Asma. "Le récepteur minéralocorticoide : une cible potentielle dans la fibrose intestinale ? Mineralocorticoid receptor antagonisl improves inflammation and fibrosis in chronic DSS colitis mouse model Neutrophil gelatinas-associated lipocalin (NGAL) is a mineralocorticoid receptor target involved in intestinal inflammation and fibrosis Inflammatory bowel diseases and food additives : to add fuel on the flames Dietary salt activates intestinal fibroblasts, thereby contributing to exacerbation of intestinal fibrosis Dietary aryl hydrocarbon receptor ligands have no anti-fibrotic properties in transforming growth factor-β1-stimulated human colonic fibroblasts Effet d'un régime riche en sel sur la fibrose intestinale dans un modèle murin de colite chronique Etude de l'interaction entre des dérivés du tryptophane et le récepteur aryl hydrocarbone dans un modèle in vitro de fibrose intestinale". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR079.
Inflammatory bowel diseases (IBD) occur in people with a genetic predisposition under the influence of environmental factors. Intestinal fibrosis is a common complication in IBD with no specific therapy which is characterized by an accumulative deposit of extra-cellular matrix produced by mesenchymal cells. Mineralocorticoid receptor (MR) is the final effector of renin-angiotensin-aldosterone system (RAAS). MR and all components of RAAS are expressed in the gastrointestinal tract and are up-regulated in the intestine from IBD patients. MR antagonism exerts beneficial properties in inflammation and fibrosis from extra-intestinal organs. We aimed to investigate whether MR antagonism had beneficial effects in intestinal fibrogenesis using murine chronic colitis and cellular models of intestinal fibrosis. MR antagonism was investigated by a dual approach using pharmacological inhibition and genetic invalidation. In the present study, we have demonstrated that pharmacological or genetic MR antagonism reduced inflammation and intestinal fibrosis in murine DSS chronic chemically-induced colitis. MR activation by aldosterone increased cell proliferation and TGF-β1 production in human colonic fibroblasts and human intestinal endothelial cells. Lipocalin associated with neutrophil gelatinase (NGAL) mediated pro-fibrotic effects via the activation of RM by aldosterone. Genetic invalidation of NGAL also reduced the SMAD-dependent TGF-β1 signaling pathway. In conclusion, we have demonstrated the MR involvement in intestinal fibrosis and these effects are mediated through NGAL. Thus, MR antagonism may represent a novel attractive approach in the treatment of intestinal fibrosis associated with IBD and may allow the repositioning molecules already available in the field of IBD
Kleta, Sylvia. "Einfluss des probiotischen Escherichia coli Nissle 1917 (EcN) auf die Infektion mit atypischen enteropathogenen E. coli (aEPEC) im porcinen in vitro-Modell." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15941.
In this study, the effects of the probiotic E. coli strain Nissle 1917 (EcN) on host cell infection with atypical enteropathogenic E. coli (aEPEC) were investigated in an in vitro porcine intestinal epithelial cell model (IPEC-J2). In pre-incubation experiments, EcN drastically reduced the infection efficiencies of aEPEC. Using confocal laser scanning microscopy and scanning electron microscopy, it was shown that EcN inhibited the attachment and formation of microcolonies, but not the formation of attaching and effacing lesions by adherent aEPEC. The inhibitory effect was mediated by the adherent properties of EcN to epithelial cells. The F1C fimbriae were identified as the most important adhesion factor of EcN in vitro. Furthermore, the H1 flagellae were also shown to be involved in the adhesion of EcN, serving as bridges between bacterial cells. Co-incubation of culture supernatants of EcN reduced the infection efficiencies of aEPEC to the same extent as in pre-incubation with EcN bacteria, indicating the secretion of an inhibitory factor by EcN. This factor was also secreted by other pathogenic and non-pathogenic E. coli strains in shaking culture and therefore does not appear to be specific for EcN. However, the outstanding ability of EcN to adhere to epithelial cells largely contributes to the secretion of sufficient concentrations of this inhibitory factor und to the influence on the aEPEC infection. The results suggest that EcN interferes with the initial adhesion of aEPEC to host cells. The inhibitory effect of EcN was found to be time-dependent. In contrast to pre-incubation experiments, co- and post-incubation of EcN actually increased the adhesion efficiencies of aEPEC and showed only minor effects on microcolony formation. This second effect of EcN on aEPEC adhesion, possibly due to a second factor, appears only to be effective when the putative inhibitory factor is either present at low concentrations or after aEPEC is already adherent to host cells.
