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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review deals with potential and possibly primary therapeutics that, through insight into the inflammatory cascade, result in more rational treatment principles replacing the classical therapy of inflammatory bowel disease (IBD), i.e. Crohn's disease (CD) and ulcerative colitis (UC). These new therapies might be useful for IBD patients, especially since the 'classical therapy' with agents like glucocorticoids, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, cyclosporin and methotrexate is often only moderately effective and may have important side-effects. Controlled trials of the novel agents mentioned in this review have not yet been performed, however.
Cytokines Cell Mol Ther 1997 Dec
PMID:Inflammatory bowel disease: potential therapeutic strategies. 974 Mar 55

Leukocyte type 12-lipoxygenase (12-LO) catalyzes the conversion of arachidonic acid (AA; C20:4) to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and linoleic acid (LA; C18:2) to 13-hydroperoxyoctadecadienoic acid (13-HPODE). Previous studies have demonstrated that 12-LO, but not 5- or 15-lipoxygenase (5-LO, 15-LO respectively), is specifically expressed in pancreatic -cells and is involved in regulating glucose-stimulated insulin secretion. Lipoxygenase products also have been linked with inflammatory pathways in endothelial cells, kidney mesangial cells, inflammatory bowel disease, and corneal epithelial cells. Therefore, 12-LO may play a role in cytokine mediated inflammation in pancreatic beta-cells (i.e. beta -cell dysfunction and cytotoxicity). Cytokines such as IL-1 stimulate both de novo 12-LO protein synthesis and enzyme activity in pancreatic beta-cells. The products generated by 12-LO may ultimately be involved in cellular events that lead to lipid peroxidation. Hydroperoxide and free radical production in beta-cells can activate intracellular signaling pathways that lead to cell death or may directly damage mitochondrial and plasma membranes. Increased 12-LO expression has also been found in islets from prediabetic Zucker fatty rats, a model that demonstrates insulin secretory defects similar to human type 2 diabetes. In this review, we present an overview of the 12-LO pathway in regulating glucose-stimulated insulin secretion in beta-cells as well as more recent data which supports the hypothesis that the 12-LO pathway participates in cytokine mediated beta-cell dysfunction and cytotoxicity.
Int J Mol Med 1998 Jan
PMID:The role of 12-lipoxygenase in pancreatic -cells (Review). 985 29

This review discusses the mechanisms and pathways of immune cell-mediated intestinal inflammation and tissue injury in inflammatory bowel disease (IBD). Our lack of understanding of how the mucosal immune system normally functions to maintain the balance between tolerance and immunity to innumerable dietary and bacterial constituents of the gut is perhaps the biggest obstacle to understanding the cause(s) of IBD, and to developing more effective treatments for these debilitating disorders. Evidence that abnormalities or disruptions in the interaction of immune cells and gut bacteria can trigger or contribute to changes in the composition, regulation and activity of the mucosal immune system that result in inflammatory immune responses and tissue injury are discussed. Based upon these studies, we propose a model to explain how a breakdown in regulation and failure to resolve immune responses in the gut mucosa results in persistent activation of T lymphocytes and other immune cells and the uncontrolled production of soluble inflammatory mediators that directly or indirectly produce the pathophysiological changes and tissue injury characteristic of IBD.
Int J Mol Med 1998 Feb
PMID:Mechanisms of immune cell-mediated tissue injury in inflammatory bowel disease (Review). 985 33

Ulcerative colitis (UC), a common form of inflammatory bowel disease, is a multifactorial disorder with significant genetic influence. Recently, evidence of linkage on chromosome 7q near the intestinal mucin gene MUC3 was reported by an affected sib-pair analysis. Previous reports indicate a possible mucin abnormality in UC patients, but whether genetic differences in a specific mucin gene are associated with UC is unknown. Here we analysed polymorphisms of variable number of tandem repeats (VNTRs) within this gene using DNAs obtained from 243 Japanese (75 patients with UC and 168 controls), and to confirm the result we undertook a two-stage examination using 328 Caucasian samples (72 and 85 with UC in the first and second stages, respectively, and 171 controls). When the frequency of patients carrying one or two rare VNTR alleles was compared with that of controls, a significant increase was found first in Japanese patients (odds ratio 2.72, 95% CI 1.17-6.32, P = 0. 0308). In Caucasians, the odds ratio was 2.80 (95% CI 1.36-5.75, P = 0.0079) in the first stage, 2.43 (95% CI 1.20-4.92, P = 0.0196) in the second stage and 2.60 (95% CI 1.41-4.80, P = 0.0024) in total. The overall odds ratio was 2.64 (95% CI 1.60-4.33, P = 0.0001). This result suggests that rare alleles of the MUC3 gene may confer genetic predisposition to UC.
Hum Mol Genet 1999 Feb
PMID:Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3. 993 38

