Background: Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. Aim: The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N-nitrosourea (NMU)-induced GC in rats. Methods: In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 μg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Results: Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group (P<0.05, P<0.01, and P<0.01). Conclusion: Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future.

No description available.

Background & aims: The inflammatory bowel diseases (IBD), Crohn‟s disease (CD) and ulcerative colitis (UC), are common causes of chronic gastrointestinal morbidity, affecting up to 1 in 250 of the general population in Northern Europe. Up to 25% of IBD is diagnosed during childhood or adolescence. The aims for this thesis were to study the epidemiology, natural history and novel genetic determinants of childhood onset IBD in Scotland. Methods: The existing repository of childhood onset and adult onset IBD patients, established at the Western General Hospital in Edinburgh, was used and expanded. Thus, anatomical location and behaviour of disease were assessed in 416 childhood onset (276 CD, 99 UC, 41 IBDU diagnosed before 17th birthday) and 1297 adult patients (596 CD, 701 UC) using the Montreal classification. Additional phenotypic (at diagnosis and at regular follow-up intervals) and epidemiological data were gathered. In this cohort, genotyping of germline variants in putative susceptibility genes (NOD1/CARD4, IL23R, ATG16L1, IRGM, FLG) was performed to enable single variant and haplotype-tagging association studies. Genotypic data of population-matched healthy controls were obtained locally (n=342) and from the Wellcome Trust Case Control Consortium (n=2937). Results: Compared with adults, childhood-onset CD was characterized by a more extensive, “panenteric” phenotype (ileocolonic plus upper GI; p<0.0001 OR23.3; 95% CI (13.4–40.6) with less isolated ileal (p<0.0001 OR 0.06 (0.03–0.1) or colonic disease (p<0.0001, OR 0.3 (0.2–0.5)). In 39%, the anatomic extent increased within 2 years. UC was also more extensive in children at diagnosis vs adults (p<0.0001 OR 5.1 (2.7–9.4)). In population-matched and age, sex and postcode-matched case-control analysis, childhood onset IBD and CD was associated with asthma (p<0.0001 OR 1.7 (1.3-2.1) and (p=0.005 OR 2.5 (1.3-4.8), respectively). Inherited variation of NOD1/CARD4 was not a strong determinant of disease susceptibility in the Scottish population (both in single marker and haplotype-tagging studies, all p>0.05 after Bonferroni correction). We found that the allelic frequency of rs11209026*A located within the IL23R gene, differed significantly between IBD/CD cases and controls (p=0.01 OR 0.51(0.3-0.9) and p=0.04 OR 0.5 (0.3-0.98)). Using a gene-wide haplotype-tagging strategy, we demonstrated that the multiple association signals of the IL23R locus are independent of rs11209026 in childhood onset IBD and CD. In Scottish children, the effect of germline variation of ATG16L1 and IRGM on CD susceptibility was relatively small (OR< 1.4), and appeared less than in adult disease. Genotype–phenotype analysis demonstrated an association of pure ileal disease with the ATG16L1 rs2241880G-allele (p=0.02 OR 1.3 (1.03–1.7)). Using binary logistic regression analysis, we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (p=0.03 OR 2.4 (1.05–5.6)). Null alleles of the epithelial barrier protein FLG have no important effect on IBD susceptibility (p>0.4), but contribute to the high prevalence of atopy, notably co-existent eczema and food allergy (p=0.0003 OR 3.3 (1.7–6.6) and p=0.0001 OR 4.5 (2.0–10.0), respectively). Conclusion: Childhood onset IBD is characterised by extensive intestinal involvement and progression of disease after diagnosis. Genetic association studies in childhood and adult IBD have provided evidence for a large number of new genomic loci. These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors, the differentiation of Th17-lymphocytes, autophagy, maintenance of epithelial barrier integrity and the orchestration of the secondary immune response.

The aetiology of the inflammatory bowel diseases ulcerative colitis and Crohn’s disease remains uncertain. Genetic studies and model systems strongly implicate components of the IL-23/type-17 axis in the pathogenesis of disease, but the cellular and molecular mediators are uncertain. Using an IL-23R^gfp reporter mouse we analysed the cellular expression of IL-23R in homeostasis and disease. Whereas steady state expression in the intestine was dominated by a collection of unconventional lymphoid cells including ;gamma& ;delta& T-cells, we found rapid accumulation of IL-23R⁺CD4<sup>+</sup T-cells occurred in evolving colitis, and demonstrate an important role for IL-10 in the regulation of IL-23R specifically upon intestinal CD4+ T-cells. Examining the role of ;gamma& ;delta& T-cells in a model of IL-23-dependent colitis, we demonstrate apparent redundancy of such cells for the development of the adaptive CD4+ Th17 response. Furthermore, treatment with FTY720 which is known to inhibit lymphocyte recirculation did not attenuate disease nor reduce intestinal Th17 cell accumulation, suggesting the mechanisms of accumulation of Th17 cells in the intestine may differ from other anatomical sites. Next, we addressed the role of IL-21, a cytokine implicated in the development and effector functions of the IL-23/Th17 axis. Remarkably, we found that although IL-21 was pathogenic in models of chronic colitis, its effects on effector T-cell subsets were model-specific and included Th17 and Th1 cells. However, increased regulatory T-cell populations and reduced Ccl5 expression were common effects between models. Paradoxically, in a model of enteric infection, IL-21 was required for host defence, with IL-21R^-/- mice developing increased bacterial colonisation and severe colitis, shown to be driven by increased Th1/IFN-;gamma& responses. These studies provide novel insights into aspects of IL-23 driven cellular and molecular pathways in homeostasis and inflammation in the intestine, with implications for future therapeutic approaches to IBD.