Ménez-Berlioz, Cécile. "Intéractions de la miltefosine avec la barrière intestinale : étude des mécanismes de capture et de transport sur un modèle in vitro de cellules CACO-2 : application à la conception d'une bithérapie antileishmanienne." Paris 11, 2006. http://www.theses.fr/2006PA114834.
Miltefosine (hexadecylphosphocholine, HePC) has recently been developed for the treatment of visceral leishmaniasis. It has the particular advantage of being active after oral administration. The oral route is preferable because it is non invasive, is often less expensive and favours compliance with treatment. There is not much information in the literature about the passage of miltefosine across the intestinal barrier. Therefore, the aims of this thesis were to study the effects of miltefosine on the intestinal epithelium and to determine the mechanisms involved in its uptake and transport, using a model of Caco-2 cells in culture. The results were applied to the development of antileishmanial bitherapy by the oral route: the ability of miltefosine to improve the oral bioavailability of another antileishmanial agent, amphotericin B, was evaluated
Tria, Scherrine. "Novel in vitro models for pathogen detection based on organic transistors integrated with living cells." Phd thesis, Ecole Nationale Supérieure des Mines de Saint-Etienne, 2013. http://tel.archives-ouvertes.fr/tel-00972057.
Domenech, Cabrera Josefa. "Bioavailability and effects of microplastics and nanoplastics on in vitro gastrointestinal models. A focus on nanopolystyrene as representative nano-sized plastic material." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/674024.
Hoy en día los plásticos se usan en incontables aplicaciones en diferentes ámbitos, como la agricultura, la medicina, la construcción o la electrónica, debido a la facilidad con que se puede modificar sus propiedades fisicoquímicas, y su producción rápida y de bajo coste. Esto ha dinamitado la generación de residuos plásticos que acaba contaminando el medioambiente. Distintos factores ambientales favorecen procesos químicos, físicos y biológicos que hacen que la basura plástica se degrade, generando los micro- y nanoplásticos (MNPLs). Además de estos, la nanotecnología genera una gran cantidad de partículas de plástico en las escalas de tamaño micro- y nano, que se usan en cosméticos o productos de limpieza, y acaban contribuyendo a la contaminación ambiental por plásticos. Este reto medioambiental está acompañado por la exposición humana. Sin embargo, las actuales limitaciones metodológicas no permiten hacer estimaciones precisas sobre el nivel de exposición humana a los MNPLs, y la escasez de datos sobre los efectos de los MNPLs en modelos de mamífero hacen que sea difícil definir si los MNPLs suponen un riesgo para la salud humana. Con el fin de contribuir al conocimiento sobre la exposición human a los MNPLs y sus posibles efectos tóxicos y genotóxicos, hemos llevado a cabo una revisión de las últimas publicaciones acerca de la distribución de los MNPLs en los alimentos y el aire que respiramos, y hemos realizado estudios en modelos in vitro para esclarecer los efectos biológicos de las nanopartículas de poliestireno (PSNPs). La revisión bibliográfica, además de señalar las limitaciones y lagunas de conocimiento que condicionan la evaluación de riesgos de los MNPLs, reveló que la ingestión es la mayor vía de exposición humana a los MNPLs. Por eso, estudiamos las interacciones de las PSNPs con diferentes modelos in vitro del intestino humano, así como la toxicidad y la genotoxicidad de los nanoplásticos en estos modelos. Con el primer estudio, confirmamos la capacidad de internalización en células Caco-2 de las PSNPs. Sin embargo, a pesar de que las PSNPs alcanzan el núcleo de las células en tan sólo 24 h, no producen efectos genotóxicos. Debido al creciente interés en los posibles efectos que pueden producir los MNPLs tras su ingestión, analizamos la internalización de las PSNPs en modelos in vitro que imitan la barrera intestinal humana, incluyendo la representación de las