Background: Abnormal expression of CD44 variant RNA has been detected in a variety of human tumors and has been shown to be a potential diagnostic marker. To date, such analysis requires time-consuming gel electrophoresis, blotting, and autoradiographic procedures, and this approach may not be suitable for routine laboratory examinations. We have developed a rapid and semiquantitative reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay (RT-PCR ELISA) method and used it to analyze CD44 expression in colon carcinoma tissues and exfoliated cancer cells in colon luminal washings. Methods and Results: RNA was extracted from sample cells and tissues and converted to cDNA. PCR amplification products, labeled by incorporation of digoxigenin-11-dUTP, were hybridized with biotinylated probes complementary to CD44 exon 12 or to exons in the standard portion (CD44s) of the gene. Hybridized DNA complexes were immobilized on streptavidin-coated microtiter plates, and the bound PCR products were detected with a peroxidase-conjugated antibody to digoxigenin. CD44-derived PCR products were quantified by absorbance of a chromogenic reaction. Elevated expression of CD44 variant exon 12 was detected initially by Southern blot analysis in all of the 9 colon carcinoma tissues, while weak expression was observed in only 3 of 9 normal mucosas. This tumor-related differential expression was confirmed by the newly developed PCR-ELISA method. Elevated expression of CD44 exon 12 was also detected in exfoliated colonic epithelial cells from 10 of 13 carcinoma cases but not in exfoliated cells from 4 patients with inflammatory bowel disease. Conclusions: Raised expression of CD44 variant exon transcripts can be detected reliably in colonic tumor tissue and in exfoliated colonic cancer cells by a semiquantitative RT-PCR ELISA method. This was shown to be as sensitive as conventional RT-PCR using chemiluminescent detection. Therefore, CD44-based RT-PCR ELISA could facilitate detection of neoplasia in clinical specimens including colon washings and naturally micturated urine.
Mol Diagn 1996 Sep
PMID:Semiquantitative Detection of Abnormal CD44 Transcripts in Colon Carcinomas by Reverse Transcription-Polymerase Chain Reaction Enzyme-linked Immunosorbant Assay (RT-PCR ELISA). 1046 57

The mechanism by which 5-aminosalicylic acid (5-ASA) reduces mucosal injury in colitis is undefined. In murine cells, 5-ASA modulates the expression of the inducible nitric oxide (NO) synthase, a potential mediator of colitic injury, but its effect on the human isoform is unknown. Given the lack of conserved regulation of iNOS expression in rodent and human systems, we sought to test the effect of 5-ASA on the expression of human iNOS in cultured enterocytes. Transformed human intestinal epithelial cells, DLD-1 and Caco-2BBe, were stimulated by IL-1beta and IFN-gamma and analyzed for iNOS upregulation and NO production in the presence of various aminosalicylates. 5-ASA, but not 4-ASA, dose-dependently inhibited NO production by both cell lines [IC50 (mM) DLD-1 =4.5, Caco-2BBe =2. 5]. 5-ASA also inhibited the expression of iNOS protein and mRNA and blocked cytokine-induced transcriptional upregulation of the iNOS gene. 5-ASA (1-5 mM) had no effect on cytokine-induced nuclear translocation of NF-kappaB or expression of IRF-1, transactivating factors which regulates the human iNOS enhancer. We conclude that 5-ASA inhibits iNOS expression and NO production at therapeutically relevant concentrations. The inhibition occurs at the level of transcriptional activation and is independent of IRF-1 and NF-kappaB. Since NO is an important final effector of mucosal injury in inflammatory bowel disease, these findings may have implications for the clinical efficacy of 5-ASA.
Int J Mol Med 1999 Oct
PMID:5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells. 1049 88

The sodium-hydrogen exchanger isoform, NHE-3 is essential for the absorption of sodium and water from intestine. Whether this protein plays any role in inflammatory bowel disease is less understood. To address this issue, NHE-3 mRNA and protein levels were estimated in the terminal ileum and colon of the rats having colitis induced with trinitrobenzenesulphonic acid (TNBS). The effect of garlic (Allium sativum) was also evaluated on the expression of NHE-3. The animals were treated with garlic extract intraperitoneally starting 2 h before the TNBS administration until day 4 post-TNBS administration and were sacrificed on day 5. In control animals, the levels of NHE-3 in colon was higher than the ileum. As a result of colitis, the levels of NHE-3 protein and mRNA increased both in the colon and terminal ileum. Garlic treatment of the colitic animals resulted in a selective suppression of NHE-3 in the terminal ileum. Colitis caused an induction of the myeloperoxidase activity, the marker of inflammation in the colon but not in the ileum. These findings suggest that induction of NHE-3 is not primarily due to inflammation. Selective suppression of this protein in ileum by garlic may cause loss of sodium chloride and water during colitis.
Mol Cell Biochem 1999 Oct
PMID:Altered expression of the Na+/H+ exchanger isoform-3 in experimental colitis: effect of garlic. 1056 86

