Home About us Contact
|
Home About us Contact | ||
|
|
||
Colonic Mucosa (colonic + mucosa)
Kinds of Colonic Mucosa Selected AbstractsDIAGNOSIS AND CLINICAL COURSE OF ULCERATIVE GASTRODUODENAL LESION ASSOCIATED WITH ULCERATIVE COLITIS: POSSIBLE RELATIONSHIP WITH POUCHITISDIGESTIVE ENDOSCOPY, Issue 4 2010Takashi Hisabe Background and Aim:, Ulcerative colitis (UC) is not only characterized by pathological lesions localized to colonic mucosa, but also to various complications involving other organs, including postoperative pouchitis. Among these complications, diffuse gastroduodenitis with lesions resembling colonic lesions has been reported, albeit rarely. The aim of the present study was to attempt to characterize the lesions of the upper gastrointestinal tract occurring as a complication of UC, and to assess the frequency and clinical course of these lesions. Methods:, A total of 322 UC patients who had undergone upper gastrointestinal endoscopy were retrospectively analyzed. We assessed the frequency of endoscopic findings, including diffuse gastroduodenal lesions resembling colonic lesions. Ulcerative gastroduodenal lesion (UGDL) associated with UC was diagnosed if lesions satisfied the following criteria: (i) improvement of the lesions with treatment of UC; and/or (ii) resemblance to UC in pathological findings. Results:, UGDL satisfying the aforementioned criteria was found in 15 (4.7%) of 322 patients. All the 15 patients had UGDL accompanied by pancolitis or after proctocolectomy. Frequency in 146 patients with pancolitis was 6.2% (nine patients) and that in 81 patients who had undergone proctocolectomy was 7.4% (six patients). Four patients with diffuse ulcerative upper-gastrointestinal mucosal inflammation (DUMI) had pouchitis. In all patients except one, the lesions resolved easily with medical treatment. Conclusions:, In more than half of the post-proctocolectomy patients, UGDL was related to the occurrence of pouchitis. The existence of characteristic UGDL must be taken into account in the diagnosis and treatment of UC, and UGDL is possibly related to the occurrence of pouchitis. [source] ILEITIS AS A MAIN RECURRENT LESION IN A PATIENT WITH ULCERATIVE COLITIS: REPORT OF A CASEDIGESTIVE ENDOSCOPY, Issue 2 2000Shuichi Sano We report a case of ulcerative colitis complicating ileitis that endoscopically and histologically resembled a colonic lesion. Eight years prior to the time of writing, the patient had undergone proctosigmoidectomy and ileocecal resection because of severe hemorrhagic lesions of ulcerative colitis. A month prior to the time of writing, bleeding from the stoma occurred. Endoscopy revealed erosions on easy-bleeding mucosa in the ileum but no active inflammatory lesions in colonic mucosa except for small erosions in the descending colon beneath the stoma. Histologic findings of biopsy specimens from the ileal mucosa showed marked inflammation including neutrophile infiltration and crypt abscesses. This is a rare case of ulcerative colitis showing ileitis as a main recurrent lesion, suggesting that careful observation of the small intestine will be required after ileocecal resection in ulcerative colitis patients. [source] Protective effect of curcumin, a Curcuma longa constituent, in early colonic inflammation in rats,DRUG DEVELOPMENT RESEARCH, Issue 6 2009Juan Manuel Sánchez-Calvo Abstract Curcumin, a polyphenol derived from the plant, Curcuma longa, has a variety of pharmacological effects, including chemotherapeutic, anti-inflammatory, antiangiogenic, and antioxidant activities. To gain a better understanding of the effects and mechanisms of action of curcumin on the acute injury caused by intra-colonic administration of acetic acid (AA) in rats, inflammation was assessed by histology and myeloperoxidase activity (MPO; an index of neutrophil infiltration in the mucosa); Th1 and Th2 cytokine production; histological and histochemical analysis of the lesions; nitrite production in colon mucosa; and the expression of iNOS, COX-1 and -2 using Western blotting and inmmunohistochemistry. We also studied the involvement of the p38 MAPK/JNK signalling pathway in the protective effect of curcumin in acute colonic inflammation. Curcumin (50,100,mg/kg/day) reduced the degree of colonic injury, the index of neutrophil infiltration and Th1 cytokine secretion, and increased IL-10 production, reduced colonic levels of nitrites, and reduced COX-2 and iNOS overexpression. A reduction in the activation of p38 and JNK MAPKs was also observed. Thus, we show that the widely used food additive, curcumin reduced the development of AA-induced colitis and alleviated the inflammatory response. Inhibition of MAPK signalling by curcumin could explain the changes on the cytokine Th1/Th2 profile, the reduction of COX-2 and iNOS signaling, as well as the decreased nitrite production in colonic mucosa, suggesting that curcumin may be useful in the treatment of ulcerative colitis. Drug Dev Res, 2009. © 2009 Wiley-Liss, Inc. [source] Neurologic manifestations of ulcerative colitisEUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2007R. Scheid Ulcerative colitis (UC) has traditionally been considered to be an inflammatory disease limited