células caliciformes (Caco-2/HT29) y las células M (Caco-2/HT29/Raji-B). Nuestros resultados apuntan a las PSNPs como agentes poco tóxicos debido a su poca capacidad para inducir ROS o otros efectos. Además, a pesar de la facilidad con la que las PSNPs internalizaron, alcanzaron el núcleo e incluso atravesaron las barreras, no produjeron genotoxicidad o daño oxidativo en el ADN de las células que forman dichos modelos. La potencial capacidad de los MNPLs para actuar como vectores de otros contaminantes tóxicos agrava el escenario de exposición. Por eso, hemos introducido un diseño de co-exposición con el objetivo de cubrir este aspecto. Nuestros resultados demostraron la interacción física entre las PSNPs y las nanopartículas de plata (AgNPs), usadas como modelo de contaminante ambiental extendido globalmente. Con este estudio, confirmamos la interacción física entre metales/MNPLs usando metodologías clásicas adaptadas a los retos actuales. Además, observamos un incremento en la internalización de las AgNPs cuando éstas fueron combinadas con PSNPs, aunque esta co-exposición no indujo efectos tóxicos. Por otro lado, demostramos que los complejos AgNPs/PSNPs internalizan en las células Caco-2 y alcanzan el núcleo celular, causando un aumento en la tendencia al daño genotóxico conforme aumenta la concentración de AgNPs cuando se combina con dosis altas de PSNPs. El nitrato de plata se introdujo paralelamente en este estudio como agente liberador de iones de plata.
Owing to the wide range of tuneable physicochemical properties, and the rapid and low-cost production, plastics present uncountable applications in industry such as product packaging, agriculture, medical applications, building or electronics, among others. This fact leads to the corresponding exponential increase in the generated plastic waste that ends up contaminating the environment. Different environmental conditions favour physical, chemical and biological processes that drive plastic waste to a continuous degradation, generating the so-called micro- and nanoplastics (MNPLs). In addition to those, rapid advances in nanotechnology have driven to the target industrial production of plastic particles in the micro- and nano-size ranges used in cosmetic or cleaning products that contribute to plastic environmental pollution. The increasing presence of MNPLs in nature represents an environmental challenge but this is also accompanied by the human exposure. Nevertheless, the current methodological limitations do not allow for accurate estimations on the levels of human exposure, and the scarcity of data on the effects of MNPLs in mammalian models hampers the understanding of whether the presence of MNPLs in different environmental niches and organisms may pose a risk for humans. Aiming to contribute to expand the knowledge on human exposure and the potential toxic and genotoxic effects of MNPLs on human health, we have reviewed the last publications referring to the occurrence of MNPLs in food and airborne, and we have performed extended in vitro studies on the biological effects of polystyrene nanoparticles (PSNPs). Our review of literature revealed ingestion as the major human exposure route to MNPLs and highlighted the knowledge gaps and limitations conditioning the MNPLs hazard assessment. Therefore, we moved forward to evaluate the interactions of PSNPs with different human gastrointestinal in vitro models, as well as toxicity and genotoxicity of the nanoplastics in those models. We confirmed the ability of PSNPs to internalise into human-derived undifferentiated Caco-2 cells. Importantly, Caco-2 cells showed signals of general stress induction after the exposure to PSNPs. However, although PSNPs reached the cell nuclei in only 24 h, cells did not show genotoxicity. Because of the heightened interest in the effects of MNPLs after their ingestion, we further analysed, the internalisation ability of PSNPs in Caco-2 based in vitro 2D models of the gut barrier which include representation of goblet (Caco-2/HT29) and microfold-cells (Caco-2/HT29/Raji-B). Our