Eosinophils have been implicated in a broad range of diseases, notably allergic conditions (for example, asthma, rhinitis and atopic dermatitis) and other inflammatory disorders (for example, inflammatory bowel disease, eosinophilic gastroenteritis and pneumonia). These disease states are characterized by an accumulation of eosinophils in tissues. Severe tissue damage ensues as eosinophils release their highly cytotoxic granular proteins. Defining the mechanisms that control recruitment of eosinophils to tissues is fundamental to understanding these disease processes and provides targets for novel drug therapy. An important discovery in this context was the identification of an eosinophil-specific chemoattractant, eotaxin. Over the past six years there has been intensive investigation into the biological effects of eotaxin and its role in specific disease processes and this is the subject of this review.
Mol Med Today 2000 Jan
PMID:Eotaxin and eosinophil recruitment: implications for human disease. 1063 71

Inflammatory bowel diseases are considered to be related to dysregulation of pro- and anti-inflammatory cytokines in the intestinal wall. We investigated the levels of TNFalpha, IFNgamma, and IL-10 mRNA expression in intestinal tissues resected from the patients with Crohn disease (CD) (n=29), ulcerative colitis (UC) (n=8), and controls (n=8) using reverse transcription-polymerase chain reaction (RT-PCR). In addition, we examined the relationship between the expression of these cytokine mRNA and their clinical conditions using CD activity index (CDAI) and Nutritional Surgical Risk Index (NSRI). Compared with controls, tissues in CD showed high levels of TNFalpha and IFNgamma mRNA expression both in inflamed and non-inflamed tissues, and showed high levels of IL-10 mRNA expression in inflamed tissues. In UC, high levels of IL-10 mRNA expression were detected both in inflamed and non-inflamed UC tissues, while those of TNFalpha and IFNgamma were not. In 80% of CD tissues (n=23), levels of IL-10 and TNFalpha expression were interrelated. While the remaining tissues (n=6) showed low levels of IL-10 expression despite high levels of TNFalpha expression in inflamed CD tissues, and 4 of these 6 patients had high CDAI and low NSRI. Furthermore, in low nutritional CD patients (NSRI <40, n=13), the levels of IL-10 mRNA to inhibit pro-inflammatory cytokines were poorer than in good nutritional patients (NSRI >/=40, n=16). These findings suggest the overexpressions of TNFalpha and IFNgamma in CD, and less producibility of IL-10 against these cytokine might lead to development of severe CD.
Int J Mol Med 2000 Apr
PMID:Interleukin-10 expression in intestine of Crohn disease. 1071 56

The idiopathic inflammatory bowel diseases (IBDs), consisting of Crohn's disease and ulcerative colitis, are complex genetic disorders involving chronic inflammation of the intestines. Multiple genetic loci have been implicated through genome-wide searches, but refinement of localization sufficient to undertake positional cloning efforts has been problematic. This difficulty can be obviated through identification of ancestrally shared regions in genetic isolates, such as the Chaldean population, a Roman Catholic group from Iraq. We analyzed four multiply affected American Chaldean families with inflammatory bowel disease not known to be related. We observed evidence for linkage and linkage disequilibrium in precisely the same region of chromosome band 1p36 reported previously in an outbred population. Maximal evidence for linkage was observed near D1S1597 by multipoint analysis (MLOD = 3.01, P = 6.1 x 10(-5)). A shared haplotype (D1S507 to D1S1628) was observed over 27 cM between two families. There was homozygous sharing of a 5 cM portion of that haplotype in one family and over a <1 cM region in the second family. Homozygous sharing of this haplotype near D1S2697 and D1S3669 was observed in one individual in a third multiply affected family, with heterozygous sharing in a fourth family. Linkage in outbred families as well as in this genetic isolate indicates that a pathophysiologically crucial IBD susceptibility gene is located in 1p36. These findings provide a unique opportunity to refine the localization and identify a major susceptibility gene for a complex genetic disorder.
Hum Mol Genet 2000 May 22
PMID:Linkage and linkage disequilibrium in chromosome band 1p36 in American Chaldeans with inflammatory bowel disease. 1081 24


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