to the colonic mucosa. However, since it has been shown that UC is frequently accompanied by various extraintestinal disorders, there is increasing evidence that UC may also manifest in the nervous system. The following review focuses particularly on these possible manifestations of UC, both in the peripheral (PNS), and in the central nervous system (CNS). A systematic literature search according to the MEDLINE database was performed for this purpose. Although a reliable differentiation may clinically not always be possible, three major pathogenic entities can be differentiated: (i) cerebrovascular disease as a consequence of thrombosis and thromboembolism; (ii) systemic and cerebral vasculitis; (iii) probably immune mediated neuropathy and cerebral demyelination. With the exception of thromboembolism and sensorineural hearing loss, evidence for a causal relationship relies merely on single case reports or retrospective case series. Considering the CNS-manifestations, similarities between UC-associated disorders of the white matter and acute disseminated encephalomyelitis (ADEM) are obvious. Epileptic seizures, unspecified encephalopathies and confusional states are most likely epiphenomena that have to be regarded symptomatic rather than as own entities. A prospective study on the neurologic aspects of UC would be very welcome. [source] Adrenomedullin and Proadrenomudullin N-Terminal 20 Peptide (PAMP) are Present in Human Colonic Epithelia and Exert an Antimicrobial EffectEXPERIMENTAL PHYSIOLOGY, Issue 5 2001K. Marutsuka The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa. AM and PAMP showed dose-dependent antimicrobial activity against E. coli. The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence. [source] Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial speciesFEBS JOURNAL, Issue 1 2004Claire Cherbuy The expression of the colonic mitochondrial 3-hydroxy 3-methyl glutaryl CoA (mHMGCoA) synthase, a key control site of ketogenesis from butyrate, is lower in germ-free (GF) than in conventional (CV) rats. In contrast, the activity of glutaminase is higher. The objective of this study was to investigate whether the intestinal flora can affect gene expression through short chain fatty acid (SCFA) and butyrate production. GF rats were inoculated with a conventional flora (Ino-CV) or with a bacterial strain producing butyrate (Clostridium paraputrificum, Ino- Cp) or not (Bifidobacterium breve, Ino- Bb). In the Ino-CV rats, mHMGCoA synthase expression was restored to the CV values 2 days after the inoculation, i.e. concomitantly with SCFA production. In the Ino- Cp group, but not in the Ino- Bb group, mHMGCoA synthase and glutaminase were expressed at the level observed in the CV rats. These data suggest that the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase and glutaminase. These modifications in gene expression by butyrate in vivo seem unrelated to a modification of histone acetylation. [source] Shigella spp. and enteroinvasive Escherichia coli pathogenicity factorsFEMS MICROBIOLOGY LETTERS, Issue 1 2005Claude Parsot Abstract Bacteria of Shigella spp. (S. boydii, S. dysenteriae, S. flexneri and S. sonnei) and enteroinvasive Escherichia coli (EIEC) are responsible for shigellosis in humans, a disease characterized by the destruction of the colonic mucosa that is induced upon bacterial invasion. Shigella spp. and EIEC strains contain a virulence plasmid of ,220 kb that encodes determinants for entry into epithelial cells and dissemination from cell to cell. This review presents the current model on mechanisms of invasion of the colonic epithelium by these bacteria and focuses on their pathogenicity factors, particularly the virulence plasmid-encoded type III secretion system. [source] An enteroaggregative Escherichia coli strain of serotype O111:H12 damages and invades cultured T84 cells and human colonic mucosaFEMS MICROBIOLOGY LETTERS, Issue 2 2001Cecilia M. Abe Abstract The pathogenic mechanisms of enteroaggregative Escherichia coli (EAEC) are not well defined. We investigated the interaction of EAEC strain 236 (serotype O111:H12) with polarised Caco-2 and T84 human intestinal epithelial cells lines, and with human jejunal and colonic mucosa. Strain 236 adhered to both polarised cell lines and to both intestinal tissue types, but caused severe damage and was invasive only in T84 cells and colonic mucosa. In contrast, prototype EAEC strain 042, which also adhered to the cultured intestinal cell lines, did not adhere to or invade jejunal or colonic tissue. These observations suggest a heterogeneity of virulence properties within the EAEC category of diarrhoea-causing E. coli. [source] Biotransformation in vitro of the 22R and 22S epimers of budesonide by human liver, bronchus, colonic mucosa and skinFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2001Julio Cortijo The pharmacological effects of glucocorticoids are greatly influenced by their pharmacokinetic properties. In the present report, the in vitro biotransformation of the 22R and 22S epimers of the topical steroid budesonide was studied in the S-9 fraction of human liver, bronchus, skin and colonic mucosa. The disappearance of unchanged epimers of