Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 1995. / Includes bibliographical references (leaves 100-107).

The physical exercise (PE) promotes effects on the gastrointestinal tract that can have negative or positive impact on the individual and may lead to hemodynamic changes and motility already established , however the repercussions of this on the colonic transport of water and electrolytes yet is not established. Objective: To evaluate the effect of PE on chronic and acute colonic transport (CT) of water and electrolytes. Methods: Wistar rats ~ 250 - 400g; (chronic group, N = 77) and weighing ~ 180 - 250g; (acute group, N = 133), coming from the animal house of the college of Medicine-Sobral, who underwent the following training protocols were used : acute training consisted of 5 days (d) consecutive swimming collective. In the 48 hours after the last session we held an individual workout 15min with 5 % of body weight , Already aerobic training took place in a session of 60min/d under 5d/week over 12 weeks in a tank at ~ 31  C. Anaerobic activity consisted of 4 sets of 10 jumps, daily for 12 week. In the initial 4 week employ 50% of body weight, an increase of 60%, 70% and 80% every 4 week. For the colic perfusion procedure animals remained on fasting for 48h , with free access to Oral rehydration solution (ORS) and then underwent the following experimental protocols: effect of chronic exercise training aerobic and anaerobic on colic transport of water and electrolytes, envolviment of parasympathetic neural pathways on colic transport from the acute exercise: bilateral cervical vagotomy; subdiaphragmatic truncal vagotomy, atropine (0,5 mg/kg, sc), envolviment of sympathetic neural pathways: esplancnotomia; guanethidine (10 mg/kg, sc); envolviment of the NO Synthase/K+ ATPâdependent channels: L-NAME (10mg/kg , sc) and glibenclamide (1mg/kg, sc). envolviment of soluble guanylate cyclase/cGMP pathway: methylene blue (Blue) (3mg/kg , s.c). After 40 min the animals were anesthetized (Ketamine/Xylazine 20-10mg/Kg-IP ), followed by laparotomy with implantation of polyvinyl cannulas (OE=50mm/OI= 30mm). The colon was perfused (0.16mL/min-Tyrode, 0,05mg/mL phenol red (VF) at 37ÂC/60min ). Variations in the concentrations of Na+, K+ , Cl-, Ca++, HC03- (mmol/L- selective Ion) and VF were used to determine the TC. Test data were analyzed by Student "t" (P < 0,05). Results: Chronic EF promoted secretion (P < 0.05) colic H2O, Na+, Cl-, K+, but did not affect the Ca++ and HC03- as compared to the sedentary (absorption). Already EF acute in vagotomized animals, or pretreated with atropine showed decreased secretory pattern or absorption. Likewise the splanchnotomy or pretreated with guanethidine animals showed absorption. Since the pretreatment with L-NAME, Blue and glibenclamimide led to a decrease in the secretory pattern or absorption. Conclusion: The results suggest that EF is able to promote secretion of water and electrolytes by a mechanism dependent on the parasympathetic and sympathetic pathways or the NO/Synthase/GC/K+ ATP-dependent channels pathway. / O Treinamento fÃsico (TF) produz efeitos sobre o trato gastrintestinal que podem ter impacto negativo ou positivo sobre o indivÃduo podendo levar à alteraÃÃes hemodinÃmicas bem como de motilidade jà estabelecidas, no entanto as repercussÃes deste sobre o transporte cÃlico (TC) de Ãgua e eletrÃlitos ainda nÃo està estabelecida. Objetivo: Avaliar o efeito do TF crÃnico e agudo sobre o TC de Ãgua e eletrÃlitos. MÃtodos: foram utilizados ratos Wistar macho, que pesando: ~ 250 â 400g; (grupo crÃnico, N= 77) e pesando ~ 180 â 250g; (grupo agudo, N= 133) advindos do biotÃrio da Faculdade de Medicina UFC-Sobral, que foram submetidos aos seguintes protocolos de treinamentos, o treinamento agudo consistiu-se de adaptaÃÃo por 5 dias (d). Com um treino individual de 15min com 5% do peso corporal no dia da perfusÃo cÃlica (PC). Jà o treinamento aerÃbico deu-se em uma sessÃo de 60min/d durante 5d/sem. ao longo de 12 sem. em um tanque Ã~31ÂC. A atividade anaerÃbica consistiu de 4 sÃries de 10 saltos, diariamente por 12 sem. Nas 4 sem. iniciais usamos 50% do peso corporal, com aumento de 60%, 70% e 80% a cada 4 sem. ApÃs esse perÃodo, para o procedimento de PC, os animais permaneceram sob jejum 48h, com livre acesso a soro de reidrataÃÃo oral (SRO) e em seguida foram submetidos aos seguintes protocolos experimentais: efeito do TF crÃnico aerÃbico e anaerÃbico sobre o TC de Ãgua e eletrÃlitos; participaÃÃo de vias neurais parassimpÃticas sobre o TC proveniente do TF agudo: vagotomia cervical bilateral; vagotomia troncular subdiafragmÃtica; atropina (0,5mg/kg, s.c); participaÃÃo de vias neurais simpÃticas: esplancnotomia; guanetidina (10 mg/kg, s.c); participaÃÃo da via NO Sintase/canais K+ ATP-dependente L-NAME (10mg/kg, s.c) e glibenclamida (1mg/Kg, s.c); participaÃÃo da via guanilato ciclase solÃvel/GMPc: azul de metileno (Azul) (3mg/kg, s.c). ApÃs 40 min. da administraÃÃo dos fÃrmacos, os animais foram anestesiados (Ketamina/Xilasina 20-10mg/Kg-IP), seguiu-se laparotomia com implante de cÃnulas de polivinil (OE=50mm/OI=30mm). O cÃlon foi perfundido (0.16mL/min - Tyrode, 0,05mg/mL de vermelho de fenol (VF) a 37ÂC/60min). VariaÃÃes das concentraÃÃes de Na+, K+, Cl-, Ca++ e HC03 (mmol/LâGasometro) foram usadas para determinar o TC. Dados analisados por mÃdiaÂEPM, testeâtâstudent (*P<0,05). Resultados: O TF crÃnico promoveu secreÃÃo (*P<0,05) cÃlica de H2O, Na+, Cl-, K+, no entanto nÃo houve diferenÃas para Ca++ e HC03- quando comparados aos sedentÃrios (absorÃÃo). Jà o TF agudo nos animais vagotomizados, ou prÃ-tratados com atropina apresentaram diminuiÃÃo do padrÃo secretor ou ainda absorÃÃo. Da mesma maneira os animais esplancnotomizados ou prÃ-tratados com guanetidina apresentaram absorÃÃo. Jà o prÃ-tratamento com L-NAME, Azul e glibenclamimda promoveram diminuiÃÃo do padrÃo secretor ou ainda absorÃÃo. ConclusÃo: Os resultados sugerem que o EF à capaz de promover secreÃÃo de Ãgua e eletrÃlitos por um mecanismo dependente das vias parassimpÃtica ou simpÃticas ou ainda a via da NO/Sintase/GC/canais de K+ ATP-dependentes.