Elevated levels of the cytokine interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD). However, the role of IL-18 in mucosal immunity and inflammation is not well understood. At mucosal and environmental interfaces, Th17 cells have been shown to contribute to protection from pathogenic infection. In contrast, regulatory T (Treg) cells maintain intestinal homeostasis by preventing aberrant inflammatory responses to the resident microbiota. We demonstrate that under homeostatic conditions, colonic Th17 cells highly express IL-18 receptor (IL-18R1) and that intestinal epithelial cell production of IL-18 acts directly on CD4⁺ T cells to limit colonic Th17 differentiation. Furthermore, whilst IL-18R1-signalling is dispensable for induction of colitis, we observed a critical role for IL-18R1-signalling in Foxp3⁺ Treg mediated control of colitis. Together, these studies demonstrate that the intestinal epithelium regulates colonic CD4⁺ T cell responses through production of the cytokine IL-18.

Cryptosporidiosis is a common infectious diarrhoeal disease of mammalian livestock and humans worldwide. The etiological organisms responsible are intestinal apicomplexans of the genus Cryptosporidium, including C. parvum, that infect intestinal epithelial cells. Immunocompromised or malnourished hosts develop severe life-threatening disease. Immunological elimination of Cryptosporidium requires CD4+ T cells and IFN-γ. Nevertheless, studies have shown innate immune responses have a significant protective role. Importantly, in T cell-deficient mice, IFN-γ is important for control of C. parvum infection. In innate immunity natural killer (NK) cells are major producers of IFN-γ and are activated by cytokines including type I IFNs but the roles of these components in immunity to Cryptosporidium infection have not been investigated. Therefore, the purpose of this project was to study the involvement of type I IFNs and NK cells in immunity to C. parvum employing in vitro and in vivo (murine) infection models. Enterocytes were shown capable of the production of type I IFNs in response to C. parvum infection. These cytokines directly inhibited parasite development in epithelial cells. Also, in neonatal SCID mice the level of infection increased after treatment with anti-type I IFN neutralising serum. A higher level of infection was observed in Rag2-/-γc-/- mice deficient in T, B and NK cells in comparison to Rag2-/- mice with a normal NK cell population and early mortality during chronic infection of adult animals was associated with the absence of NK cells. Using cultures of SCID mouse splenocytes, NK cells were the main source of IFN-γ in response to C. parvum antigen stimulation. However, IFN-γ was also found to have a protective role in Rag2-/-γc-/- mice, implying cells other than lymphocytes produce this cytokine. In conclusion, this is the first study to indicate important protective roles for type I IFNs and NK cells in innate immunity against C. parvum.

Thesis (Ph. D.)--University of Adelaide, Dept. of Medicine, 1984. / Some mounted ill. Includes bibliographical references (leaves 203-263).

Thesis--University of Copenhagen. / Bibliography: p 205-227.