budesonide was measured during 90 min of incubation by high performance liquid chromatography. The rate of disappearance was high in human liver while little biotransformation occurred in bronchial tissue and colonic mucosa, and none was detected in the skin. A marked decay of the initial concentration of unchanged budesonide epimers was noticed after 2 h incubation in cultured human hepatocytes, while only a small decrease was observed after 24 h incubation in cultured human airway smooth muscle cells and BEAS-2B cells. The 22R epimer of budesonide suffered greater in vitro biotransformation than the 22S epimer in human hepatic, bronchial and colonic tissues. These findings extend those of other studies, and confirm that the high therapeutic ratio of budesonide is due to negligible local biotransformation combined with high level of liver metabolism for locally absorbed budesonide. [source] Polypoid prolapsing mucosal folds with diverticulosis and colonic muco-submucosal elongated polypsGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 1 2006Nobuo Kanazawa Background: In 1991, Kelly first reported the presence of red or brown mucosal protrusions or polyps associated with diverticular disease and described this syndrome as ,polypoid prolapsing mucosal folds in diverticular disease.' In 1994, Matake et al. independently reported several long mucosal intraluminal protrusions as ,colonic muco-submucosal elongated polyps.' The purpose of the present study is to address the relationship between the two syndromes. Methods: We performed a careful review of the published work on the clinicopathological features of these syndromes. Results: The clinical symptoms associated with these two syndromes do not differ notably. Because of the mucosal redundancy of the colonic mucosa, the excessive propulsive power of peristalsis may play an important role in generating both types of polyps. Neither ,polypoid prolapsing mucosal folds in diverticular disease' nor ,colonic muco-submucosal elongated polyps' fit into any of the conventional classifications, and their histological characteristics are similar. In addition, we describe the diagnosis and clinical management at our institution of an emergent case of polypoid prolapsing mucosal folds in diverticular disease. Conclusion: In light of their similar etiology and pathology, we propose that these conditions are different manifestations of the same entity. Unifying these two classifications into one makes the diagnosis of either type of polyp less onerous for clinicians, endoscopists and pathologists. As a consequence, it is likely that more cases will be diagnosed and reported. The accumulation of more cases will lead to deeper understanding and further clinicopathological characterization of diverticular polyps. [source] Preserved Na+/H+ exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis,INFLAMMATORY BOWEL DISEASES, Issue 7 2010Sunil Yeruva PhD Abstract Background: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na+ absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na+ absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na+ absorptive protein, the Na+/H+ exchanger isoform 3 (NHE3) in biopsies from UC patients. Methods: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-,), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na+ absorptive capacity was assessed by 22Na+ isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. Results: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na+ absorption was strongly reduced by ,80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. Conclusions: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients. (Inflamm Bowel Dis 2010) [source] GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 5 2009Motohiro Kobayashi MD Abstract Background: A diffuse lymphocyte infiltrate is 1 of the characteristic features of ulcerative colitis (UC). Such lymphocyte recruitment requires lymphocyte rolling mediated by L-selectin ligand carbohydrates (6-sulfo sialyl Lewis X-capped O -glycans) and/or mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on high endothelial venule (HEV)-like vessels. The present study was undertaken to elucidate the role of MAdCAM-1 posttranslationally modified ("decorated") with L-selectin ligand carbohydrates in UC pathogenesis and consequent clinical outcomes. Methods: Biopsy specimens composed of active and remission phases of UC as well as normal colonic mucosa were immunostained for CD34, MAdCAM-1, and MECA-79, and the immunostained sections were quantitatively analyzed. Reverse-transcriptase polymerase chain reaction (RT-PCR) was carried out to evaluate transcripts of MAdCAM-1 and N -acetylglucosamine-6- O -sulfotransferases (GlcNAc6STs). CHO and Lec2 cells transfected with CD34 and MAdCAM-1 together with enzymes involved in L-selectin ligand carbohydrate biosynthesis were analyzed by immunofluorescence, FACS, and Western blotting to characterize the biochemical properties of GlcNAc6STs. Results: The number of MAdCAM-1+ vessels was increased in UC, with no significant difference between active and remission phases. An increased ratio of MECA-79+ to MAdCAM-1+ vessels with preferential GlcNAc6ST-1 transcripts was