Orientador: Jose Barreto Campello Carvalheira / Tese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T00:26:02Z (GMT). No. of bitstreams: 1 Flores_MarceloBeneditodaSilva_D.pdf: 2957448 bytes, checksum: f168cee98307f1e264e0d77d10a83423 (MD5) Previous issue date: 2012 / Resumo: O câncer colorretal é um dos maiores problemas de saúde em todo o mundo acometendo 1 milhão de pessoas por ano. O índice de morte associado a essa doença é de aproximadamente 33% no mundo desenvolvido. A associação entre a obesidade e o risco para o desenvolvimento desse câncer é observada tanto em homens quanto em mulheres. A inflamação e a hiperinsulinemia, condições verificadas na obesidade podem contribuir, a princípio, para o risco de desenvolvimento do câncer colorretal. O fator de necrose tumoral alfa (TNF-alfa) é um dos mais importantes mediadores da resposta inflamatória e sua alta expressão pelo tecido adiposo é verificada nas condições de obesidade tanto em modelos animais quanto em humanos. O TNF-alfa contribui para a desregulação da via da sinalização insulínica através da fosforilação em serina dos substratos do receptor desse hormônio (IRS) mediada pela ativação de quinases como c-jun N terminal quinase (JNK) e da quinase inibidora do fator nuclear NF-kB (IKK). A ativação dessas quinases induz a fosforilação inibitória do substrato 1 do receptor de insulina (IRS-1) através da serina 307 (Ser307). Esse mecanismo reduz a ativação da via da fosfatidilinositol 3-quinase (PI3K)/Akt e da proteína alvo da rapamicina em mamíferos (mTOR) mediada pela insulina. TNF-alfa foi, a princípio, identificado como um agente antitumoral. Atualmente essa citoquina é reconhecida como uma promotora da tumorigênese e que associa a inflamação ao câncer. A importância do TNF-alfa e de seus mediadores intracelulares, JNK e IKK, como promotores do câncer de cólon é corroborada por estudos farmacológicos que utilizaram o azoximetano (AOM) ou AOM associado ao dextran sulfato de sódio (DSS) como indutores do câncer colorretal. Ademais, o aumento das concentrações do TNF-alfa associado à obesidade é um mecanismo comprovado de aumento do câncer de fígado em modelos animais. Embora as evidências de que a inflamação e a hiperinsulinemia tenham um envolvimento em potencial na gênese tumoral mediada pela obesidade, à avaliação sistemática da contribuição independente desses fatores para o desenvolvimento do câncer colorretal ainda é inconsistente. Neste trabalho, foi avaliado se a obesidade modulou a sinalização insulínica e a inflamação em tecido colônico e nos tumores colorretais. Foi mostrado que a resposta inflamatória anormal induzida pela obesidade promoveu de forma contundente o câncer colorretal / Abstract: Colorectal cancer (CRC) remains a major health burden with more than 1 million cases worldwide and a disease-specific mortality of approximately 33% in the developed world. The association between obesity and the risk for CRC development is observed in both men and women. In addition to its association with obesity, inflammation and hyperinsulinemia also primarily may contribute to the risk for development of CRC. Among the major mediators of the inflammatory response is tumor necrosis factor (TNF-alfa), whose overexpression in adipose tissue is a common feature in human and animal models of obesity. TNF-alfa contributes to the deregulation of the insulin-signaling pathway, including serine phosphorylation of insulin-receptor substrate (IRS) proteins by kinases such as c-jun N terminal kinase (JNK) and inhibitor of nuclear factor-kB kinase (IKK). JNK and IKK activation induce inhibitory serine 307(Ser307) phosphorylation of IRS-1, which decreases insulin-mediated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation. TNF-alfa, first identified as an antitumor agent, now also is recognized as a tumor-promoting cytokine that links inflammation and cancer. The importance of TNF-alfa and its intracellular mediators, such as JNK and IKK, as colonic tumorigenic promoters is strengthened by knockout and pharmacologic studies, using azoxymethane (AOM) or AOM combined with dextran sulfate sodium (DSS) as inducers of colorectal carcinogenesis. Furthermore, the increased TNF-alfa levels associated with obesity are a potent liver tumor promoter in mice. Although the evidence for the potential involvement of inflammation and hyperinsulinemia in the development of obesity-mediated cancer is quite extensive, a systematic evaluation of the independent contribution of these factors to CRC development is lacking. Here, we examined whether obesity modulates insulin signaling and inflammation in the colon and CRC. We show that the obesity induced abnormal inflammatory response strongly promotes CRC / Doutorado / Clinica Medica / Doutor em Clínica Médica