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Orientadores: Luiz Sergio Leonardi, Michel Cremer, Luis Alberto Magna / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T11:06:50Z (GMT). No. of bitstreams: 1 Trentini_ElianeAnrain_M.pdf: 2064169 bytes, checksum: 0b3a3597ddde6867786067aded166323 (MD5) Previous issue date: 2006 / Resumo: Não há, ainda, um modelo ideal de reconstrução das lesões extensas da via biliar. A reconstrução em Y de Roux é clássica, com vantagens como baixa incidência de refluxo de conteúdo intestinal para as vias biliares. Porém, como não é anatômica, ela dificulta enormemente ou impede o acesso endoscópico à via biliar. Uma técnica fisiológica para a substituição do colédoco é a interposição de segmento pediculado de jejuno entre a via biliar e o duodeno, descrita desde 1950 e realizada com êxito em número expressivo de pacientes. Contudo, esta técnica não se tornou amplamente utilizada. Com o intuito de reconstruir a via biliar de maneira fisiológica foi proposta a aplicação do princípio de Monti às vias biliares, que já está estabelecido em humanos para vias urinárias. Nesta técnica, faz-se a detubularização e retubularização transversa de um segmento de jejuno, promovendo uma modificação no sentido das pregas mucosas, tornando-as longitudinais o que facilita o fluxo de líquidos no seu interior. Ao aplicá-la na reconstrução das vias biliares possibilita-se, sobretudo, o acesso endoscópico, diagnóstico e terapêutico, às vias biliares. No presente estudo, foram operados 13 cães: inicialmente foi realizada ligadura laparoscópica do colédoco dos cães para provocar dilatação da via biliar e icterícia obstrutiva. Após uma semana, foi realizada derivação biliodigestiva por laparotomia com a interposição do tubo jejunal acima descrito entre a via biliar dilatada e o duodeno. Os cães foram submetidos a dosagens bioquímicas de transaminases glutâmico-pirúvica e glutâmico-oxalacética, bilirrubinas totais, fosfatase alcalina e gamaglutamiltransferase no pré-operatório das cirurgias e semanalmente, até a eutanásia, realizada seis semanas após a derivação biliodigestiva, quando foi realizada nova laparotomia e ressecção da peça via biliar-tubo jejunal-duodeno em monobloco para análise macroscópica. Foi coletada bile dos cães por ocasião da derivação biliodigestiva e no sacrifício. Dos 13 submetidos a ligadura laparoscópica de colédoco, um foi excluído porque não alcançou significativa dilatação da via biliar. Após a derivação biliodigestiva três cães morreram; destes três, apenas um apresentou peritonite à necropsia. Portanto, nove cães tiveram seus dados submetidos à análise estatística. Eles apresentaram icterícia obstrutiva após sete dias de ligadura do colédoco, comprovada por exames bioquímicos. Todos os nove animais apresentaram redução gradativa, estatisticamente significativa, de sua colestase após derivação biliodigestiva com a interposição do tubo jejunal pediculado e mantiveram-se saudáveis até o término do experimento. Os valores médios de bilirrubina total, fosfatase alcalina e gamaglutamiltransferase uma semana após ligadura da via biliar foram: 4,39; 3251,7 ; 66,1. Os valores dessas variáveis seis semanas após a derivação biliodigestiva foram 0,11 ; 323,1 ; 10,7, respectivamente. Concluiu-se que o tubo de segmento jejunal interposto entre o colédoco previamente ligado e o duodeno foi eficaz na descompressão da via biliar. A análise macroscópica das peças coletadas mostrou boa integração via biliar-tubo e tubo-duodeno. Com a abertura longitudinal das peças observou-se ótima cicatrização das estruturas anastomosadas e perviedade do tubo jejunal / Abstract: An ideal model for reconstruction of extensive lesions of the biliary tract has not been found so far. The Roux-en-Y reconstruction is a classic reconstruction and presents advantages as the low incidence of intestine contents reflux to the biliary tract. However, since this is not anatomical, it impedes or impairs the endoscopic access to the biliary tract. A physiological technique to replace the common bile duct is the interposition of a pediculated segment of jejunum between the biliary tract and the duodenum, described since 1950 and successfully performed in several patients. However, this technique has not been widely adopted. The present experimental study was proposed for reconstruction of the biliary tract in a physiological manner, by application of the Monti principle to the biliary tract, which is well established in humans for the urinary tract. This technique comprises detubulization and transverse retubulization of a segment of jejunum, changing the mucosal folds in longitudinal direction, thus enhancing the flow of liquids inside it. Its application for reconstruction of the biliary tract would allow endoscopic access to the biliary tract, for both diagnostic and therapeutic purposes. Thirteen dogs were operated in the present study; initially, laparoscopic ligation of the common bile duct of dogs was performed to induce extrahepatic cholestasis. After one week, biliodigestive derivation was performed by laparotomy with interposition of the aforementioned jejunal tube between the dilated biliary tract and the duodenum. The dogs were submitted to biochemical dosage of alanine and aspartate transaminases, total bilirrubin, alkaline phosphatase and gamma-glutamyltransferase preoperatively and weekly for six weeks postoperatively. Another laparotomy was then performed with resection of a monoblock specimen from the biliary tract-jejunal tube-duodenum for macroscopic analysis and the animals were killed. Bile was collected from the dogs upon biliodigestive derivation and upon killing. From the 13 animals submitted to laparoscopic ligation of the common bile duct, one was excluded because significant dilation of the biliary tract was not achieved. Three dogs died after biliodigestive derivation; among these, only one exhibited peritonitis upon autopsy. Thus, data on nine dogs were submitted to statistical analysis. These dogs exhibited obstructive jaundice at seven days after ligation of the common bile duct, as demonstrated by biochemical examinations. All nine animals presented statistically significant gradual reduction of cholestasis after biliodigestive derivation by interposition of a pediculated jejunal tube and were healthy until study completion. The mean values of total bilirubin, alkaline phosphatase and gamma glutamyltransferase at one week after ligation of the biliary tract were: 4.39; 3251.7; and 66.1. The values of these variables at six weeks after biliodigestive derivation were 0.11 ; 323.1 and 10.7, respectively. It was concluded that interposition of a jejunal segment tube between the previously ligated common bile duct and the duodenum was effective for decompression of the biliary tract. Macroscopic analysis of the collected specimens revealed good integration between the biliary tract and the tube and between the tube and the duodenum. Longitudinal sectioning of the specimens revealed optimal healing of the anastomosed structures and patency of the jejunal tube / Mestrado / Cirurgia / Mestre em Cirurgia