observed in the active phase of UC compared to the remission phase. MAdCAM-1 protein was colocalized with L-selectin ligand carbohydrates at the luminal surface of HEV-like vessels in situ. GlcNAc6ST-1 preferentially utilizes MAdCAM-1 as a scaffold protein for GlcNAc-6- O -sulfation in L-selectin ligand carbohydrate biosynthesis. Conclusions: UC disease activity is not regulated by expression of MAdCAM-1 protein itself, but rather by GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates. (Inflamm Bowel Dis 2008) [source] Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naďve ulcerative colitis during active and quiescent diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2009Reikei Matsuda MD Abstract Background: Cytokines have validated roles in the immunopathogenesis of inflammatory bowel disease (IBD). This study was to investigate the expressions of tumor necrosis factor (TNF)-,, interleukin (IL)-6, IL-8, and IL-10 mRNAs in the colonic mucosa of patients with ulcerative colitis (UC) during active and quiescent UC. Methods: At colonoscopy, biopsies were taken from inflamed and non-inflamed mucosa of patients with steroid-naive UC (n = 15), non-IBD inflammatory colitis controls (ICC, n = 6), and non-colitis controls (NCC, n = 14). The presence of extensive mononuclear cells and neutrophils infiltrate in the lamina propria, cryptitis, and epithelial damage defined an inflammatory lesion in the mucosa. Quantitative cytokine mRNA expressions in biopsies were measured by real-time polymerase chain reaction (PCR). Results: Of 15 UC patients, 3 remitted with 5-aminosalicylate and 11 received granulocytapheresis; of these, 10 remitted. At baseline, IL-6, IL-8, TNF-,, and IL-10 mRNAs were high in inflamed mucosa compared with NCC (P < 0.01). In active UC, IL-6, IL-8 and IL-10 mRNAs were high compared with non-inflamed mucosa (P = 0.03, P = 0.03, P < 0.05, respectively). Both TNF-, mRNA (P = 0.03) and IL-6 mRNA (P = 0.04) were higher in UC compared with ICC. Even in non-inflamed mucosa, IL-8 and TNF-, mRNA expressions were high compared with NCC. Both IL-6 and IL-8 mRNAs decreased to normal levels after granulocytapheresis. Conclusions: During active UC, all 4 cytokine mRNA levels were high; only IL-6 and IL-8 mRNAs decreased to normal levels during remission. IL-8 mRNA was high even at sites of endoscopically quiescent UC during active disease. Steroid naďve patients respond well to granulocytapheresis. (Inflamm Bowel Dis 2008) [source] Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5INFLAMMATORY BOWEL DISEASES, Issue 12 2008Rinse K. Weersma MD Abstract Background: Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus. We studied the association of RUNX3 in a cohort of IBD patients and analyzed the interaction with SLC22A4/5. RUNX3 and OCTN1 mRNA expression was assessed in inflamed and noninflamed mucosa from patients and controls. Methods: 543 IBD patients (309 CD / 234 UC) and 296 controls were included. Four single nucleotide polymorphisms (SNPs) and 4 microsatellite markers were studied for RUNX3. Five SNPs (including SNP-207G,C and SNP1672C,T) were analyzed for SLC22A4/5. RUNX3, and OCTN1 expression in mucosal tissue from 30 patients (14 UC / 16 CD) and 6 controls were determined by quantitative polymerase chain reaction. Results: A significant association between RUNX3 -SNP rs2236851 and UC (OR 1.61; 95% confidence interval [CI] 1.11,2.32, P = 0.020) was found. Carriership is associated with pancolitis (odds ratio [OR] 1.86; 95% CI 1.08,3.21). SLC22A4/5 -SNPs rs272893 and rs273900 are associated with CD (OR 2.16; 95% CI 1.21,3.59 and OR 2.40; 95% CI 1.43,4.05). We found epistasis for carriership of a risk-associated allele in RUNX3 and SLC22A4/5 for UC patients versus CD patients (OR 3.83; 95% CI 1.26,11.67). RUNX3 mRNA expression is increased (P = 0.01) in inflamed colonic mucosa of UC patients compared to noninflamed mucosa and controls. Conclusions: We provide evidence for the genetic association of RUNX3 with UC and for CD with the IBD5 locus including SLC22A4/5. An epistatic effect of RUNX3 and SLC22A4 was associated with an increased risk for UC. Our data suggest a role for RUNX3 in UC susceptibility. (Inflamm Bowel Dis 2008) [source] Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 4 2008Rebecca Carey MD Abstract Background: While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation. Methods: Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies. Results: Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3+/CD4+ lymphocytes, and affected colon biopsies of IBD patients. The frequency of pSTAT3+ PB granulocytes and colon epithelial and lamina propria cells was highly correlated with the degree of mucosal inflammation. Microarray and Ingenuity Systems bioinformatics analysis identified IL-6:STAT3-dependent biological networks upregulated in IBD patients which control leukocyte recruitment, HLA expression, angiogenesis, and tissue remodeling. Conclusions: A proinflammatory IL6:STAT3 biologic network is upregulated in active pediatric IBD patients at diagnosis and during therapy. Specific targeting of this network may be effective in reducing mucosal inflammation. (Inflamm Bowel Dis 