findings describe PSNPs as weak toxicants due to their low ability to induce ROS or other toxic effects. Similar to that found in the undifferentiated Caco-2 model, PSNPs did not exert genotoxic or oxidative DNA damage despite having a great internalisation capacity which allowed reaching cell nuclei and translocation across the barriers. Although literature regarding MNPLs health effects show controversy, the exposure scenario is aggravated if the MNPLs’ ability as carriers of other hazard contaminants is considered. Therefore, we attempted to cover this aspect by introducing the co-exposure design. Our results demonstrated the physical interaction between PSNPs and a widespread legacy pollutant, silver nanoparticles (AgNPs). Importantly, we proved the adaptability of classical methodological approaches to novel technical challenges as it is the visualisation of the metals/MNPLs interplay. In addition, we observed an enhancement of AgNPs internalisation by undifferentiated Caco-2 cells, after the co-exposure to AgNPs/PSNPs, but not a higher induction of toxic effects after the co-treatment. On the other hand, AgNPs/PSNPs complexes internalised and reached Caco-2 cell nuclei, causing an increasing tendency to genotoxic damage as the AgNPs concentration increases when combined with high doses of PSNPs. Silver nitrate (AgNO3) was included in this study as a surrogate of silver ion releasing agent to confirm that the effects induced by AgNPs were not caused by released ions.
Universitat Autònoma de Barcelona. Programa de Doctorat en Genètica
Benkhelifa, Samir. "Evaluation des mécanismes d'absorption intestinale des céphalosporines a-aminées : utilisation de modèles "in vitro" et "ex vivo"." Paris 5, 1995. http://www.theses.fr/1995PA05P620.
Clarke, Sarah Louise. "Analysis of murine intestinal intraepithelial lymphocytes in vitro." Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412544.
Patient, J. D. "Development of an in-vitro epithelial-myofibroblast intestinal model." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33617/.
Alhamoruni, Abdissalam Ag Ali. "In vitro studies of huam intestinal permeability and modulation." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537654.
Fordham, Robert Peter. "Maturation of intestinal epithelial progenitors, in vitro and in vivo." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648458.
Accoceberry, Isabelle. "Microsporidiose humaine intestinale a enterocytozoon bieneusi modeles in vivo et in vitro - purification des spores du parasite." Paris 6, 2001. http://www.theses.fr/2001PA066002.
Tomlinson, Sophie. "Development of an in vivo-like in vitro intestinal epithelial model." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523450.
Eastwood, Martin. "An In Vitro Approach to Assess Intestinal Drug Metabolism and Transport." Thesis, University of Manchester, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493464.
Black, Annie. "Angiogénèse in vitro dans un modèle d'équivalent dermo-épidermique humain." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq26166.pdf.
Winsor, Geoffrey L. "The intestinal epithelial cell as a central component of the intestinal cytokine network, an in vitro model of chemokine production." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0017/MQ57337.pdf.
Bajka, Balazs Hendrik. "The characterization of an in vitro model of small intestinal permeability dysfunction /." Title page and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09SB/09sbb165.pdf.
Fitzhenry, Robert James. "Interactions of enteropathogenic and enterohaemorrhagic escherichia coli with intestinal mucosae in vitro." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407237.
Baxter, P. S. "An in vitro and in vitro study by electrical methods of small intestinal ion transport in cystic fibrosis." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596483.
Betts, Andrea M. "An investigation into the intestinal absorption of melphalan in vivo and in vitro." Thesis, University of Aberdeen, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235651.