Soluble dietary fibers (SDF) are fermented more than insoluble dietary fibers (IDF), but their effect on colonic bacterial community structure and function remains unclear. Thus, bacterial community composition and function in the colon of BALB/c mice (n = 7) fed with a high level (approximately 20%) of typical SDF, oat-derived beta-glucan (G), microcrystalline cellulose (M) as IDF, or their mixture (GM), were compared. Mice in group G showed a lowest average feed intake (p < 0.05) but no change on the average body weight gain (p > 0.05) compared to other groups, which may be associated with the highest concentration of colonic propionate (p < 0.05) in these mice. The bacterial alpha-diversity of group G was significantly lower than other groups (p < 0.01). In group G, the relative abundance of bacteria belonging to the phylum Bacteroidetes was significantly increased, whereas bacteria from the phylum Firmicutes were significantly decreased (p < 0.01). The core bacteria for different treatments showed distinct differences. Bacteroides, Dehalobacterium, and Prevotella, including known acetogens and carbohydrate fermenting organisms, were significantly increased in relative abundance in group G. In contrast, Adlercreutzia, Odoribacter, and Coprococcus were significantly more abundant in group M, whereas Oscillospira, Desulfovibrio, and Ruminoccaceae, typical hydrogenotrophs equipped with multiple carbohydrate active enzymes, were remarkably enriched in group GM (p < 0.05). The relative abundance of bacteria from the three classes of Proteobacteria, Betaproteobacteria, Gammaproteobacteria (including Enterobacteriaceae) and Deltaproteobacteria, were significantly more abundant in group G, indicating a higher ratio of conditional pathogenic bacteria in mice fed dietary beta-glucan in current study. The predicted colonic microbial function showed an enrichment of "Energy metabolism" and "Carbohydrate metabolism" pathways in mice from group G and M, suggesting that the altered bacterial community in the colon of mice with the two dietary fibers probably resulted in a more efficient degradation of dietary polysaccharides. Our result suggests that the influence of dietary beta-glucan (SDF) on colonic bacterial community of mice was more extensively than MCC (IDF). Co-supplementation of the two fibers may help to increase the bacterial diversity and reduce the conditional pathogens in the colon of mice.

Colonic epithelial glycoproteins were histochemically studied in rats during the induction of colorectal cancer with 1,2,-dimethylhydrazine-diHCl (DMH). 310 male Wistar rats were separated into 3 groups: 10 control rats were sacrificed without treatment, 150 rats were given weekly subcutaneous injections of the carcinogen and 150 rats were given sham Injections on the same schedule. Groups of rats (10 control and 10 treated) were sacrificed at various time intervals in an effort to obtain a large number of pre-neoplastic rat colons to be used to determine whether histochemical changes could be detected prior to morphologic change. Three histochemically distinct regions in the Wistar rat distal colon have been described using recently developed techniques. Two major histochemical changes have been shown to occur prior to malignancy. Change 'A' represented a decrease or loss of sulphate from the glycoproteins; this was the earliest and predominant change and has been shown to occur prior to any identifiable morphologic change. Change 'B' represented a decrease or loss of sulphate occurring in the same cells as a decrease or loss of side chain 0-acetylation of sialic acid residues; this change occured later and to a lesser extent than change 'A'. The data suggests that histochemical change may be a premalignant marker, however, further investigations are necessary to firmly establish this conclusion. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Les douleurs abdominales chroniques, souvent associées à une hypersensibilité viscérale d’origine colique (HSVC), sont l’un des symptômes majeurs constatés lors du syndrome de l’intestin irritable (SII). Le SII est une colopathie chronique fonctionnelle touchant environ 11% de la population mondiale et altérant significativement la qualité de vie des patients. L’étiologie multifactorielle de cette pathologie rend la physiopathologie complexe. Les gastroentérites infectieuses ont été décrites comme l’un des facteurs de risque dans le développement du SII-post-infectieux (SII-PI). Le SII-PI survient en effet dans 4 à 31% des cas suite à une gastroentérite aigüe d’origine bactérienne, virale ou parasitaire. Ces infections peuvent avoir de nombreuses répercussions et en particulier sur l’intégrité de la barrière épithéliale intestinale, le système immunitaire ou encore sur le microbiote intestinal. Par ailleurs, suite à une infection parasitaire, le risque de développer un SII est de 40% contre seulement 14% suite à une infection bactérienne.Blastocystis est le parasite intestinal le plus fréquemment retrouvé chez l’Homme. Néanmoins, malgré de récentes études épidémiologiques rapportant une plus forte prévalence de ce parasite chez les patients atteints de SII, son rôle en santé humaine reste débattu. De plus, d’autres études rapportent que les individus porteurs de ce parasite présentent des douleurs abdominales et sont atteints d’une dysbiose intestinale. Actuellement, l’absence d’un modèle animal d’infection par Blastocystis reproductible ne permet pas d’étudier les mécanismes physiopathologiques liés à l’infection et donc d’explorer la contribution éventuelle de ce parasite dans le SII.Les objectifs de ce travail de thèse étaient tout d’abord de mettre en place un modèle murin d’infection expérimentale par Blastocystis pour dans un deuxième temps évaluer si ce parasite est capable d’induire une HSVC et une dysbiose intestinale avec l’objectif d’établir un nouveau modèle de SII d’origine infectieuse chez le rat. Pour répondre au premier objectif, le pouvoir infectieux de différents sous-types et différentes formes du parasite (formes vacuolaires ou kystes), isolés de cultures axéniques ou purifiés à partir de selles de patients et d’animaux a été évalué chez des animaux de laboratoire (rats et souris). Nous avons ainsi réussi à établir un modèle reproductible d’infection chronique par Blastocystis chez le rat de laboratoire à l’aide de kystes purifiés à partir de selles humaines.L’utilisation de ce modèle in vivo, nous a permis de mettre en évidence que le sous-type 4 (ST4) de Blastocystis induit une HSVC sans origine inflammatoire chez les rats expérimentalement infectés. De plus, les animaux développent un comportement type anxio-dépressif corrélé à l’HSVC. La dysbiose intestinale associée à l’infection se caractérise par une augmentation de la richesse bactérienne et une diminution du ratio Firmicutes/Bacteroidetes. Par ailleurs, nous avons corrélé l’HSVC à l’augmentation de l’abondance relative du genre Bacteroides et la diminution de l’abondance relative de la famille des Clostridiaceae, bactéries productrices d’acides gras à chaine courte (AGCC). Une diminution des taux d’AGCC fécaux a d’ailleurs été constatée chez les rats infectés. De plus, nous avons mis en évidence une augmentation de l’activité de protéases à sérine dans les fèces des animaux infectés pouvant expliquer l’HSVC.Ces données suggèrent qu’une infection gastro-intestinale par Blastocystis serait associée à une hypersensibilité viscérale d’origine colique (HSVC) et à un déséquilibre de la flore intestinale (dysbiose). Ainsi, ce nouveau modèle d’infection pourrait être un bon modèle de SII d’origine infectieuse et pourrait donc contribuer à un meilleur diagnostic et au développement de nouvelles stratégies thérapeutiques pour des pathologies chroniques de l’intestin chez certains individus. / Chronic abdominal pain often associated with colonic hypersensitivity (CHS) is one of the major symptoms of irritable bowel syndrome (IBS). IBS is a functional chronic disorder affecting ~11% of worldwide population and disturbing patients’ quality of life. Etiology is multifactorial and thus pathophysiology is complex and remains poorly understood. Infectious gastroenteritis has been described as one of the risk factors for development of post-infectious IBS (PI-IBS). PI-IBS can occur in 4-31% of patients following acute gastroenteritis of bacterial, viral or parasitic origin. Numerous studies support a role for pathogen-mediated modifications in the resident intestinal