2007) [source] Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitisINFLAMMATORY BOWEL DISEASES, Issue 3 2004Tsunekazu Mizushima MD Abstract Background: FTY720 is a novel reagent that possesses potent immunosuppressive activity. The immunosuppression induced by FTY720 is mediated by completely different mechanisms from those of conventional immunosuppressants, that is, by altering the tissue distribution of lymphocytes rather than inhibiting activation. In this study, we examined the efficacy of FTY720 in the treatment of chronic colitis in an interleukin-10 gene-deficient (IL-10,/,) mouse model. Methods: FTY720 was administered orally for 4 weeks to IL-10,/,mice with clinical signs of colitis. The gross and histologic appearance of the colon and the numbers, phenotype, cytokine production, and apoptosis of lymphocytes were compared with those characteristics in a control group. Results: Single-dose administration of FTY720 resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. Four-week administration resulted in a significant reduction of the CD4+ T lymphocytes subpopulation in the colonic lamina propria and IFN-, production of the colonic lymphocytes, accompanied by a significant decrease in the severity of colitis. Conclusions: Treatment of established colitis in IL-10,/, mice with FTY720 ameliorated the colitis, probably as a result of decreasing the number of lymphocytes in the colonic mucosa and an associated reduction in IFN-, production. [source] Increased expression of fatty acid synthase in human aberrant crypt foci: Possible target for colorectal cancer preventionINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Kathleen E. Kearney Abstract Aberrant crypt foci (ACF), the earliest identified monoclonal lesions in the colon, provide insights into changes that promote and/or accompany the transformation of normal colonic epithelial cells to colorectal cancer. Fatty acid synthase (FAS), the primary enzyme involved in de novo lipogenesis from carbohydrates, is expressed at low levels in most normal human tissues but is elevated in several human neoplasms including colorectal adenomas and carcinomas. To determine if this pathway is altered even earlier in colorectal tumorigenesis, 35 human ACF from 21 patients were evaluated for the immunohistochemical expression of FAS. Sections of colon cancer served as positive controls, and normal colonic mucosa distant from cancer or ACF served as negative controls. FAS expression was increased in 30 (86%) ACF compared with that in adjacent normal colonic mucosa. The expression of FAS in ACF was not related to the degree of dysplasia or to the number of crypts in the ACF. The over expression of FAS in a high proportion of ACF suggests that this enzyme plays an important role very early in colorectal tumorigenesis and may be a target for chemoprevention. © 2009 UICC [source] A specific inducible nitric oxide inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male ApcMin/+ miceINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Hiroyuki Kohno Abstract It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the ApcMin/+ mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the ApcMin/+ mouse treated with DSS. Male C57BL/6J ApcMin/+ and Apc+/+ mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-, and interleukin (IL)-1,. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the ApcMin/+ mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNF, and IL-1, of colonic mucosa in the DSS-treated ApcMin/+ mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc+/+ mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the ApcMin/+ mice. © 2007 Wiley-Liss, Inc. [source] Dietary seed oil rich in conjugated linolenic acid from bitter melon inhibits azoxymethane-induced rat colon carcinogenesis through elevation of colonic PPAR, expression and alteration of lipid compositionINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Hiroyuki Kohno Abstract Our previous short-term experiment demonstrated that seed oil from bitter melon (Momordica charantia) (BMO), which is rich in cis(c)9, trans(t)11, t13 -conjugated linolenic acid (CLN), inhibited the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). In our study, the possible inhibitory effect of dietary administration of BMO on the development of colonic neoplasms was investigated using an animal colon carcinogenesis model initiated with a colon carcinogen AOM. Male F344 rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce colon neoplasms. They also received diets containing 0.01%, 0.1% or 1% BMO for 32 weeks, starting 1 week before the first dosing of AOM. At the termination of the study (32 weeks), AOM induced 83% incidence (15/18 rats) of colonic adenocarcinoma. Dietary supplementation with 0.01% and 0.1% BMO caused significant reduction in the incidence (47% inhibition by 0.01% BMO, p<0.02; 40% inhibition by 0.1% BMO, p<0.05; and 17% inhibition by 1% BMO) and the multiplicity (64% inhibition by 0.01% BMO, p<0.005; 58% inhibition by 0.1% BMO, p<0.02; and 48% inhibition by 1% BMO, p<0.05) of colonic adenocarcinoma, though a clear dose response was not observed. Such inhibition was associated with the increased content of CLA (c9,t11-18:2) in the lipid composition in colonic mucosa and liver. Also, BMO administration in diet enhanced expression of peroxisome proliferator-activated receptor (PPAR) , protein in the nonlesional colonic mucosa. These findings suggest that BMO rich in CLN can suppress AOM-induced colon carcinogenesis and the inhibition might be caused, in part, by modification of lipid composition in the colon and liver and/or increased expression of PPAR, protein level in the colon mucosa. © 2004 Wiley-Liss, Inc. [source] Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: A multicenter studyJOURNAL OF CLINICAL APHERESIS, Issue 1 2001Takashi Shimoyama Abstract Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 ± 3.60 mg prednisolone (mean ± SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 ± 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse. J. Clin. Apheresis. 16:1-9, 2001. © 2001 Wiley-Liss, Inc. [source] Bacterial flora in irritable bowel syndrome: role in pathophysiology, implications for managementJOURNAL OF DIGESTIVE DISEASES, Issue 1 2007Eamonn M M QUIGLEY Irritable bowel syndrome (IBS) may, in part at least, result from a dysfunctional interaction between the indigenous flora and the intestinal mucosa which, in turn, leads to immune activation in the colonic mucosa. Some propose a role for bacterial overgrowth as a common causative factor in the pathogenesis of symptoms in IBS; other evidence points to more subtle qualitative changes in the colonic flora; both hypotheses remain to be confirmed but the likelihood that bacterial overgrowth will prove to be a major factor in IBS now seems remote. Nevertheless, short-term therapy with either antibiotics or probiotics does seem to reduce symptoms among IBS patients. It seems most likely that the benefits of antibiotic therapy are mediated through subtle and, perhaps, localized, quantitative and/or qualitative changes in the colonic flora. How probiotics exert their effects remain to be defined but an anti-inflammatory effect seems likely. While this approach to the management of IBS is in its infancy, it is evident that manipulation of the flora, whether through the administration of antibiotics or probiotics, deserves further attention in IBS. [source] Differential expression of CCR5 and CRTH2 on infiltrated cells in colonic mucosa of patients with ulcerative colitisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2003KOJI MATSUZAKI Abstract Background and Aim:, The pathogenesis of ulcerative colitis (UC) is unclear, but abnormal infiltration of T lymphocytes in the colonic mucosa has been implicated in the mucosal tissue damage. The abnormal cytokine production because of a T helper (h)1/Th2 imbalance may play an important role in continuing inflammation in the colonic mucosa. In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients. Methods:, Tissue samples were obtained by colonic biopsies from patients with UC or colonic polyps, with informed consent. Immunohistochemical analysis was performed on periodate, lysine-paraformaldehyde-fixed serial cryostat sections using the labeled streptavidin biotin method. Monoclonal antibodies against CD4, CCR5 or CRTH2 were used as primary antibodies. The number of cells expressing CD4, CCR5 or CRTH2 per unit area was calculated by using an image analyzer. Results:, In the patients with UC, the numbers of CD4- and CCR5-positive cells were significantly increased in inflamed mucosa, and appeared to be correlated with the disease activity. The infiltration of CRTH2-positive cells was predominantly observed in the mildly inflamed or the margin of inflamed mucosa of UC patients. Conclusion:, There is a possibility that Th1 responses significantly occur in colonic mucosa with severe inflammation, while Th2 responses mainly occur with mild inflammation in UC patients. The Th1/Th2 imbalance in colonic mucosa may be related to the disease progression of UC. [source] ,, T cell receptor repertoire in blood and colonic mucosa of rhesus macaquesJOURNAL OF MEDICAL PRIMATOLOGY, Issue 6 2000Eva Rakasz Although their precise roles are not well defined, ,, T lymphocytes are recognized as regular components of immune responses. These cells express a limited T cell receptor repertoire and they can be stimulated by soluble ligands without conventional processing and presentation by major histocompatibility antigens. Progress in this area has been limited by the substantial differences between murine and human ,, T cells and the lack of knowledge about these cells in nonhuman primates. We used molecular analysis of T cell receptor diversity to characterize ,, T cell populations from peripheral blood and colon of rhesus macaques (Macaca mulatta). The ,, T cell receptor diversity was limited and distinct for these tissue compartments, particularly in the TCRGV2 family. Furthermore, the TCRDV1+ subset of peripheral blood ,, T cells showed signs of progressive oligoclonalization as a function of age. Similar observations have been reported for human tissue samples and our results validate rhesus macaques as an appropriate animal model for studying primate ,, T cell populations. [source] Clinical trial: five or ten cycles of granulocyte,monocyte apheresis show equivalent efficacy and safety in ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2010A. U. DIGNASS Aliment Pharmacol Ther,31, 1286,1295 Summary Background, Ulcerative colitis is characterized by leucocyte infiltration into the colonic mucosa. Granulocyte,monocyte apheresis depletes these cells. Aim, To assess the non-inferiority of 5,10 apheresis treatments in patients with steroid-dependent or steroid-refractory ulcerative colitis. Methods, A total of 196 adults with moderate,severe ulcerative colitis were randomized 1:1 to 5 (n = 96) or 10 (n = 90) open label apheresis treatments. The primary endpoint was non-inferiority of clinical activity index score after 12 weeks. Results, The intent-to-treat population comprised 82 and 80 patients for the 5- and 10-treatment groups, respectively. The difference between the two groups in mean clinical activity index was 0.24 with an upper 95% confidence interval of 1.17, which was below a predefined non-inferiority threshold of 1.33. Clinical activity index score improved from baseline in both groups (from 8.7 to 5.6 with 5 treatments, and from 8.8 to 5.4 with 10), with no significant difference between the groups (P = 0.200). Outcomes for the 5- and 10-treatment groups were similar , Clinical remission: 44% and 40%, respectively (P = 0.636); clinical response: 56% and 59%, respectively (P = 0.753). The treatment was well tolerated in both groups. Conclusions, This prospective study comparing apheresis regimens in ulcerative colitis demonstrates that 5 treatments were not inferior to 10 treatments in steroid-refractory or -dependent ulcerative colitis. [source] Long-term effects on the digestive tract of feeding large amounts of resistant starch: A study in pigsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 11 2007Daniel Martínez-Puig Abstract The present study aimed to assess the digestive consequences of the long-term intake of two starches providing different amounts of resistant starch. Growing pigs were used as the animal model and meal-fed for 14 weeks on a diet containing a high amount of either raw potato starch (RPS) or corn starch (CS). Digestive adaptation was chronologically evaluated by measuring organic matter (OM), crude protein (CP), neutral detergent fibre (NDF) and starch digestibility. After 97 days, whole-tract digestibility of OM, CP and NDF was lower for RPS- compared to CS-fed pigs, whereas no differences were observed in faecal starch digestibility. In contrast, starch digestibility was reduced in the proximal compartments (ileum, caecum and proximal colon) of animals fed the RPS diet. The concentration of short-chain fatty acids (SCFAs; P < 0.05), and purine bases (PBs; P < 0.01) was also higher in distal colon and rectum of animals fed the RPS diet. Changes in bacterial community structure (dendogram analyses) were seen in the rectum. Biodiversity tends to increase more in RPS compared to CS fed animals (34.1 vs. 28.8; P = 0.07). Among SCFAs, the proportion of butyrate was two-fold higher in proximal colon digesta of RPS compared to CS fed pigs (0.20 vs. 0.11; P < 0.05). Increased butyrate formation in the colon reduced the number of apoptosis per crypt in the proximal colonic mucosa (0.38 vs. 0.62; P < 0.05). RPS fermentation reduced indices associated with damage to intestinal epithelial cells, such as crypt cell hyperproliferation and magnesium excretion. Long-term ingestion of RPS induces pronounced changes of the digestive tract and their microflora, modifying mineral absorption and colonic morphology for which health benefits are likely to be associated. Copyright © 2007 Society of Chemical Industry [source] Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis , methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosaALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008G. R. LICHTENSTEIN Summary Background, Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to maximize 5-ASA release in the colon where it acts topically on the colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract. Aims, To review methods for assessing 5-ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions. Methods, PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies. Results, In-vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5-ASA release kinetics and bioaccessibility. Gamma-scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5-ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter-subject variability and other confounding factors. Conclusion, While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions. [source] Efficacy and safety of oral ridogrel in the treatment of ulcerative colitis: two multicentre, randomized, double-blind studiesALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002G. N. J. Tytgat Background: Ridogrel at low doses inhibits thromboxane synthase. Oral ridogrel, from 5 mg once daily to 150 mg twice daily, improves the endoscopic appearance of colonic mucosa and clinical manifestations in mild to moderate ulcerative colitis. Aim: One US trial and one international trial were conducted to determine the effect of ridogrel on mild to severe active ulcerative colitis. Methods: Two 12-week, double-blind, randomized, parallel-group trials were conducted. A