microbiota, epithelial barrier integrity and immune activation in PI-IBS. Interestingly, the risk of IBS is highest with protozoal enteritis, with ~40% of individuals developing IBS against ~14% following bacterial infection. Blastocystis is the most common intestinal parasite found in human intestinal tract. Nevertheless, clinical relevance remains controversial, despite recent epidemiological studies showing a higher prevalence of this parasite in IBS patients. Interestingly, studies report that individuals carrying Blastocystis display abdominal pain and intestinal dysbiosis. Currently, the lack of reproducible animal model of Blastocystis infection does not allow to study the pathological mechanisms related to infection and thus to explore the potential contribution of this parasite in IBS.The aims of this study were first to develop a murine model of Blastocystis infection and then to investigate whether this parasite could lead to the development of intestinal dysbiosis associated CHS with the aim of developing a new PI-IBS rat model.The first aim was to evaluate the infectivity of different parasitic subtypes and stages (vacuolar and cystic forms) isolated from axenic cultures or purified from human or animal feces, into laboratory animals (rats and mice). Interestingly, we succeeded in the development of a reproducible model of chronic infection by Blastocystis in laboratory rats using cysts purified from human stool.Using this animal model, we found that Blastocystis ST4 induced non inflammatory CHS in infected rats. In addition infected rats developed anxiety- and depressive-like behavior correlated with CHS. Infection associated intestinal dysbiosis was characterized by increased bacterial richness and decreased Firmicutes/Bacteroidetes ratio. Interestingly, we correlated CHS with the increase in the relative abundance of genus Bacteroides and the decrease in the relative abundance of the family Clostridiaceae, some bacteria producing Short Chain Fatty Acids (SCFAs). Indeed, fecal SCFAs levels were decreased in infected rats. These decreases were correlated with the relative abundance of genus Oscillospira which was also described increased in Blastocystis individual carriers. In addition, we have demonstrated an increase in fecal serine protease activity in infected animals that may explain development of CHS.These data suggest that a gastrointestinal infection with Blastocystis may be associated with the establishment of intestinal dysbiosis associated CHS. Thus, this new infectious model could be a good model of PI-IBS and could therefore contribute to a better diagnosis and development of new therapeutic strategies for chronic bowel diseases.

(en) Charles University in Prague Faculty of Pharmacy Hradec Králové Department of Pharmacology  Toxicology Student: Růžena Kubíčková Supervisors: Prof. Manuela Morato PharmDr. Ivan Vokřál, PhD. Title of diploma thesis: Differential reactivity of the longitudinal and circular muscle of the rat distal colon Physiological regulation of the function of the large intestine is neurohumoral. The neural part of this regulation implies the vegetative nervous system, which is crucial for the control of the gastrointestinal tract (GIT) motility. Concerning the humoral part of the regulation, recent studies showed that angiotensin II (Ang II) causes contraction of the colonic smooth muscle and, thus, can also influence the motility of the colon. However, there are no known studies that have described this process in detail. The aims of this work were (1) to compare the reactivity of the longitudinal and circular muscles of the rat distal colon to potassium chloride (KCl), acetylcholine (ACh) and Ang II, (2) to compare the observed results between male and female rats, and (3) to characterize the receptors mediating the response to Ang II. For purpose of the project, adult, 10-12 weeks old Wistar Han rats of both genders were used. Strips of the the rat distal colon were mounted in organ baths along their...

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21449号 / 医博第4416号 / 新制||医||1032(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 松原 和夫, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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No / Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA–FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA-FFA is an excellent candidate for CRC chemoprevention in CAC.