US trial compared 0.5 mg, 2.5 mg and 5 mg of ridogrel once daily with placebo. An international trial compared 0.5 mg of ridogrel once daily with 2.5 mg and 5.0 mg of ridogrel once daily and 800 mg of mesalazine (known as mesalamine in the USA) three times daily. The primary efficacy outcome measure was the rate of complete remission. Results: In the US trial, complete remission was achieved in 20.8% of patients in the 0.5 mg ridogrel group, 17.9% in the 2.5 mg ridogrel group, 20.6% in the 5.0 mg ridogrel group and 13.6% in the placebo group. In the international trial, 14.4% of patients in the 0.5 mg ridogrel group, 19.6% in the 2.5 mg ridogrel group, 19.4% in the 5.0 mg ridogrel group and 16.4% in the mesalazine group experienced complete remission. In the international trial, rates of complete remission at the end-point were greater in the 2.5 mg and 5.0 mg ridogrel groups than in the 0.5 mg ridogrel group, but the differences were not statistically significant. In the US trial, rates of complete remission at the end-point were greater in the 2.5 mg and 5.0 mg ridogrel groups than in the placebo group, but the differences were not statistically significant. Approximately 30% of the patients in each group discontinued treatment before the 12-week end-point owing to a lack of therapeutic response. All doses of ridogrel were well tolerated and comparable with placebo or mesalazine in terms of safety. Conclusions: No significant differences in the primary efficacy outcome measure were found between either the 2.5 mg or the 5.0 mg dose of ridogrel and placebo in the US trial and between either the 2.5 mg or the 5.0 mg dose of ridogrel and the 0.5 mg dose of ridogrel, a surrogate dose for placebo, in the international trial. There was no clear indication in either trial of an effective dose of ridogrel in the treatment of ulcerative colitis. [source] Role of inducible nitric oxide synthase in dextran sulphate sodium-induced colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2000Y. Yoshida Summary Background: Different authors have postulated both toxic and protective effects for nitric oxide (NO) in the pathophysiology of active inflammation. Aim: To examine the role of NO, especially that produced by the inducible form of nitric oxide synthase (iNOS), by investigating the effects of NOS inhibitors and NO donors on inflammation in experimental acute colitis. Methods: Acute colitis was induced in rats by dextran sulphate sodium (DSS). White blood cell counts and levels of thiobarbituric acid reactants in the portal blood were determined, as were histological changes in the colonic mucosa. We then evaluated the effects of NG -nitro- l -arginine methyl ester ( l -NAME), aminoguanidine (AG) and an NO donor on DSS-induced changes in these inflammatory parameters. Results and Conclusions: Inhibition of NO production by either l -NAME or AG worsened DSS-induced inflammation, suggesting a protective role for NO in acute colitis. On the other hand, a NO donor also exaggerated DSS-induced inflammatory parameters, suggesting that acute colitis may be aggravated by either too much or too little NO. These results suggest that medical treatment of ulcerative colitis must aim for maintenance of appropriate NO levels in the intestinal mucosa. [source] Progressive up-regulation of genes encoding DNA methyltransferases in the colorectal adenoma-carcinoma sequenceMOLECULAR CARCINOGENESIS, Issue 9 2007Wolfgang M. Schmidt Abstract Epigenetic silencing is a prominent feature of cancer. Here, we investigated the expression of DNA demethylase and three DNA methyltransferases during colorectal tumorigenesis comparing the genes encoding DNA methyltransferases 1 (DNMT1), 3A, and 3B (DNMT3A and DNMT3B) with methyl-CpG binding domain protein 2 (MBD2), recently described as the only active DNA demethylase. Total RNA isolated from normal colonic mucosa (n,=,24), benign adenomas (n,=,18), and malignant colorectal carcinomas (n,=,32) was analyzed by reverse transcriptase-PCR with subsequent quantification by capillary gel electrophoresis. In contrast to MBD2, expression of DNMT1 and DNMT3A increased in parallel to the degree of dysplasia, with significant overexpression in the malignant lesion when compared with mucosa or with benign lesions (DNMT1). Pairwise comparisons between tumors and matched, adjacent healthy mucosa tissue (n,=,13) revealed that expression of all three genes encoding DNA methyltransferases increased by two- to three-fold. Our data suggest a relevant role of the DNA methyltransferases during colorectal tumorigenesis. This increase is not counterbalanced by enhanced expression of the demethylating component MBD2. As a consequence, epigenetic regulation in the adenoma-carcinoma sequence may be driven by increased methylating activity rather than suppressed demethylation. © 2007 Wiley-Liss, Inc. [source] Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancerMOLECULAR CARCINOGENESIS, Issue 2 2004Lianhui Tao Abstract Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, ,-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9- cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer. © 2004 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||